Nutrient defieciency and aggression

Melvyn R. Werbach, M.D. Journal Of Orthomolecular Medicine Vol. 7, No. 1, 1995 Introduction The aggressive behavioral syndrome is marked by restlessness, irritability, impulsivity and a proneness to violence. Diagnostically, it overlaps the DSM III-R diagnoses of Attention-deficit Hyperactivity Disorder, Conduct Disorder, Oppositional Defiant Disorder and Antisocial Personality Disorder. When the syndrome is attributed to organic factors, it would frequently be classified as an Organic Personality Syndrome.1 Constitutional factors, including genetics and the effects of disease and physical trauma, are known to play a major role in determining proneness to overaggressive behaviors. The importance of psychological factors is also well known. By contrast, the contribution of nutritional factors to such behaviors is often unrecognized, and therefore not properly addressed. 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.

"Afibbers" pdf file of discussion about minerals

Can You Hang on to Magnesium? For magnesium to get into cells it requires thiamine (vitamin B1). Try thiamine 100mgs daily – if you are already taking some in a multivitamin preparation, then take the B1 at 100mg a day. For magnesium to be retained inside cells you need good antioxidant status. Selenium is the main mineral antioxidant. Food tables are unreliable because food content is dependent on soil levels of selenium. Assuming good soil levels, (which is a big assumption), foods rich in selenium include wholegrains, organ meats, butter, garlic and onion. Seafoods are rich in selenium and obviously not dependent on soil levels. Boron is necessary for normal calcium and magnesium metabolism. I also find boron very useful for arthritis, perhaps because of its effect on calcium and magnesium. For arthritis you need 9mgs a day for 3 months, then reduce to a maintenance dose of 3-6mgs daily. At present the only way I know how to ascertain whether or not magnesium levels are replete is to measure a red cell magnesium. http://www.immunesupport.com/library/showarticle.cfm/id/2892 Richard Boron may not be advantageous for Mg. as stated above, or the site above could be altogether wrong. Boron and its involvement with attention deficit disorder is a concept that appears not to have been considered before. Boron, phenols and/or histamine may possibly cause thinning of the middle part of the brain where nerve fibres cross over. This part of the brain is called the corpus callosum. Damage to this area (prior to birth) causes learning disabilities. Boron increases copper in the body. High copper levels cause reductions in thiamine (vitamin B1). Lack of thiamine causes many problems associated with ADD. A lack of this vitamin reduces oxygen supply to the brain. Low cholinesterase levels are associated with a thiamine deficiency. Lack of thiamine may indirectly lower the neurotransmitter dopamine. There are below normal dopamine levels in hyperactive children. Low cholinesterase levels are sometimes associated with asthma. Boron interferes with the metabolism of phenols. Phenylalanine (a phenol) is able to reduce serotonin levels. Serotonin levels are reduced in children with ADD. The medication Ritalin used in the treatment of ADD inhibits the metabolism of coumarins (phenols). Low and high histamine levels are also discussed. Boron reduces pyridoxine (vitamin B6) levels in the body. The importance of this occurrence to the reduction of the symptoms of ADD is covered throughout the book. A brief description of how boron interacts with body nutrients is discussed. Boron has the ability to cause an excess or depletion of vital substances. This causes a spin off in alteration of other nutrients. For example, boron has an indirect effect of reducing zinc levels in the body. Boron increases calcium retention in the body. Calcium reduces zinc. As outlined in this book, boron plays a role in excreting pyridoxine (vitamin B6) from the body. Vitamin B6 is necessary for zinc absorption. Vitamin B6 and zinc play major roles in neurotransmitter function. Neurotransmitters are chemicals that relay messages between nerves in the body. Some neurotransmitters have a relaxing effect whilst others have a stimulatory effect. An imbalance of neurotransmitters (as discussed throughout this book) may cause symptoms of ADHD/ADD. Nausea during pregnancy is associated with a deficiency of vitamin B6 (pyridoxine) and zinc. Acute toxicity of boron presents with nausea, vomiting, lethargy, dermatitis and diarrhoea. ADD is possibly linked to the food the mother consumed during pregnancy. A diet (during pregnancy) giving a high intake of boron containing foods together with a high intake of calcium containing foods may be a contributing factor to the ADD symptoms of the child. Water supplies containing high levels of calcium and/or copper reduce zinc absorption in the body. Boron is found in apples, pears, grapes, nuts, leafy green vegetables and legumes. My levels of copper were high, and zinc was low. My hair analysis of Boron was fairly normal, but just a tad to the low side. Hmmmmm????? So is my problem more that I need B1 to absorb the Mg. Questions to ask Dr. Gersten.

Pyroluria info

Clinical Use and Diagnosis: Pyrrole disorder-characterized by elevated urine kryptopyrrole test, resulting in a dramatic deficiency of zinc and vitamin B6. Identified frequently in behavior disorders, autism, aspergers, adhd, add, depression, bipolar disorders,assaultive/aggressive/violent behavior, other mental and emotional conditions and schizophrenia. It is an inborn error of the pyrrole chemistry. Common symptoms include: Poor tolerance of physical and emotional stress, poor anger control, emotional mood swings, depression, anxiety, poor short term memory, frequent infections, inability to tan, poor dream recall, abnormal fat distribution, sensitivity to light and sound and tactile sensitivites. The decisive laboratory test is analysis of Kryptopyrrole in urine. Treatment: Treatment of pyroluria consists of a replacement of zinc and vitamin B6. Because the treatment is metabolic rather than pharmacologic, it needs to be titrated to individual requirements. A variety of factors are taken into consideration when developing a treatment regimen. Both zinc and B6 supplementation need to be directed by a practitioner as too much can be toxic, use of wrong form ineffective, and avoiding competing minerals and supplements may be necessary.

Lack of B6 and tics, food allergies, behaviors...

The following addresses TS/OCD/ADD. The diagnosis would lie in the degree of vitamin B6 dependency/deficiency, and how long the person has been in this state. Carl Hansen, Jr. M.D. of Minneapolis describes celiac disease in several of his TS patients. This could be a pathway to vitamin B6 deficiency via malabsorption. Streptococcal infections have also been associated with TS. This could be a combination of the hyaluronidase's (an enzyme produced by the hemolytic strep that depolymerizes the ground substance of tissue) or streptokinase's actions on the blood brain barrier, the drain of vitamin B6 from the bacteria's own useage, the body's requirement of B6 for immunity, and the antibiotic's B6 antagonistic properties. A pre-exising B6 dependency/deficiency could be uncovered. TOURETTE SYNDROME, ALLERGY AND THE B6 DEPENDENCY STATE I have my Bachelor's degree in Biology, specializing in Medical Technology, and in graduate school, I took graduate courses in biochemistry. I work as a medical technologist performing and verifying clinical laboratory tests in Chemistry, Hematology and Blood Bank at Mt.Carmel East Medical Center in Columbus, Ohio. I do not have TS but my son, Jason (13 yrs old) has TS with OCD. ADD has not been formally diagnosed, although he has problems with organization, distractibility, and the ability to switch gears. My son has had allergies since he was a baby. He is sensitive to red dye #40 with tired splitting headaches which make him scream until he is exhausted and sleeps. This, of course, hasn't happened in several years since he has avoided the dye. He also is allergic to sulfa, molds, dust, grass, trees, and most airborn allergens. He has been on the vitamins below for 1.5 months and the teachers have said that he is a different kid. Medications that he had been on made him progressively worse, and so we made a personal decision to discontinue meds altogether. He now is motivated in school, concentrates and finishes his work, and is less disruptive with his tics in class. At home he still has his tics and compulsions, but they are shorter lived and occur less often. He has had a set back this week due to a new semester with a new schedule, plus a very moldy, rainy few days. We gave him a little extra calcium-magnesium and one extra vitamin B3. He said that this gave him relief from his symptoms (he has never said this before with anything else). I solidified my theory on the premise that Jason is probably mildly vitamin B6 dependent. He was either born requiring high amounts of B6, and/or B6 antagonists attacked early in his first year of life. B6 antagonists are hydrazines (plant growth regulators, tartrazine, etc), DOPA found in certain beans, penicillinamine, antioxidants in petroleum, many drugs including penicillin, erythromycin, phenobarbital, tetracycline, corticosteroids, sulfamethoxazole, etc. Amino acids began building up in his system, from decreased transamination, etc. Serotonin became decreased from tryptophan not being able to be utilized. Allergies developed (which is in association with low B6), I believe allergy produces swings in histamine levels which causes a constant fluctuation in neurotransmitters capable of producing mood swings and rages. The conservation of vitamin B6 (when not abundantly available) causes it to be used by the prevailing neurotransmitter system at any given time, leaving other neurotransmitter systems less than optimally functional. Histamine receptors have been found to trigger dopamine receptors directly. Histamine is also a neurotransmitter affected by deficient vitamin B6. Its receptor sites are probably increased to compensate. Kinins released into the body's tissues in response to immune complexes can damage the blood brain barrier, thus altering the sensitivity of brain cells to acetylcholine, serotonin, dopamine, histamine, epineprine and norepineprine. I found that L-dopa doesn't readily form dopamine in B6 deficiency, so probably dopamine is reduced causing an increase in dopamine receptor sites along with an increase the norepinephrine and epinephrine (which are formed from dopamine) receptors sites. These increased receptor sites make the nerves more excitable and false transmitters or true neurotransmitters can set them off with explosive qualities. These false transmitters can be phenolic substances, such as food additives, drugs, etc. The enzyme, phenol sulfotransferase (PST), detoxifies and eliminates phenolics (drugs, food additives, serotonin, dopamine (to name a few). In the brain, sulfation is used while glucuronidation prevails elsewhere. Cysteine requires B6 to enzymatically release sulfur for sulfation of these phenols by PST. Considering this, the neurotransmitters would would be conserved to a certain extent (their sulfation and elimination would be slowed down). ADD may happen when these false transmitters create background "noise", and if there is a real message to get through via other neurons, it is masked. When a true message is fired, it may have too strong of a signal, creating a strong impulsion, which can lead to the development of a tic or compulsion if the impulsion is acted upon and repeated creating a sort of conditioned reflex network of nerves. Mental, motor, and vocal tics can develop this way. According to my_ Biochemistry_ by Lehninger textbook from my graduate student in Biology days, tryptophan is broken down in Vitamin B3 deficiency to make nicotinic acid. Tryptophan is found in meat and is plentiful, if you are a meat eater. Tryptophan is the precursor for serotonin. I also looked up Vitamin B3 and how it could be connected to the issues of allergy and serotonin defiency in the brain. I found that Vitamin B3 is used to make NAD, NADP, which are coenzymes used in making histamine and serotonin (to name a few), and are essential in oxidative-reductive cellular metabolism. The B3 is needed due to tryptophan's inability to be broken down to nicotinic acid without adequate B6. So, if Vitamins B3 and B6 are being used for histamine production, then serotonin production suffers. Tryptophan then must be used in a higher frequency to make nicotinic acid. In Vitamin B6 deficiency, this cannot happen, because the enzyme kynurinase, that catalyzes the cleavage of 3 hydroxykynurine (an intermediate in tryptophan catabolism), contains pyridoxal phosphate (an active coenzyme form of Vitamin B6). In Vitamin B6 deficiency, large amounts of L-kynurenine are excreted in the urine, because of its high plasma levels. This is described in "Elevated plasma kynurenine in Tourette syndrome", _Molecular & Chemical Neuropathology_21(1): 55-60,1994 Jan. Kynurenine itself is metabolised to other substances, several of which are known to have effects on neurones. (per a research study done at University College London Medical School Harlow, England by Sheila L. Handley, BPharm, Ph.D. 1994) Large amounts of tryptophan which is broken down to ineffectively try to produce nicotinic acid reduces the amount of serotonin produced. Ineffective tryptophan utilization also uses alot of oxygen with tryptophan 2,3-dioxygenase. Low serotonin levels could cause obsessive compulsive behaviour, depression, and other mood related disorders. B6 is also required for the decarboxylase step of serotonin, histamine, and catecholamine pathways in the brain. In low B6, conservation takes place, so that B6 is used for fewer enzymes. When allergy strikes, the production of histamine causes a further imbalance of neurotransmitters, causing serotonin and/or catecholamine production to be further depleted. Sherry A Rogers, M.D., a specialist in environmental medicine, reports that all of the TS cases she has seen have a least one nutrient deficiency, and usually several. And she notes that all of these patients have hidden mold, dust, chemical and food sensitivities. ("Tourette Syndrome", _Health Counselor_, Vol.7, No.4) Acetylcholine is produced by acetyl CoA and choline. The choline is supplied through lecithin in Jason's supplements. In vitamin B6 deficiency, acetyl CoA would be made by fatty acid oxidation. So acetycholine could be functional with an adequate supply of fatty acids (evening primrose oil or flax oil might be useful). Acetylcholine could be in shorter supply in the parasympathetic system (relaxation) due to overuse in the sympathetic system where norepinephrine usually rules. The parasympathetic nervous system would need to have more acetylcholine in TS and associated disorders, it seems. Relaxation through the parasympathetic nervous system (which uses acetylcholine), where the heart rate is slowed, the blood pressure is lowered, the food is digested well, etc. is difficult in TS. Acetylcholine is probably overactive in the sympathetic autonomic nervous system, trying to stimulate the low supply of catecholamines, which would be decreased due to B6 deficiency/dependency. The receptors sites for catecholamines would be hyperexcitable and increased in number. The net usage of catecholamines could be normal to decreased due to increased stimulation by acetylcholine, depending on the availability of B6 in the body, and the conservation by low sulfation by PST. Conditions of emotional stress are known to produce more ticcing in TS. In short term stress, norepineprine, dopamine, and epineprine should be able to be produced by the conservation tactics of the body, but in long term stress, these would be exhausted, especially when another B6 dependent system is triggered. Likewise, the same would happen when histamine and serotonin are produced in short term and long term allergy. But as you might expect, the short term conditions would be explosive events with all of those increased receptor sites! Acetylcholine is also involved in the contraction of voluntary muscle cells and many other motor nerves, which are in heavy use in TS. Many people with TS are helped by exercise, where cardiac output and increased body temperature over a period of time inhibit the sympathetic nervous system. It may also help to clear toxic waste, such as kynurenine. Adequate water intake would be required to catabolize acetylcholine by cholinesterase. In my opinion acetylcholine is needed in B6 deficiency/dependency to run the nervous system. Fatty acids are essential to its success in this situation. Fatty acids require NADPH2, and NADH2 for their synthesis, and thus Vitamin B3. Water is also an utmost requirement in keeping acetylcholine from becoming a continuous firecracker. Jason has a water bottle close by most times and drinks tons of water. Water has always calmed him down. It may also dilute the kynurenine, excess amino acids and promote their excretion. If you look at the material written on the Canadian Mennonite families that have been studied with Tourette's disorder, you will see a high frequency of autoimmune and rare conditions. These findings are consistent with what one can expect with other Tourette's patients. For example, there is a high frequency of allergic conditions. My informal survey of TS and allergy results from the online TS support group are: With a total of 25 respondents with TS: 96% have allergies (24 out of 25) 56% have mold allergies 72% have obsessive complulsive traits (18 out of 25) 67% of those with obsessive compulsive traits have mold allergies 3 respondents thought they may have mold allergies, but weren't sure 52% have pollen allergies (ragweed, grass, tree, etc) 56% of those with obsessive compulsive traits have pollen allergy 48 % have animal allergies (cats, dogs, horse) 39% of those with obsessive compulsive traits have animal allergies 40% have dust allergy 39% of those with obsessive compulsive traits have dust allergy 20% have penicillin allergy 28 % of those with obsessive compulsive traits have penicillin allergy 20 % have miscellaneous allergies 11% of those with obsessive compulsive traits have miscellaneous allergies 16 % have food allergies 22 % of those with obsessive complulsive traits have food allergies 8% have sulfa allergy 11% of those with obsessive compulsive traits have sulfa allergy All of our frequent posters responded. The types of allergies are typically respiratory and airborne. Molds and pollens are the top allergens. 79% of the people with mold allergies also had pollen allergies, which are seasonal. Bonnie Grimaldi, BSMT (ASCP) 11283 Meadowcroft St. Pickerington, Ohio 43147 (614) 837-7545

B6/P5P is a pseudo phenolic

Title: The effects of pyridoxal-5-phosphate on sulfotransferase activity: actions on tyrosyl protein sulfotransferase and phenol sulfotransferase. Authors: Rosemary H Waring, Robert M Harris and Victoria L Griffiths, School of Biosciences, University of Birmingham, Birmingham. B15 2TT. UK Introduction Sulfotransferase enzymes use PAPS (3’-phospho-adenosive-5’-phosphosulfate) to transfer sulfate residues onto a wide variety of substrates. TPST substrates require sulfation for efficient function while sulfation by SULT 1A1 greatly alters substrate properties, usually decreasing their activity. a) Tyrosylprotein sulfotransferase (TPST) Substrates - tyrosine residues on gastrin, cholecystokinin, mucin proteins Methods TPST activity was measured (using gastrin as substrate) with radiolabelled 35S-PAPS as sulfate donor; assays were incubated at 37°C for 40 minutes. All assays were performed in quadruplicate). Enzyme sources were a) platelet pellets prepared by centrifugation from time-expired platelet packs from the Birmingham Blood Transfusion Service and b) human colon adenocarcinoma HT-29 cells which synthesise mucin proteins and are thought to be the best model for the human g.i. tract. These were grown in McCoys 5A medium supplemented with 10% fetal bovine serum and glutamine/penicillin/streptomycin at 37°C till confluent, then harvested and centrifuged to give a cell membrane pellet. This was resuspended in phosphate buffered saline, then sonicated before assay. Cells were also grown after confluence for 24 hours with varying concentrations of P5P. P5P was also added directly to the platelet assay (0-2.5μM) MgCl2 was added at varying concentrations (0-5μM) before the start of the TPST assay. Results TPST activity was present in both human platelets and HT-29 cells. This enzyme activity was inhibited in the presence of P5P (Fig. 1). Direct effects of MgCl2 on the assay are shown in Fig. 2. As can be seen, MgCl2 concentration had no significant effects on the TPST activity of HT-29 cells but activated TPST activity in platelets (there are different isoforms of the enzyme). The concentration of 0.4μM P5P was then chosen as showing clear reduction of TPST activity in initial experiments (See Fig. 1). Human platelets were treated directly with this concentration while the HT-29 cells were incubated with it for 24h. Varying amounts of MgCl2 were then added to the assays (see Fig. 3). As can be seen, levels of MgCl2 at 0.5μM or greater removed the inhibition caused by 0.4μM P5P. Enzyme assays and Western blotting with specific anti-TPST antibodies showed that P5P did not affect the expression of TPST. All results were carried out in quadruplicate and are expressed as means ± SD. (SD <= 5.3%). b) SULT1A1 (Phenolsulphotransferase) Substrates – Phenols, catecholamines, flavonoids, steroids. Methods SULT1A1 activity was measured using 4-nitrophenol as a substrate (this also picks up any of the SULT1A2 isoform, although this is only present to a small extent in platelet preparations). Again radiolabelled 35S-PAPS was used in the assay as a sulfate donor. The enzyme sources were cytosols from platelets and HT-29 cells, prepared as before and assayed under standard conditions. Results SULT1A1 activity was present in both human platelets and HT-29 cells. This activity was inhibited by P5P (Fig. 4). However, this inhibition was only significant in the platelets; the HT-29 cell SULT1A1 seemed relatively unaffected. Treatment with MgCl2 (1.0μM) on cells exposed to 1.0 μM P5P restored the activity in platelets (Fig. 6) but had no significant effects in the HT-29 cells, which in any case were not greatly affected by the P5P (Fig. 4) SULT1A1 activity in platelets was almost unaffected by MgCl2 although SULT1A1 activity in HT-29 cells decreased slightly with increasing Mg (Fig. 5). Our previous studies have shown that the isoenzymes in these tissues have different activities and slightly different properties. Incubation of HT-29 cells with P5P had no effect on enzyme expression, as seen by Western blotting and enzyme activity. All results were carried out in quadruplicate and are expressed as means ±SD. (SD <= 5.4%). Conclusions 1. Platelet and HT-29 cells show TPST activity which is inhibited by P5P, though only the platelet isoform is greatly affected. This inhibition is reversed by MgCl2 in roughly equimolar amounts. 2. Platelet and HT-29 cells show SULT1A1 activity which is inhibited by P5P, although only the platelet isoform is greatly affected. Again this inhibition is reversed by MgCl2 in roughly equimolar amounts. 3. Neither TPST nor SULT1A1 expression is altered by P5P, which only affects the enzyme activity directly. 4. From the literature, P5P has a pseudo-phenolic structure which is believed to interact with those phenol sulfotransferases for which phenolic rings are a substrate. However, addition of Mg2+ may form a complex which no longer interacts with the enzyme. From the therapeutic point of view, Mg2+ ions should be supplied in at least a 2:1 ratio with P5P to reverse any inhibition and activate those sulfotransferases which respond to increased magnesium levels particularly the platelet enzymes.

Cofactors for neurotransmitters

Tourette Syndrome, B6 dependency, allergy BonnieGr bonniegr at aol.com Thu Feb 8 13:19:55 EST 1996 I have been putting the puzzle pieces together on the subject of Tourette Syndrome, using medline documents, college textbooks, etc. Please read the following long rationale document that I have prepared, and comment by e-mail (BonnieGr at aol.com). It is my hope that more research will be done to validate my theory. Enjoy! The following addresses TS/OCD/ADD. The diagnosis would lie in the degree of vitamin B6 dependency/deficiency, and how long the person has been in this state. Carl Hansen, Jr. M.D. of Minneapolis describes celiac disease in several of his TS patients. This could be a pathway to vitamin B6 deficiency via malabsorption. Streptococcal infections have also been associated with TS. This could be a combination of the hyaluronidase's (an enzyme produced by the hemolytic strep that depolymerizes the ground substance of tissue) or streptokinase's actions on the blood brain barrier, the drain of vitamin B6 from the bacteria's own useage, the body's requirement of B6 for immunity, and the antibiotic's B6 antagonistic properties. A pre-exising B6 dependency/deficiency could be uncovered. TOURETTE SYNDROME, ALLERGY AND THE B6 DEPENDENCY STATE I have my Bachelor's degree in Biology, specializing in Medical Technology, and in graduate school, I took graduate courses in biochemistry. I work as a medical technologist performing and verifying clinical laboratory tests in Chemistry, Hematology and Blood Bank at Mt.Carmel East Medical Center in Columbus, Ohio. I do not have TS but my son, Jason (13 yrs old) has TS with OCD. ADD has not been formally diagnosed, although he has problems with organization, distractibility, and the ability to switch gears. My son has had allergies since he was a baby. He is sensitive to red dye #40 with tired splitting headaches which make him scream until he is exhausted and sleeps. This, of course, hasn't happened in several years since he has avoided the dye. He also is allergic to sulfa, molds, dust, grass, trees, and most airborn allergens. He has been on the vitamins below for 1.5 months and the teachers have said that he is a different kid. Medications that he had been on made him progressively worse, and so we made a personal decision to discontinue meds altogether. He now is motivated in school, concentrates and finishes his work, and is less disruptive with his tics in class. At home he still has his tics and compulsions, but they are shorter lived and occur less often. He has had a set back this week due to a new semester with a new schedule, plus a very moldy, rainy few days. We gave him a little extra calcium-magnesium and one extra vitamin B3. He said that this gave him relief from his symptoms (he has never said this before with anything else). I solidified my theory on the premise that Jason is probably mildly vitamin B6 dependent. He was either born requiring high amounts of B6, and/or B6 antagonists attacked early in his first year of life. B6 antagonists are hydrazines (plant growth regulators, tartrazine, etc), DOPA found in certain beans, penicillinamine, antioxidants in petroleum, many drugs including penicillin, erythromycin, phenobarbital, tetracycline, corticosteroids, sulfamethoxazole, etc. Amino acids began building up in his system, from decreased transamination, etc. Serotonin became decreased from tryptophan not being able to be utilized. Allergies developed (which is in association with low B6), I believe allergy produces swings in histamine levels which causes a constant fluctuation in neurotransmitters capable of producing mood swings and rages. The conservation of vitamin B6 (when not abundantly available) causes it to be used by the prevailing neurotransmitter system at any given time, leaving other neurotransmitter systems less than optimally functional. Histamine receptors have been found to trigger dopamine receptors directly. Histamine is also a neurotransmitter affected by deficient vitamin B6. Its receptor sites are probably increased to compensate. Kinins released into the body's tissues in response to immune complexes can damage the blood brain barrier, thus altering the sensitivity of brain cells to acetylcholine, serotonin, dopamine, histamine, epinephrine and norepinephrine. I found that L-dopa doesn't readily form dopamine in B6 deficiency, so probably dopamine is reduced causing an increase in dopamine receptor sites along with an increase the norepinephrine and epinephrine (which are formed from dopamine) receptors sites. These increased receptor sites make the nerves more excitable and false transmitters or true neurotransmitters can set them off with explosive qualities. These false transmitters can be phenolic substances, such as food additives, drugs, etc. The enzyme, phenol sulfotransferase (PST), detoxifies and eliminates phenolics (drugs, food additives, serotonin, dopamine (to name a few). In the brain, sulfation is used while glucuronidation prevails elsewhere. Cysteine requires B6 to enzymatically release sulfur for sulfation of these phenols by PST. Considering this, the neurotransmitters would would be conserved to a certain extent (their sulfation and elimination would be slowed down). ADD may happen when these false transmitters create background "noise", and if there is a real message to get through via other neurons, it is masked. When a true message is fired, it may have too strong of a signal, creating a strong impulsion, which can lead to the development of a tic or compulsion if the impulsion is acted upon and repeated creating a sort of conditioned reflex network of nerves. Mental, motor, and vocal tics can develop this way. According to my_ Biochemistry_ by Lehninger textbook from my graduate student in Biology days, tryptophan is broken down in Vitamin B3 deficiency to make nicotinic acid. Tryptophan is found in meat and is plentiful, if you are a meat eater. Tryptophan is the precursor for serotonin. I also looked up Vitamin B3 and how it could be connected to the issues of allergy and serotonin defiency in the brain. I found that Vitamin B3 is used to make NAD, NADP, which are coenzymes used in making histamine and serotonin (to name a few), and are essential in oxidative-reductive cellular metabolism. The B3 is needed due to tryptophan's inability to be broken down to nicotinic acid without adequate B6. So, if Vitamins B3 and B6 are being used for histamine production, then serotonin production suffers. Tryptophan then must be used in a higher frequency to make nicotinic acid. In Vitamin B6 deficiency, this cannot happen, because the enzyme kynurinase, that catalyzes the cleavage of 3 hydroxykynurine (an intermediate in tryptophan catabolism), contains pyridoxal phosphate (an active coenzyme form of Vitamin B6). In Vitamin B6 deficiency, large amounts of L-kynurenine are excreted in the urine, because of its high plasma levels. This is described in "Elevated plasma kynurenine in Tourette syndrome", _Molecular & Chemical Neuropathology_21(1): 55-60,1994 Jan. Kynurenine itself is metabolised to other substances, several of which are known to have effects on neurones. (per a research study done at University College London Medical School Harlow, England by Sheila L. Handley, BPharm, Ph.D. 1994) Large amounts of tryptophan which is broken down to ineffectively try to produce nicotinic acid reduces the amount of serotonin produced. Ineffective tryptophan utilization also uses alot of oxygen with tryptophan 2,3-dioxygenase. Low serotonin levels could cause obsessive compulsive behaviour, depression, and other mood related disorders. B6 is also required for the decarboxylase step of serotonin, histamine, and catecholamine pathways in the brain. In low B6, conservation takes place, so that B6 is used for fewer enzymes. When allergy strikes, the production of histamine causes a further imbalance of neurotransmitters, causing serotonin and/or catecholamine production to be further depleted. Sherry A Rogers, M.D., a specialist in environmental medicine, reports that all of the TS cases she has seen have a least one nutrient deficiency, and usually several. And she notes that all of these patients have hidden mold, dust, chemical and food sensitivities. ("Tourette Syndrome", _Health Counselor_, Vol.7, No.4) Acetylcholine is produced by acetyl CoA and choline. The choline is supplied through lecithin in Jason's supplements. In vitamin B6 deficiency, acetyl CoA would be made by fatty acid oxidation. So acetycholine could be functional with an adequate supply of fatty acids (evening primrose oil or flax oil might be useful). Acetylcholine could be in shorter supply in the parasympathetic system (relaxation) due to overuse in the sympathetic system where norepinephrine usually rules. The parasympathetic nervous system would need to have more acetylcholine in TS and associated disorders, it seems. Relaxation through the parasympathetic nervous system (which uses acetylcholine), where the heart rate is slowed, the blood pressure is lowered, the food is digested well, etc. is difficult in TS. Acetylcholine is probably overactive in the sympathetic autonomic nervous system, trying to stimulate the low supply of catecholamines, which would be decreased due to B6 deficiency/dependency. The receptors sites for catecholamines would be hyperexcitable and increased in number. The net usage of catecholamines could be normal to decreased due to increased stimulation by acetylcholine, depending on the availability of B6 in the body, and the conservation by low sulfation by PST. Conditions of emotional stress are known to produce more ticcing in TS. In short term stress, norepineprine, dopamine, and epineprine should be able to be produced by the conservation tactics of the body, but in long term stress, these would be exhausted, especially when another B6 dependent system is triggered. Likewise, the same would happen when histamine and serotonin are produced in short term and long term allergy. But as you might expect, the short term conditions would be explosive events with all of those increased receptor sites! Acetylcholine is also involved in the contraction of voluntary muscle cells and many other motor nerves, which are in heavy use in TS. Many people with TS are helped by exercise, where cardiac output and increased body temperature over a period of time inhibit the sympathetic nervous system. It may also help to clear toxic waste, such as kynurenine. Adequate water intake would be required to catabolize acetylcholine by cholinesterase. In my opinion acetylcholine is needed in B6 deficiency/dependency to run the nervous system. Fatty acids are essential to its success in this situation. Fatty acids require NADPH2, and NADH2 for their synthesis, and thus Vitamin B3. Water is also an utmost requirement in keeping acetylcholine from becoming a continuous firecracker. Jason has a water bottle close by most times and drinks tons of water. Water has always calmed him down. It may also dilute the kynurenine, excess amino acids and promote their excretion. If you look at the material written on the Canadian Mennonite families that have been studied with Tourette's disorder, you will see a high frequency of autoimmune and rare conditions. These findings are consistent with what one can expect with other Tourette's patients. For example, there is a high frequency of allergic conditions. My informal survey of TS and allergy results from the online TS support group are: With a total of 25 respondents with TS: 96% have allergies (24 out of 25) 56% have mold allergies 72% have obsessive complulsive traits (18 out of 25) 67% of those with obsessive compulsive traits have mold allergies 3 respondents thought they may have mold allergies, but weren't sure 52% have pollen allergies (ragweed, grass, tree, etc) 56% of those with obsessive compulsive traits have pollen allergy 48 % have animal allergies (cats, dogs, horse) 39% of those with obsessive compulsive traits have animal allergies 40% have dust allergy 39% of those with obsessive compulsive traits have dust allergy 20% have penicillin allergy 28 % of those with obsessive compulsive traits have penicillin allergy 20 % have miscellaneous allergies 11% of those with obsessive compulsive traits have miscellaneous allergies 16 % have food allergies 22 % of those with obsessive complulsive traits have food allergies 8% have sulfa allergy 11% of those with obsessive compulsive traits have sulfa allergy All of our frequent posters responded. The types of allergies are typically respiratory and airborne. Molds and pollens are the top allergens. 79% of the people with mold allergies also had pollen allergies, which are seasonal. Bonnie Grimaldi, BSMT (ASCP) 11283 Meadowcroft St. Pickerington, Ohio 43147 (614) 837-7545

Woody McGinnis' recommendations for nutrients.

Strategy: Assure Generous Levels of the Key Nutrients 1. Vitamin B6: Pyridoxal-5-phosphate is activated form. 2. Magnesium: glycinate form most absorbable. 3. Zinc: Picolinate form most absorbable. Dose away from minerals and food which block absorption. Balance with manganese. Warts, stretch marks, flecks subside. 4. Calcium: Assure RDA of about one gram daily plus some require extra. 5. Selenium: Doses up to 200 mcg daily as anti-oxidant and to bind mercury. 6. Vitamin A: Cod liver oil for all behavioral children unless allergic to cod. 7. Vitamin C: Twice-daily dosing rationale; also helps regularize bowel movement. 8. Vitamin E: Important chain-breaking anti-oxidant. 9. Fish Oil: Quiet inflammation with EPA. High EPA/DHA preparations available. 10. Evening Primrose Oil: Good for the gut, growth and immunity. Particularly Important for Immunity: Zn, Vitamin A, GLA

Oxidative stress and neurochemicals

Oxidative stress and chronic fatigue syndrome Another speaker, Christian Renna, DO, presented an interesting thesis that without sufficient serotonin and antioxidant defenses, the brain decides that it's not safe to produce dopamine and norepinephrine—hence chronic fatigue and related neurosomatic disorders. A central feature of chronic fatigue-like disorders is a deficiency of norepinephrine. But simply increasing norepinephrine through pharmacological means is not appropriate, since the brain is already overwhelmed with stress, and thus with free radicals. In Renna's view, both stress reduction and antioxidant supplements are absolutely necessary to help the brain produce and maintain inhibitory and excitatory neurotransmitters in proper ratios. This applies not only to those diagnosed with chronic fatigue, but to all of us, especially as we age. In the presence of excess free radicals, the brain seeks to protect itself by lowering its activity. This means lower production of excitatory neurotransmitters such as dopamine, and less energy production in the mitochondria. Every neuron has an excitatory threshold beyond which it will not fire, Renna explained. Instead, the overstimulated neuron shifts to an “escape pathway,” preventing the synthesis of dopamine and norepinephrine. In chronic fatigue, the neuroexcitatory threshold is set too low. Raising it requires increasing the brain's safety mechanisms: serotonin and antioxidants. “If the cell doesn't need to fear oxidative stress, the mitochondria light up like Las Vegas,” Renna said. He also pointed out that many chronic fatigue patients responded well to fen/phen, which was a combination of a serotonin-raising drug and an amphetamine analogue. “Overcoming serotonin deficiency allows the brain to tolerate more norepinephrine,” Renna said. He didn't favor long-term use of antidepressants, however. He felt such use prevented the patient from achieving a more complete recovery. The point is to help the brain produce more of its own serotonin. Thus, we need to address the necessity of lowering stress—not only emotional stress, but also stress coming from chronic low-grade infections, toxins (including endotoxins [toxins produced within the body] originating in the gut under conditions of dysbiosis, meaning an overgrowth of harmful intestinal flora), excess calories, insufficient sleep or any other source. “The more gentle the stimulation, the better,” Renna said. “So don't rush.” In addition, we must make sure the patient's antioxidant defenses are adequate before we use any kind of stimulant. “If a person is not energetic, maybe it's not safe for them to be energetic,” Renna said, again reinforcing the point about low serotonin and depleted antioxidant defenses. Both need to be corrected through stress reduction, diet, the right exercise and supplements. The brain will produce more dopamine when it becomes safe to do so. Dopamine is a very energizing, feel-good neurotransmitter; in addition, dopamine stimulates the release of nerve growth factors. But dopamine has its dark side. “Dopamine is the most dangerous of all neurotransmitters because the brain needs to defend itself against overstimulation,” Renna explained. When serotonin is low, the threshold for what constitutes overstimulation is also set low. Low serotonin, low dopamine, and low energy production in cerebral mitochondria all lead to a cascade of harmful consequences. Since the brain is in constant chemical communication with the rest of the body, including the endocrine system and the immune system (in fact Renna calls the immune system “morcelized brain”), the whole body suffers. We see this not only in the chronic fatigue syndrome, but above all in aging. Tofu has recently come under suspicion as deleterious to the brain. In an ironic reversal of our previous beliefs, coffee and tea are now seen as neuroprotective, while tofu is increasingly under attack. Renna also discussed neuroprotective supplements. His special emphasis was on flavonoids as particularly effective antioxidants and neuroprotectants. Flavonoids (such as those present in blueberries and bilberries, green tea, grape seed extract, and various fruits and vegetables) not only raise glutathione levels, but also help prevent inflammation by inhibiting the enzymes in the lipoxygenase family (LOX), which NSAIDs and COX-2 inhibitors cannot do. Renna added folic acid, SAMe and acetyl-l-carnitine to the list of essential neuroprotective supplements. As for the so-called smart drugs, such as deprenyl and piracetam, these too are worth looking into, according to Renna. They increase energy production while reducing oxidative stress (acetyl-l-carnitine works the same way). Tofu has recently come under suspicion as deleterious to the brain. In an ironic reversal of our previous beliefs, coffee and tea are now seen as neuroprotective, while tofu is increasingly under attack. Renna takes his patients off tofu, at least until there is some solid new evidence of its safety. Both Perlmutter and Renna covered a huge territory, at times overwhelming the audience. Permutter focused on the “anti-inflammatory breakthrough”: preventing and fighting inflammation in the prevention and treatment of Alzheimer's disease, as well as on the use of intravenous glutathione, the body's chief detoxifying compound, as a new and potentially revolutionary treatment for Parkinson's disease. Perlmutter also touched on the production of energy in the cerebral mitochondria, a subject developed more fully by Renna. The main message was clear: we already know a great deal about preventing and treating brain diseases and age-related cognitive and motor dysfunction. Relatively simple measures such as reducing caloric intake and taking fish oil, NSAIDs, lipoic acid and CoQ10 could save millions from terrible brain diseases. It is high time to start implementing this knowledge on a much broader scale. Antioxidants against vitamins: lipoic acid and selenium improve the survival of AIDS patients The excitement over the new anti-retroviral drugs designed to fight the AIDS virus is yielding to a sober assessment of their limitations. By now it has been shown that these drugs do not fully restore immune function. They are not the long-awaited cure. Their side effects are so severe that many AIDS patients drop out of treatment. In addition, the majority of the virus is in the latent stage in the nuclei of T cells, and antiviral drugs cannot affect latent viruses. Are there effective alternative treatments? An affirmative answer was compellingly presented by two speakers: Raxit Jariwalla, PhD, a research scientist at California Institute for Medical Research in San Jose, and Lynn Patrick, ND, medical director of HIV Wellness Program in Tucson, Arizona. The speakers cited study after study showing improved survival rate for AIDS patients who used certain critical supplements known to reduce oxidative stress (a major factor in the progression of the disease) and, in some cases, to significantly suppress viral reproduction. Both presenters singled out lipoic acid as particularly important. All antioxidants are also anti-inflammatory agents, but lipoic acid is regarded as an especially effective anti-inflammatory. It has been known for almost a decade that lipoic acid effectively inhibits the replication of the AIDS virus in vitro. This is not surprising in view of our knowledge that lipoic acid inhibits the activation of Nuclear Factor kappa B (NFkB), which is believed to play an important role in the activation of the HIV virus. Essentially, the latent virus is activated by certain inflammatory cytokines that result from the activation of NFkB. These cytokines include Tumor Necrosis Factor alpha (TNF alpha)—hence the goal of reducing TNF alpha, and the similarity between alternative treatments against AIDS and hepatitis, Dr. Patrick pointed out. Both protocols emphasize lipoic acid, selenium and a combination of various other antioxidants. In addition, many AIDS patients are co-infected with Hepatitis C. “All AIDS patients need liver support,” Patrick said. In addition to 500 mg of lipoic acid/day, she also uses silymarin, shown to be remarkably effective in restoring liver health. Lyn Patrick largely confirmed Dr. Jariwalla's primary emphasis on lipoic acid, stating that “lipoic acid is of extreme importance for HIV patients.” She reinforced this with some added details. Studies have found that lipoic acid inhibits reverse transcriptase (a viral enzyme needed for replication), and makes AZT significantly more effective. Another obvious reason for the importance of lipoic acid for HIV patients is its ability to raise glutathione, our chief detoxifier and a crucial endogenous antioxidant. Glutathione is low in all serious illnesses. When the levels of glutathione rise, the result is reduced oxidative stress. The role of oxidative stress has been neglected in the discussion of AIDS, with the public getting the impression that the sole factor in the progression of this disease is the presence of AIDS virus, commonly referred to as HIV. Yet oxidative stress and consequent inflammation play a major role in whether symptoms of AIDS will appear at all, and in the rate of progression. Some people who are HIV positive do not show any symptoms of AIDS. Interestingly, this group tends to have a higher intake of antioxidants, from diet or supplements or both. Even merely taking a multivitamin turned out to reduce the risk of developing the symptoms of AIDS by 33% in HIV-positive individuals. While lipoic acid plays a starring role in the alternative treatment for HIV patients, another thiol (i.e. sulfur-containing) antioxidant, the acetylated form of cysteine known as NAC, appears to be somewhat helpful as well. NAC too helps raise the levels of glutathione, but by itself it is not likely to have enough effect in AIDS patients; lipoic acid is far more efficient at raising glutathione and blocking NFkB. The special effectiveness of lipoic acid may derive from the fact that it's a dithiol (it has two sulfur groups), while NAC is a monothiol. NAC is more effective when used with other antioxidants. In particular, it synergizes with high-dose ascorbate. High-dose ascorbate, Dr. Jariwalla stated, is unique in that it recycles itself to the reduced state. It also produces “dramatic dose-dependent suppression of viral reproduction.” It is believed that high-dose ascorbate suppresses viral replication through a different mechanism than thiol antioxidants (lipoic acid and NAC) and selenium. Some participants suggested that intravenous delivery of ascorbate would be most effective, due to the large dose required (6 to 12 grams if taken orally). Selenium also plays a starring role in anti-viral regimens. It too inhibits NFkB. But the main reason that selenium is known as “birth control for viruses” derives from the fact that many viruses, including HIV, need selenium to replicate. Interestingly, in a selenium-rich milieu the viral genes that control replication stay turned off. In addition, selenium is required by T cells, and potentiates the action of interleukin-2. An AIDS patient is ten times more likely to die if s/he is selenium-deficient, according to Dr. Patrick. She uses the dose of 400 mcg per day. Vitamin E is known to play an important part in bolstering immunity and reducing inflammation. Like lipoic acid, vitamin E also inhibits NFkB, essential for viral replication. Dr. Patrick stressed that only the succinate form of vitamin E inhibits both the activation of NFkB and the binding of activated NFkB to DNA, as shown by the research of Dr. Lester Packer in the early nineties. Vitamin E has also been shown to enhance the action of AZT. Thus, the form of vitamin E known as alpha-tocopheryl-succinate (“dry E” in popular parlance) is of crucial importance for HIV patients. It is possible, however, that gamma-tocopherol, being a COX-2 inhibitor, is also of value. Vitamin A and beta carotene have been found helpful, as has zinc—but only in small doses. Zinc supplements in excess of 10 to 15 mg appear to increase disease progression. We don't know very much about zinc and HIV, but we do know that zinc is important for the immune system. Zinc activates the thymus hormone thymulin, which plays a part in the differentiation of T cells. Zinc is also involved in protease and integrase enzymes. It seems that supplementing with 12 mg of elemental zinc works best, according to Patrick. HIV infection has also been linked to deficiencies in B6, B12 and folate—the methylating factors. There is a “rampant deficiency” of B12 among AIDS patients, according to Dr. Patrick. Such nutritional deficiencies in patients with full-blown AIDS result mainly from their poor absorption of nutrients due to gut problems, Patrick explained. Thus doses need to be especially large. Most HIV patients are also glutamine-deficient, Patrick said. This is true of anyone under chronic severe stress, even though glutamine is abundant in any protein-rich diet (interestingly, the immune dysfunction seen in AIDS resembles the symptoms of protein-calorie malnutrition). Glutamine helps stop diarrhea and prevents muscle wasting. Large doses are needed (Patrick uses 40 g/day in four divided doses), but the cost is only $31 per week versus $1000 a week it would take for growth hormone treatment, another therapy aimed at preventing wasting. Patrick mentioned yet another supplement: acetyl-l-carnitine. AZT is a mitochondrial toxin. It turns out that the combination of acetyl-l-carnitine and lipoic acid can reverse this toxicity. After learning about the effectiveness of lipoic acid, NAC, Vitamin E, high-dose ascorbate and other supplements in fighting the HIV virus and improving the survival rate of AIDS patients, it was sad to hear that AIDS activists have largely lost interest in alternative therapies and are mostly waiting for the next “miracle drug.” So far, the drugs have proven highly toxic and not effective in many patients. We need to seriously consider the preventive and therapeutic use of supplements such as lipoic acid. In Dr. Jariwalla's words, “nutrients are compelling candidates for treatment of immune dysfunction underlying AIDS.” Much is to be gained from paying attention to the developments in the alternative treatment for AIDS. Cellular immunity decreases not only in the course of AIDS, but also during aging. It is of utmost importance that we learn how to sustain a healthy immune system that can fight viruses and bacteria. Thus, the results presented in the lectures on AIDS are of special interest for anti-aging medicine. Antioxidants, with special emphasis on lipoic acid and selenium, once again show their amazing potential.

B6 and phenols. Finally, an explanation!

Enzyme Stuff discussion on excessive B vitamins

Sometimes parents are advised to give very excessively high doses of B6 for their children with autism spectrum conditions. However, experience shows that many children have very terrible reactions to supplements with excessively high doses of B6. The ARI information from over several decades also shows that the majority of people with autism do not benefit from high B6 vitamin supplements although some do. A high does is about 50 mg, a very high dose 100 mg, and excessively high often way over that. While some B6 as well as other basic vitamins are beneficial, excessive amounts may be too much neuro- stimulant particularly for neurologically sensitive people. It is important to check with a qualified medical doctor for your situation when taking anything over the Recommended Daily Allowance of anything.

Why so many negative reactions and why might some do okay with it? For one thing, most all sources agree that B vitamins work as a team together and should be taken in the proper ratios - a balance of B vitamins. Taking an excessive amount of just one or two individual vitamins in the B family can cause deficiencies in other B vitamins. So you might just be trading one problem for another.

Another problem is that many synthetically made B6 vitamins may be made from coal-tar. Coal-tar derived synthetics include artificial colorings and flavorings. So if someone has a sulfate processing problem, or is sensitive to artificial additives of this nature, or doesn't tolerate phenolic compounds or artificial additives, then they may very likely not tolerate B6 vitamins if they are synthetically derived. If you are not tolerating B vitamins, you might want to look at a non- synthetic source of nutrients. More information and several non-synthetic formulations are at the link below. In the middle of this page are some links that go to research showing why taking lots of synthetic supplements is not always the most healthful, and you might want to try getting as much nutrition from natural sources as possible. Nutrition and enzymes (general diet strategies)

Pyroluria

Pyrrole Disorder

Omega 3s can worsen mental symptoms in bipolar or schizophrenic patients.... if they have a pyrrole disorder. This phenotype is dramatically short of arachidonic acid & giving omega 3 oils aggravates the situation since omega 3 and omega 6 EFA's are in competition for delta 5,6 desaturases. We use red blood cell membrane analysis for EFA's if we suspect this problem. Pyroluric mental patients will usually get worse if given fish oils, DHA, EPA, etc. They thrive on Primrose Oil, a good source of AA and other omega 6s. (June 23, 2003)

Most persons with pyroluria respond very quickly to the B-6, Zn, C, E therapy..... Major improvements are often seen by the 2nd day, and almost always by the end of the first week. The exceptions are: (1) persons with severe mental illness (schizophrenia or bipolar), (2) persons with other significant chemical imbalances, and (3) patients with a major malabsorptive condition. When pyroluria is diagnosed along with another chemical imbalance, I like to track a patient during the first 6-8 weeks to determine which is the dominant imbalance. If major improvement occurs immediately, it's because pyroluria has been corrected. Some patients report a nice early improvement followed by a plateau, and then another advance. Schizophrenic and bipolar pyrolurics usually report some progress after a few weeks, but it may take 3-6 months to get to steady state. The biggest problem with the Kp analysis is getting a proper sample to the lab. The kryptopyrrole molecule is unstable and will disappear rapidly at room temperature or if exposed to bright light. The urine sample must be placed in a freezer immediately after acquisition. Kp can be lost in the freezer if the temperature isn't well below 32 degrees F. We've also learned that exposure to bright light results in breakdown of the Kp molecule. Finally, the sample must be maintained in a frozen condition during shipment. I would greatly suspect any Kp value below 3.0. Usually this means the sample didn't get to the lab in proper condition. With respect to reference levels: We consider a healthy level to be between 4-8 mcg/dL. We consider persons between 10 and 20 to have mild pyroluria, and a good response to treatment is usually reported. Persons exhibiting 20 to 50 mcg/dL have moderate pyroluria, which can be a devastating condition. Persons above 50 mcg/dL have severe pyroluria. Longitudinal testing of pyrolurics has shown that major variations can occur during a day. For example, Arthur Shawcross (famous NY serial killer) had levels ranging from 35 to 203, with higher levels observed during stressful periods in prison. However, he always tested as pyroluric in multiple tests. Stresses, illnesses, injury, etc can be expected to elevate Kp levels. Medical history and review of symptoms are vital to this diagnosis. The major challenge in differential diagnosis of pyroluria is the similarity in symptoms between pyroluria and overmethylation (low blood histamine). Another problem is that symptoms of pyroluria are greatly muted in undermethylated, obsessive/compulsive persons. These persons may be high achievers, with great internal tension..... Persons with pyroluria alone tend to underachieve, partly because of a poor short term memory and associated reading problems. (Nov 10, 2003)

We've obtained hair Zn and plasma Zn levels (simultaneously) about 40,000 times. Low hair zinc correlates beautifully with low plasma levels. However, very elevated Zn in hair nearly always means Zn deficiency and loss plasma Zn levels. Most of the time this involves a Pyrrole disorder which results in very high Zn excretion in urine (and hair). In a healthy person without metal-metabolism problem, only about 4 percent of excreted Zn leaves through the kidneys. [28 Nov 03] Symptoms of pyroluria include (1) stunting of growth, (2) unpleasant body odor, (3) delayed puberty, and (4) skin stretch marks. This family's symptoms are certainly consistent with pyroluria. Pyroluria definitely runs in families. We have a mother in Kane County, IL who has 15 children & all of them tested pyroluric. The mother had a Kp level of over 150 herself

Neurotransmitters

Abstract

A composition and method for treating Attention Deficit/Hyperactivity Disorder (ADHD) is provided which can be used both with and without ethical drugs now used to treat ADHD. The composition contains dimethylaminoethanol (DMAE), omega 3-fatty acids, betaine, oligomeric proanthocyanidins (OPC), folic acid, vitamins C, E, B₁₂, B₆, B₅ and beta-carotene and minerals (calcium, magnesium, zinc and selenium). Ethical drugs such as amphetamines, methylphenidate HCl and pemoline are known to control ADHD, but each has significant side effects when used in their therapeutic dose. When combining the composition with such ethical drugs, the amount of the ethical drug can be lowered below a level which causes undesirable side effects which is an important feature. Preferred compositions contain one or more of lecithin, choline, 5-hydroxytryptophan, tyrosine, Reishi Extract, Kava Extract, Gingko, Ginseng and St. John's Wort.

DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

It is apparent that there is a need for the treatment of ADHD without the serious side effects of the aforementioned known drugs now used for treating ADHD. This invention provides a safe and efficacious combination of natural products which can be used with or without a reduced dosage of known ethical drugs used for ADHD. Dimethylaminoethanol (DMAE) is a natural chemical (found in fish) and has a p-acetamidobenzoate salt formerly prescribed for short attention span and hyperactivity. This drug is now available as an over-the-counter (OTC) nutrient supplement. Unlike most stimulant drugs, which tend to produce a short "up" cycle followed by a quick "come down", DMAE's effects are long lasting and more subtle. People who take DMAE report that after three or four weeks, they feel a mild stimulation continually, without side effects. The quintessential "nootropic" DMAE focuses on specific cortical brain functions associated with the direct intensification of consciousness. Side effects are very rare--high doses may result in insomnia, headache or tense muscles, which disappear if the dose is lowered. No serious adverse effects have been reported with DMAE. DMAE it is hypothesized accelerates the brain's synthesis and turnover of the neurotransmitter, acetylcholine, by redirecting choline synthesis to the cortex. Acetylcholine is the neurotransmitter that the brain uses for short term and long term memory and also helps in concentrating and focusing. Clinical studies including a double blind clinical study comparing DMAE and Ritalin, demonstrated significant test score improvements for both DMAE and Ritalin vs. placebo in ADHD children. DMAE has been shown to increase levels of choline in the brain due to DMAE's superior ability to cross the Blood-Brain Barrier. DMAE has been shown to elevate mood and allow a sounder sleep. DMAE has also been shown to decrease the accumulation of lipofuscin in the brain and to increase attention span and improved concentration. DMAE and derivatives thereof such as its p-acetamido benzoate salt and its bitartrate salt is an important component in the composition of this invention for treating Attention Deficit/Hyperactivity Disorder. Amounts of DMAE of up to 1000 mg, or more, preferably 200-800 mg are used. The brain consists of about 60% fat (lipids). In clinical studies with children with Attention Deficit/Hyperactivity Disorder, supplements of omega-3 fatty acids [eicosapentaenoic acid (EPA), and docosahexanoic acid (DHA)] vs. placebo, have demonstrated improved mood, enhanced clarity of thinking, more serenity and mental clarity of thinking, better concentration and better vision for those taking omega-3 fatty acids. Omega-3 fatty acids (e.g., EPA and DHA; fish oil) are an important component of the composition of the invention and are used in an amount of up to about 1200 mg or more, preferably 200-800 mg. Since the brain contains so much fat (lipids), it is hypothesized the brain has to be protected from free radicals forming "lipid peroxidation" which can cause brain disorders. Antioxidants such as vitamin C, E and A, preferably beta-carotene, improve memory performance and are included in the composition of the invention for this purpose. Vitamin C is used in an amount up to about 1500 mg or more, preferably 200-1000 mg; vitamin E up to about 800 IU or more, preferably 400 IU; and Vitamin A up to about 25,000 IU or more, preferably 10,000-25,000 IU. Recently, U.S. Pat. No. 5,719,178 claimed the use of proanthocyanidins (derived from the conifer bark), an antioxidant, in the treatment of APHD. The general class of oligomeric proanthocyanidins (OPC), which include conifer bark extract, grape seed extract, pine bark extract and the protective phenolic compounds from natural sources including bioflavonoids it is hypothesized can reduce free radical damage causing APHD and are included in the composition of the invention. These "free radical inhibitors" can pass through the Blood-Brain Barrier to protect the brain. OPCs have been shown to possess antihistamine, anti-inflammatory and immune-boosting effects as well as inhibiting the breakdown of the catecholamine neurotransmitters. OPCs increase attention span, increase focus and decrease emotional activity in ADHD persons and are used in the composition of the invention in an amount of about 200 mg or more, preferably 50-150 mg. Faulty neurotransmission is considered the main reason for ADHD. Acetylcholine is involved with learning and memory. Serotonin is involved with mood, emotional balance and impulse control. Catecholamines speed up the rate at which one neuron signals another. It is an important feature of this invention that there be a proper balance between the neurotransmitters for "normal" mental and emotional function. ADHD is a complex disorder involving an unbalance in several neurotransmitters. This invention uses a multi-step approach to fully treat ADHD disorder and the body according to this invention must have "methyl donors" to synthesize the brain chemicals, which accounts for their mood elevating and cognitive effects. Betaine or trimethylglycine, folic acid and vitamin B₁₂ are methyl donors, which are included in the composition of the invention. Betaine is used in an amount up to about 750 mg or more, preferably 100-500 mg. Folic acid is used in an amount up to 1.2 mg or more, preferably 0.4-1 mg and Vitamin B₁₂ up to about 40 mcg or more, preferably 3-30 mcg. In addition to the vitamins mentioned, the body uses vitamin B₅ to form acetylcholine and vitamin B₆ to form serotonin and L-Dopa into Dopamine, which accounts for their effect of increased alertness and mood. These vitamins are included in the composition of the invention. Vitamin B₅ is used up to about 250 mg or more, preferably 50-250 mg and Vitamin B₆ up to about 25 mg or more, preferably 5-25 mg. There are some vital minerals that affect the functioning of the brain. Calcium is a second messenger in neuronal membranes and it acts like a traffic signal for uptake and release of neurotransmitters. A "green light" from calcium permits release of a neurotransmitter into the synaptic intersection and a "red light" halts its passage into the receiving neuron. Calcium regulates the speed, intensity and clarity of every message that passes between brain cells. Magnesium is the second most important mineral in the brain. A study found low magnesium levels in 95% of ADHD children. Supplements of magnesium at a level of 6 mg/lb. of the child showed a decrease in hyperactivity. Zinc is the third most important mineral in the brain, where it acts like an antioxidant and also acts on the surface of the neurons as an electrical "contact" for neurotransmission. Selenium has been shown to protect the integrity of message sending between neurons by preventing free-radical attacks. One or more of these minerals, preferably all, are included in the composition of the invention in amounts up to about 150% of their RDA or more, preferably 100%. Calcium is preferably used at a level of 200 to 1200 mg, magnesium 100 to 500 mg, zinc 5 to 50 mg and selenium 40 to 120 mcg. 5-Hydroxytryptophan (5-HT), the precursor of serotonin, is also included in a preferred composition of the invention in an amount up to 75 mg or more, preferably 25-50 mg. Tyrosine, an amino acid, is a precursor of the catecholamines and used as a food supplement and improves alertness and elevated mood. Tyrosine is included in the composition of the invention in an amount up to 300 mg or more, preferably 50-250 mg. Like omega-3 fatty acids, phospholipids are important for optimal brain health, and are found in high concentrations in the brain. They help the brain cells communicate and influence how well the receptors function. Lecithin is a phospholipid found in certain foods and available as a food implement. Lecithin provides a very available source of choline required for acetylcholine. Lecithin and cytidine 5-diphosocholine (CDP) supplements increase alertness and motivation. Lecithin is used in an amount up to 2000 mg or more, preferably 600-1800 mg. Choline is also included in a preferred composition of the invention in an amount up to 800 mg or more, preferably 100-500 mg. Another important component of a preferred composition of the invention is Reishi extract derived from mushrooms. Reishi extract calms the mind, eases tension, improves memory and sharpens concentration and focus which are all important effects for treating Attention Deficit/Hyperactivity Disorder according to this invention. Reishi extract is used in an amount up to 2000 mg or more, preferably 500-1500 mg. Kava (Piper Methysticum) is a plant grown in the South Pacific and contains kavalactones, which influence a number of brain receptors involved with relaxation and mental clarity. In a study the results showed kava superior to placebo, with improvements in anxiety, mood, tension and fears with increased alertness. With the anxiety that is part of ADHD, kava extract is included in the composition to provide a calming effect and increase concentration. Kava is used in an amount up to 200 mg or more, preferably 50-150 mg. Gingko Biloba extract contains flavonoids and terpene lactones. Gingko improves communication between nerve cells and enhances blood flow to the brain. It also acts as a powerful antioxidant. Ginseng extract has been found to improve blood circulation and provide mental clarity. Researchers have evaluated the cognitive effects of gingko/ginseng. A double blind, placebo controlled study showed improvements in memory and overall cognitive function for those taking both gingko and ginseng and both are in preferred embodiments of the invention. Gingko is used in an amount up to 200 mg or more, preferably 30-120 mg and Ginseng up to about 200 mg or more, preferably 50-150 mg. The herb, St. John's Wort, affects five neurotransmitters in the brain: serotonin, noradrenaline, dopamine, gamma-aminobutyric acid (GABA) and interleukin-6. Because St. John's Wort affects these neurotransmitters, it helps balance them to provide "normality" and is a preferred component in the composition of the invention for treating ADHD in an amount up to about 800 mg or more, preferably 100-600 mg. In the combination of the aforementioned "natural" therapy, with ethical drugs, in addition to amphetamines, methylphenidate HCl, and pemoline, the composition of the invention can be used also with fluoxetine, sertraline, paroxetine, fluoxamine, citalopram, venlafaxine, bupropion, nefazodone and mirtazapien, among others. While the above components as described are the preferred components to be used in the composition of the invention it will be appreciated to those skilled in the art that known derivatives, e.g., salts, may be employed. As set forth hereinabove, it is an important feature of the invention that the components act together to provide a synergistic effect by effecting different pathways of action, i.e., by normalizing the several neurotransmitters and receptor sites responsible for ADHD. While the present invention has been particularly described, in conjunction with a specific preferred embodiment, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description. It is therefore contemplated that the appended claims will embrace any such alternatives, modifications and variations as falling within the true scope and spirit of the present invention.