ZINC DEFICIENCY, METAL METABOLISM, AND BEHAVIOR DISORDERS

ZINC DEFICIENCY, METAL METABOLISM, AND BEHAVIOR DISORDERS by William J. Walsh INTRODUCTION Most Americans receive all the zinc they need if they have a reasonably well-balanced diet involving the major food groups. However, many persons are born with a metal-metabolism disorder which results in zinc depletion regardless of diet. Zinc is a component of more than 80 enzymes. High concentrations have been found in brain hippocampus, and many medical researchers believe that zinc is a neurotransmitter. Low zinc levels at these sites could reduce the inhibition of neuron activity, thus leading to abnormal behavior. The discovery of zinc "finger proteins" in the past decade has led to a vastly improved understanding of how cells replicate and divide. There role in behavior is not yet clear, but could be involved in the transport or availability of zinc. Recent research has shown zinc to be far more important than previously believed and low levels of zinc are associated with behavior disorders. Many of the patients of the Carl Pfeiffer Treatment Center suffer from behavior disorders. The most common ones are attention deficit hyperactive disorder (ADHD), oppositional defiant disorder (ODD), obsessive compulsive disorder (OCD), and conduct disorder (CD). These patients typically have a history of extensive counseling and multiple medications and many have experienced residential care. They represent a narrow and rather uncharacteristic segment of the general population. A high percentage of behavior disordered persons exhibit abnormal levels of copper, zinc, lead, cadmium, calcium, magnesium and manganese in blood, urine, and tissues, based on chemical analysis results from thousands of patients. With regard to zinc, this condition appears to involve a malfunction of the metal-binding protein metallothionein. Most of these patients have symptoms of zinc deficiency along with depressed levels of zinc in their blood plasma. The high incidence of zinc deficiency in assaultive young males was illustrated in a recent study1 which found elevated serum copper and depressed plasma zinc concentration, compared to normal controls. This study confirmed our clinical observations of zinc depletion in more than 4,000 behavior disordered patients. Our clinical observations and research have indicated that the copper/zinc ratio appears to be more decisively important than either of the individual metals alone. Zinc deficiency often results in elevated blood levels of copper, due to the dynamic competition of these metals in the body. Elevated blood copper has been associated with episodic violence, hyperactivity, learning disabilities, and depression. DIAGNOSIS OF ZINC DEFICIENCY Zinc deficiency is difficult to diagnose since no single laboratory test or combination of tests is decisive in every case. For example, blood levels are sometimes normal in zinc deficient persons due to homeostasis. Urine and hair tissue levels are often elevated in zinc deficiency because of "short circuiting" of zinc through the body and high rates of excretion. The two principal factors which lead our Center's physicians to a diagnosis of zinc deficiency are: 1) depressed plasma zinc, and 2) presence of clinical symptoms of zinc depletion which are alleviated by zinc supplementation2, 3, 4, 5, 6, and 7. Since zinc tolerance tests show plasma levels to be affected for 6 hours following zinc supplementation8 and 9, zinc supplements are avoided for 24 hours prior to sampling of plasma. The clinical symptoms associated with zinc deficiency or depletion include the following: * Eczema, acne, and/or psoriasis10, 11, 12, 13, and 14, * Poor wound healing, including leg ulcers and oral lesions15 and 16, * Lines of Beau on the fingernails17, * Growth retardation18, 19, 20, and 21, * Delayed sexual maturation22, * Hypogeusia or poor taste acuity23 and 24, and * Chronic immunodeficiency and frequent infections25 and 26. A "working diagnosis" of zinc deficiency can be made if clinical symptoms of zinc deficiency are clearly evident from the initial physical examination and medical history. Usually more than one or the above symptoms are present in zinc deficiency. This initial diagnosis is later supported or negated by laboratory analysis for plasma zinc along with observed response (or non-response) to zinc supplementation. The Carl Pfeiffer Treatment Center generally retests plasma zinc and evaluates symptoms after 4-6 months of treatment to determine if dosages need adjustment. TREATMENT OF ZINC DEPLETION Zinc depletion is corrected by supplementation with zinc (picolinate or gluconate) along with augmenting nutrients including L-cysteine, pyridoxine, ascorbic acid, and vitamin E. Manganese is also useful in promoting proper metallothionein function. If copper levels are elevated, effective treatment must also enhance the release of copper from tissues and copper excretion. L-cysteine helps mobilize and excrete copper while enhancing zinc absorption. Correction of zinc deficiency is best accomplished under the care of a physician or nutritionist who is experienced in metal metabolism disorders. Indiscriminant dosages of zinc to persons who do not need it can cause anemia and imbalanced trace metals. Treatment of mild or moderate zinc depletion can take months to complete. Some cases of severe zinc depletion require a year or more to resolve. Achievement of a proper zinc balance is slowed by growth spurts, injury, illness, or severe stress. In addition, persons with malabsorption or Type A blood respond to treatment more slowly. DISCUSSION We find that zinc deficient individuals usually respond well to inexpensive supplementation with zinc and augmenting nutrients. Many patients who previously experienced years of counseling, psychotherapy, aggressive medication programs, and/or residential treatment become greatly improved and respond to less intensive (and less expensive) therapies. Zinc deficiency can be corrected, but not cured. If treatment is discontinued, the prior zinc deficiency will reemerge with all symptoms gradually returning. Zinc deficiency, like diabetes, requires life long treatment. Fortunately, it is a simple, low cost, safe treatment. The Center involves the collaboration of biochemists and medical doctors. We believe that this coupling of disciplines provides an ideal capability for biochemical evaluation and medical treatment. REFERENCES 1. Walsh, W.J., Isaacson, H.R., Rahman, F., Hall, A., and Young, I.J., "Elevated blood copper:zinc ratios in assaultive young males", Neuroscience Annual Meeting, Abstract of Papers, Miami Beach, 1994 (In Print). 2. Cunnane, S.C., Zinc: Clinical and Biochemical Significance, CRC Press, Inc., Boca Raton, FL (1988). 3. Prasad, A.S., "Deficiency of zinc in man and its toxicity", in Trace Elements in Human Health and Disease, Vol. 1, Academic Press, New York, 1976. 4. Prasad, A.S., "Clinical and biochemical spectrum of zinc deficiency in human subjects", in Current Topics in Nutrition and Disease, Vol 6, New York, 1982. 5. Smith, J.C., Holbrook, J.T., and Danford, D.E., "Analysis and evaluation of zinc and copper in human plasma and serum", J. Amer. College of Nutr., 4:627-638 (1985). 6. Kleimola, V., et al, "The zinc, copper, and iron status in children with chronic diseases", in Trace Element Analytical Chemistry in Medicine and Biology, Walter de Gruyter, New York (1983). 7. Reding, P., DuChateau, J., and Bataille, C., "Oral zinc supplementation improves hepatic encephalopathy", Lancet, ii, 493 (1984). 8. Pohit, J., Saha, K.C., and Pal, B., "A zinc tolerance test", Clin. Chim. Acta, 114: 279 (1981). 9. Pecoud, A., Donzel, P., and Schelling, J.L., "Effects of foodstuffs on the absorption of zinc sulphate", Clin. Pharmacol. Ther., 17, 469 (1975). 10. Molokhia, M.M. and Portnoy, B., "Zinc and copper in dermatology", in Zinc and Copper in Medicine, Charles C. Thomas, Springfield, IL (1980). 11. Schmidt, K., et.al., "Determination of trace element concentrations in psoriatic and non-psoriatic scales with special attention to zinc", in Trace Element Analytical Chemistry in Medicine and Biology, Vol. 1, Walter de Gruyter, New York (1980). 12. McMillan, E.M., and Rowe, D., "Plasma zinc in psoriasis. Relation to surface area involvement", Br. J. Dermatol., 108, 301 (1983). 13. Ecker, R.J. and Schroeder, A.L., "Acrodermatitis and acquired zinc deficiency", Arch. Dermatol., 114: 937 (1978). 14. Withers, A.F., Baker, H., and Musa, M, "Plasma zinc in psoriasis", Lancet, ii: 278 (1968). 15. Van Rij, A.M., "Zinc supplements in surgery", in Zinc and Copper in Medicine, Charles C. Thomas, Springfield, IL (1982). 16. Henzel, J.H., et al., "Zinc concentrations within healing wounds: significance of post-operative zincuria on availability and requirements during tissue repair", Arch. Surg., 349: 357 (1970). 17. Weismann, K., "Lines of Beau: Possible markers of zinc deficiency", Acta Dermatol. Venereol., 57: 88 (1977). 18. Collipp, P.J., et al., "Zinc deficiency: Improvement in growth and growth hormone levels with oral zinc therapy", Ann. Nutr. Metab., 26: 287 (1982). 19. Hambridge, K.M., and Walravens, P.A., "Zinc deficiency in infants and preadolescent children", in Trace Elements in Human Health and Disease, Vol. 1, Prasad, A.S. and Oberleas, D., Eds., Academic Press, New York (1976). 20. Golden, B.E. and Golden, M.H.N., "Effect of zinc supplementation on the dietary intake, rate of weight gain and energy cost of tissue deposition in children recovering from severe malnutrition", Am. J. Clin. Nutr., 34: 900 (1981). 21. Laditan, A.O. and Ette, S.I., "Plasma zinc and copper during the acute phase of protein-energy malnutrition (PEM) and after recovery", Trop. Geogr. Med., 34: 77 (1982). 22. Sandstead, H.H., Prasad, A.S., et al., "Human zinc deficiency, endocrine manifestations, and response to treatment", Amer. J. Clin. Nutr., 20:422 (1967). 23. Heinkin, R.I., and Bradley, D.F., "Hypogeusia corrected by nickel and zinc", Life Sci., 9: 701 (1970). 24. Sprenger, K.B.G. et al., "Improvement of uremic neuropathy and hypogeusia by dialysate zinc supplementation: a double-blind study", Kidney Int., Suppl. 16: 5315 (1983). 25. Cunningham-Rundles, C., et al., "Zinc deficiency, depressed thymic hormones and T-lymphocyte dysfunction in patients with hypogammaglobulinemia", Clin. Immunol. Immunopathol., 21: 387 (1981). 26. Good, R.A., et al., "Zinc and immunity", in Clinical, Biochemical, and Nutritional Aspects of Trace Elements, Prasad, A.S. Ed., Alan R. Liss, New York (1982). Health Research Institute Pfeiffer Treatment Center HRI Pharmacy 4575 Weaver Parkway - Warrenville, IL 60555-4039 (630) 505-0300 - (630) 836-0667 fax Questions or Comments:info@HRIPTC.org | Home Page | Services | Pharmacy | Research | Education | Patient Info | Directions | All contents Copyright (c) 2004 Health Research Institute. All rights reserved. HRI is a Not-for-Profit 501c3.

Vitamin B6 Imbalance

Proper Name: Pyridoxine Hydrochloride Common Name: Vitamin B6 Evidence of Efficacy: statement to the effect of Vitamin B6 deficiency or imbalance plays a role in the symptoms of mood disorders. Observational and experimental studies have shown an association between vitamin B6 and aggression1, anxiety2,3,4, ADHD5,6,7,8,9,10,11,12, bipolar disorder13,14, depression15, 16 ,17 ,18 ,19 ,20 ,21 ,22 ,23 ,24 ,25 ,26, obsessive compulsive disorder27,28, premenstrual syndrome29, 30, 31, 32, 33,3 4,3 5,36 ,37, 38, ,39 ,40, 41, 42,43 ,44, 45, 46, 47, 48, 49, 50 ,5 1,52, 53,and schizophrenia54, 55, 56, 57, 58, 59,6 0,6 1,62 ,63 ,64 .65 References: 1. Noted in McLaren DS. Clinical manifestations of nutritional disorders, in ME Shils, VR Young, Eds. Modern Nutrition in Health and Disease, Seventh Edition. Philadelphia, Lea & Febiger, 1988. 2. Heseker H, Kubler W, Pudel V, Westenhoffer J. Psychological disorders as early symptoms of a mild-moderate vitamin deficiency. Ann N Y Acad Sci 669:352-7, 1992. 3. Hoes MJ et al. Hyperventilation syndrome, treatment with L-tryptophan and pyridoxine; Predictive value of xanthurenic acid excretion. J Orthomol Psychiatry 10(1):7-15, 1981. 4. Buist RA. Anxiety neurosis: The lactate connection. Int Clin Nutr Rev 5:1-4, 1985. 5. Coleman M et al. Serotonin in Down’s syndrome. Amsterdam, North Holland, 1973. 6. Kleijnen J, Knipschild P. Niacin and vitamin B6 in mental functioning: a review of controlled trials in humans. Biol Psychiatry 29(9):931-41, 1991. 7. Haslam RH, Dalby JT. Blood serotonin levels in the attention-deficit disorder. Letter. N Engl J Med 309(31):1328-9, 1983. 8. Brenner A. The effects of megadoses of selected B complex vitamins on children with hyperkinesis: Controlled studies with long-term follow-up. J Learn Disabil 15(5):258-64, 1982. 9. Klieger JA, Altshuler CH, Krakow L, Hollister L. Abnormal pyridoxine metabolism in toxemia of pregnancy. Ann N Y Acad Sci 166:288-96, 1969. 10. Coleman M et al. A preliminary study of the effect of pyridoxine administration in a subgroup of hyperkinetic children: A double-blind crossover comparison with methylphenidate. Biol Psychiatry 14(5):741-51, 1979. 11. Brenner A, Wapnir R. A pyridoxine-dependent behavioral disorder unmasked by Isoniazid. Am J Dis Child 132:773-6, 1978. 12. Bhagavan HN et al. The effect of pyridoxine hydrochloride on blood serotonin and pyridoxal phosphate contents in hyperactive children. Pediatrics 55:437-41, 1975. 13. Moller SE et al. Tryptophan availability in endogenous depression – relation to efficacy of L-tryptophan treatment. Adv Biol Psychiatry 10:30-46, 1983. 14. The pharmacokinetics of oral L-tryptophan: Effects of dose and concomitant pyridoxine, allopurinol or nicotinamide administration. Adv Biol Psychiatry 10:67-81, 1983. 15. Noted in McLaren DS. Clinical manifestations of nutritional disorders, in ME Shils, VR Young, Eds. Modern Nutrition in Health and Disease, Seventh Edition. Philadelphia, Lea & Febiger, 1988. 16. Bell I et al. Complex vitamin patterns in geriatric and young adult inpatients with major depression. J Am Geriatr Soc 39:252-7, 1991. 17. Stewart TW, Harrison W, Quitkin F, et al. Low B6 levels in depressed outpatients. Biol Psychiatry 19(4):613-16, 1984. 18. Russ CS et al. Vitamin B6 status of depressed and obsessive-compulsive patients. Nutr Rep Int 27(4):867-73, 1983. 19. Carney MW, Ravindran A, Rinsler MG, et al. Thiamine, riboflavin and pyridoxine deficiency in psychiatric inpatients. Br J Psychiatry 141:271-2, 1982. 20. Carney MW, Williams DG, Sheffield BF. Thiamin and pyridoxine lack in newly-admitted psychiatric patients. Br J Psychiatry 135:249-54, 1979. 21. Nobbs B. Pyridoxal phosphate status in clinical depression. Letter. Lancet i:405, 1974. 22. Bermond P. Therapy of side effects of oral contraceptive agents with vitamin B6. Acta Vitaminol Enzymol 4(1-2):45-54, 1982. 23. Adams PW, Wynn V, Rose DP, et al. Effect of pyridoxine hydrocholoride (vitamin B6) upon depression associated with oral contraception. Lancet ii:899-904, 1973. 24. Adams PW, Wynn V, Seed M, Folkard J. Vitamin B6, depression, and oral contraception. Letter. Lancet ii:516-17, 1974. 25. Benton D, Haller J, Fordy J. Vitamin supplementation for 1 year improves mood. Neuropsychobiology 32(2):98-105, 1995. 26. Hallert C, Astrom J, Walan A. Reversal of psychopathology in adult coeliac disease with the aid of pyridoxine (vitamin B6). Scand J Gastroenterol 18(2):299-304, 1983. 27. Yaryura-Tobias JA. Presentation to the Third World Congress of Biological Psychiatry, Stockholm – reported in Clinical Psychiatrty News. September, 1981. 28. Yaryura-Tobias JA, Bhagavan HN. L-tryptophan in obsessive-compulsive disorders. Am J Psychiatry 134(11):1298-9, 1977. 29. Mira M, Stewart PM, Abraham SF. Vitamin and trace element status in premenstrual syndrome. Am J Clin Nutr 47(4):636-41, 1988. 30. Gallant MP, Bowering J, Short SH, et al. Pyridoxine and magnesium status in women with premenstrual syndrome. Nutr Res 7:243-52, 1987. 31. Stewart A. Clinical and biochemical effects of nutritional supplementation on the premenstrual syndrome. J Reprod Med 32(6):435-41, 1987. 32. Richie CD, Singkamani R. Plasma pyridoxal-5’-phosphate in women with the premenstrual syndrome. Hum Nutr Clin Nutr 40C:75-80, 1986. 33. Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology 35:1466-8, 1985; Waterston JA, Gilligan BS. Pyridoxine neuropathy. Med J Aust 146:640-2, 1987. 34. Guy Abraham – personal communication reported in Piesse JW. Nutrition factors in the premenstrual syndrome: A review. Int Clin Nutr Rev 4(2):54-81, 1984. 35. Abraham GE. Nutrition and the premenstrual tension syndromes. J Appl Nutr 36(2):103-17, 1985; Hargrove JT, Abraham GT. Effect of vitamin B6 on infertility in women with the premenstrual syndrome. Infertility 2:315: 1979. 36. Leklem JE. Vitamin B6: The pill, pregnancy and premenstrual syndrome. Abstract. J Am Coll Nutr. 11(5):624, 1992. 37. Kleijnen J, Ter Riet G, Knipschild P. Vitamin B6 in the treatment of premenstrual syndrome – a review. Br J Obstet Gynaecol 97(9):847-52, 1990. Berman MK et al. Vitamin B-6 in premenstrual syndrome. J Am Diet Assoc 90(6):859-61, 1990. 38. Doll H, Brown S, Thurston A, Vessey M. Pyridoxine (vitamin B6) and the premenstrual syndrome: A randomized crossover trial. J R Coll Gen Pract 39:364-8, 1989. 39. Brush MG, Bennett T, Hansen K. Pyridoxine in the treatment of premenstrual syndrome: A retrospective survey in 630 patients. Br J Clin Pract 42(11):448-52, 1988. 40. Kendall KE, Schnurr PP. The effects of vitamin B6 supplementation on premenstrual symptoms. Obstet Gynecol 70(2):145-9, 1987. 41. David R. Rubinow, biological psychiatry branch, National Institute of Mental Health (USA) – quoted by Clin Psychiatry News, December, 1987. 42. Hagen I et al. No effect of vitamin B-6 against premenstrual tension: A controlled clinical study. Acta Obstet Gynecol Scand 64:667, 1985. 43. Williams MJ, Harris RI, Dean BC. Controlled trial of pyridoxine in the premenstrual syndrome. J Int Med Res 13:174-9, 1985. 44. Barr W. Pyridoxine supplements in the premenstrual syndrome. Practitioner 228:425-7, 1984. 45. Mattes JA, Martin D. Pyridoxine in premenstrual depression. Hum Nutr Appl Nutr 36(2):131-3, 1982. 46. Abraham GE, Hargrove JT. Effect of vitamin B-6 on premenstrual symptomatology in women with premenstrual tension syndrome: A double-blind crossover study. Infertility 3:155-65, 1980. 47. Day JB. Clinical trials in the premenstrual syndrome. Curr Med Res Opin (Suppl 6) 5:40-5, 1979. 48. Kerr GD. The management of the premenstrual syndrome. Curr Med Res Opin (Suppl 4) 4:29-34, 1977. 49. Stokes J, Mendels J. Pyridoxine and premenstrual tension. Letter. Lancet i:1177-8, 1972. 50. Piesse JW. Nutrition factors in the premenstrual syndrome. Int Clin Nutr Rev 4(2):54-81, 1984. 51. Lee CM, Leklem JE. Blood magnesium constancy with vitamin B-6 supplementation in pre- and post-menopausal women. Ann Clin Lab Sci 14(2):151-4, 1984. 52. Abraham GE et al. Effect of vitamin B6 on plasma and red blood cell magnesium levels in premenopausal women. Ann Clin Lab Sci 11(4):333-6, 1981. 53. Holley J et al. Effect of vitamin B6 nutritional status on the uptake of [3H]-oestradiol into the uterus, liver and hypothalamus of the rat. J Steroid Biochem 18:161-6, 1983. 54. Pfeiffer CC, Audette L. Pyroluria – Zinc and B6 deficiencies. Int Clin Nutr Rev 8(3):107-10; 1988. 55. Pfeiffer CC. The schizophrenias ’76. Biol Psychiatry 2:773-5, 1976. 56. Pfeiffer CC, Bacchi D. Copper, zinc, manganese, niacin and pyridoxine in the schizophrenias. J Appl Nutr 27:9-39, 1975. 57. Pfeiffer CC. Observations on trace and toxic elements in hair and serum. J Orthomol Psychiatry 3(4):259-64, 1974. 58. Cruz R, Vogel WH. Pyroluria: A poor marker in chronic schizophrenia. Am J Psychiatry 135(10):1239-40, 1978. 59. Parry GJ. Sensory neuropathy with low-dose pyridoxine. Neurology 35:1466:8, 1985. 60. Kleijnen J, Knipschild P. Niacin and vitamin B6 in mental functioning: a review of controlled trials in humans. Biol Psychiatry 29(9):931-41, 1991. 61. Brooks SC et al. An unusual schizophrenic illness responsive to pyridoxine HCl (B6) subsequent to phenothiazine and butyrophenone toxicities. Biol Psychiatry 18(11):1321-8, 1983. 62. Yamauchi M. Effects of L-dopa and vitamin B6 on electroencephalograms of schizophrenic patients: A preliminary report. Folia Psychiatrica et Neurologica Japonica 30(2):121-51, 1976. 63. Sandyk R, Pardeshi R. Pyridoxine improves drug-induced parkinsonism and psychosis in a schizophrenic patients. J Neurosci 53(3-4):225-32, 1990. 64. Petrie WM, Ban TA, Anath JV. The use of nicotinic acid and pyridoxine in the treatment of schizophrenia. Int Pharmacopsychiatry 16(4):245-50, 1981. 65. Ananth JV, Ban TA, Lehmann HE. Potentiation of therapeutic effects of nicotinic acid by pyridoxine in chronic schizophrenics. Can Psychiatr Assoc J 18:377-83, 1973.

Common Treatments: Inositol

	Inositol, an 'unofficial' B-vitamin, is a cyclic 6-carbon compound quite similar to glucose. In animal cells, it occurs as a component of phospholipids and it stored predominantly in the brain, spinal cord nerves, cerebral spinal fluid, skeletal muscle, and heart muscle. The human body contains more inositol than any other vitamin except niacin. Source Inositol is available from both plant and animal sources. The plant form in which inositol is available is phytic acid, which can bind with minerals and so affect their absorption negatively. The action of the intestinal bacteria liberates inositol from phytic acid, which is found in citrus fruits, nuts, seeds and legumes, wheat germ, brewers yeast, bananas, liver, beef brains and heart, whole grains such as brown rice, oat flakes, unrefined molasses, raisins and vegetables such as cabbage. Function; Reasons For Use Inositol is simply a hexane molecule (ringed structure of 6 carbons) with 6 hydroxyl groups (OH) attached. Inositol is used by the body to complete the synthesis of certain phospholipids, important components of every cell membrane. Inositol is also used to make Inositol Triphosphate (IP3), an important secondary messenger in various cell signaling events. Inositol is also lipotropic, meaning it associates with lipids (fats). Its lipotropic characteristics have been used to help move fatty material from the liver, into the intestines where they can be effectively removed with fiber. Inositol works closely with choline as one of the primary components of the cell membrane. It is also needed for growth and survival of cells in bone marrow, eye membranes, and the intestines. Inositol appears to be a precursor of the phosphoinosities (compounds that may be important in hormonal action) especially in the brain. Proper action of several brain neurotransmitters, such as acetylcholine and serotonin, require inositol. Inositol encourages hair growth and can help prevent baldness. Like choline, inositol helps to move fat out of the liver, and helps prevent serious liver disorders, as well as disorders involving high cholesterol. Serotonin and acetylcholine, two neurotransmitters, both depend upon inositol, and supplementation can therefore assist in the reduction of depression and panic attacks. A reduction in brain inositol levels may induce depression as evidenced by low inositol levels in the cerebrospinal fluid of patients with depression. In a 1-month, double-blind, placebo-controlled study of 28 patients with depression, inositol demonstrated therapeutic results similar to tricyclic antidepressants without the side-effects. Additional studies have revealed that inositol supplementation is an effective treatment in panic and obsessive compulsive disorders. Loss of inositol from nerve cells is the primary reason for diabetic neuropathy, so inositol supplementation can assist in improving this condition. Phytic acid, the plant source of inositol, has been shown to have anticancer properties, which may be one reason why a high-fiber diet protects against many cancers. Inositol also has a prominent calming effect on the central nervous system, so it may be helpful to those with insomnia. Studies on brain waves have shown that it has an effect similar to that of librium or valium. It can gradually lower blood pressure, and can be helpful in cases of schizophrenia, hypoglycemia, and those with high serum copper and low serum zinc levels. Because it stimulates muscles of the alimentary canal, inositol is helpful in cases of constipation. It can also induce labor contractions in pregnant women. Intake of caffeine is known to deplete the bodies supply of inositol. Directions The RDA is 100mg per day, but be aware that this dosage is the minimum that you require to ward off deficiency of this particular nutrient. In the therapeutic use of this nutrient, the dosage is usually increased considerably, but the toxicity level must be kept in mind. It is best used with choline, which should be taken in the same amount as inositol. It is best to take the entire B-group vitamins with it. Vitamin E, vitamin C as well as folic acid and linoleic acid are thought to increase the functioning of inositol. Side-Effects Although no toxic effects are known, diarrhea has been noted with the intake of very high dosage.

Methylation Overview

http://www.alternativementalhealth.com/articles/pfeiffer.htm Methylation Effective "markers" for methylation are (1) whole blood histamine (ref. levels 40-70 mcg/dL), available from Quest and LabCorp; (2) Absolute Basophils (ref. levels 30-50), available from Direct Healthcare, Inc in the Chicago area. One-carbon (methyl) groups are involved in numerous important biochemical reactions in the body, including genetic expression, neurotransmitter synthesis and metabolism, etc. Methylation (more properly, the methyl/folate ratio) is a major factor in the rate-limiting step (the tetrahydrobiopterin reaction) in the synthesis of serotonin, dopamine, and norepinephrine in the brain. Undermethylated persons tend to be depleted in these 3 neurotransmitters, and the opposite is true for overmethylation. Inositol is especially helpful for undermethylated persons (for example most persons with OCD), but can cause negative side effects in those who are overmethylated. Since Inositol is one of the primary second messengers in neurotransmission, it's surprising is isn't more commonly used. It's especially useful in reducing anxiety and enhancing sleep. If you can confirm the presence of undermethylation, the patient should benefit from (1) aggressive doses of l-methionine, calcium, magnesium, along with augmenting nutrients zinc, B-6, Inositol, Vitamin A & C and (2) strict avoidance of folic acid, choline, DMAE, and copper supplements. A quick way to test for need for methylation therapy is to carry out a cautious trial of SAMe. Within a week or two you should have your answer. If she clearly is improving on the SAMs (which is frightfully expensive)..... you can get usually the same benefits (albeit more slowly) using methionine plus calcium, magnesium, and B-6. This should be side-effect free unless (a) the methylation is begun too abruptly or (b) the patient has a rare genetic enzyme disorder which disrupts the SAM cycle. We've found that direct methylation is usually more successful than tinkering with the SAM cycle. The primary way humans receive most of their methyl groups is from dietary methionine. It's often hard to improve on Mother Nature. (Jan 20, 2003) Aggressive methylation therapy can be very successful, but usually involves a very slow response. Typically, treatment with methionine, calcium, magnesium, B-6, etc requires about 2 months before the patient before any progress is evident --- and 6-12 months are required for all of the benefits to be attained. Please note that whole blood histamine is a marker for innate methylation tendency, but is not an indicator of wellness or the degree to which undermethylation has been overcome. Undermethylated patients can become quite well without their histamine lab results changing at all. One way to speed up the process of recovery is to use SAMe supplements in the beginning. Undermethylated patients usually report nice progress after the first week or two. SAMe is quite expensive, and can be gradually replaced by methionine after a couple of months. Nearly all severely undermethylated persons have low serotonin levels and present with a history of depression, internal anxiety, and OCD. Many have a history of perfectionism and high accomplishment in the early years. Unfortunately this population also has a tendency for non-compliance with any treatment. The late and great Carl Pfeiffer would occasionally resort to use of the anti-histamines Benedryl or Dilantin in high-histamine persons who were slow to respond. Avoidance of folate supplements is essential for most undermethylated persons, an exception being autism. Some practitioners like to tinker with the SAM cycle to promote conversion of homocysteine to methionine, but this can deplete the cystathione pathway and result in deficiencies of glutathione, cysteine, etc. Some persons have a genetic enzyme weakness which can disrupt the SAM cycle Undermethylated adults typically require 2,000 - 3,000 mg/day of methionine for several months to see good results. Also, augmenting nutrients such as calcium, magnesium, B-6, and zinc are essential. TMG generally provides some benefits to undermethylated persons, but tends to make oxidative stress protections worse by diminishing the amount of homocysteine which converts via the cystathione pathway of the SAM cycle. TMG certainly is a promising nutrient for such persons, and adding some cysteine or glutathione can overcome the cystathione pathway deficit. Personally, I believe the use of SAMe is the quickest way to help an undermethylated, high-histamine person. Most OCD patients (both obsessive thoughts AND compulsive actions) exhibit undermethylation and associated low levels of serotonin, dopamine, and norepinephrine. Choline is anti-dopaminergic and often makes OCD patients worse. Generally OCD patients respond nicely to methionine, SAMe, calcium, magnesium, B-6, inositol, TMG, and zinc. Most OCD patients get worse if given supplements of DMAE, choline, copper, or folic acid. 500 to 1000 mg/day of inositol will probably be needed to provide good response. (9 Jan, 2003) Over-methylation Conditions associated with overmethylation: Anxiety/Panic disorders, anxious depression, hyperactivity, learning disabilities, low motivation, "space cadet" syndrome, paranoid schizophrenia, hallucinations. High in serotonin, dopamine, and norepinephrine. Many persons who suffer from anxiety along with depression are over-methylated. Methyl is an important chemical group consisting of one carbon and three hydrogen atoms (CH3). Over-methylation (too many added methyl groups) results in excessive levels of the neurotransmitters dopamine, norepinephrine, and serotonin. Typical symptoms include chemical and food sensitivities, underachievement, upper body pain, and an adverse reaction to serotonin-enhancing substances such as Prozac, Paxil, Zoloft, St. John’s Wort, and SAMe6. They have a physical tendency to be very depressed in folates (a form of folic acid), niacin and Vitamin B-12, and biochemical treatment focuses on supplementation of these nutrients. These persons are also overloaded in copper and methionine (a sulfur-containing amino acid) and supplements of these nutrients must be strictly avoided. Choline Phosphatidyl choline is also very effective in protecting DHA/EPA from free radical oxidative stress..... another good reason to take it. In my experience DMAE is especially effective for increasing acetylcholine levels in the brain, since it passes the blood/brain barrier & converts to choline. I like to use this for overmethylated persons who have excessive dopamine and norepinephrine levels. However, enhancing acetylcholine activity must be avoided in persons who genetically are overloaded in this NT. Choline, DMAE, and phosphatidyl choline can cause nasty symptoms in these persons (about 10% of the population). Persons with innately high acetylcholine levels tend to be very tense and sometimes nearly catatonic. They have very high anxiety, but usually keep it inside. They also usually have a history of seasonal allergies, perfectionism, and OCD tendencies. Increasing acetylcholine activity can be a disaster for them. Those deficient in acetylcholine usually present with nervous legs, are prone to pacing, and are quite voluble. Their misery is plain to everyone. Therapies to increase acetylcholine activity can be extraordinarily helpful for this population. (March 6, 2003) Inositol can cause negative side effects in those who are overmethylated. Histapenia (Low Histamine - over-methylated) Low-histamine depressives are usually nervous, anxious individuals who are prone to paranoia and despair. No seasonal allergies, but many food allergies and chemical sensitivity. Low libido. Obsessions but not compulsions. Heavy body hair. Nervous legs. Grandiosity. Many have a history of hyperactivity, learning disabilities and underachievement. They are over-methylated which results in elevated dopamine and norepinephrine levels. Treatment focuses on B3, C, B12, with about 2-4 months required for correction of the imbalance. Also DMAE, choline, manganese, zinc, omega-3 essential oils, C and E. They should avoid methionine, SAMe, Inositol, TMG and DMG. One thing that is absolutely certain is that methionine and/or SAMe usually harm low-histamine (overmethylated persons). The generalization that perfume and other chemical sensitivities are associated with overmethylation, low blood histamine, and elevated norepinephaine. is exactly that...a general rule with many exceptions. However, the correlation seems to be above 90 percent in the case of perfume sensitivity. Whenever a patient enters our clinic wearing a mask to filter out inhalant chemicals, we immediately suspect the overmethylation syndrome. The chemical testing usually confirms this diagnosis, but there definitely are a few persons who have severe perfume sensitivity for other reasons. We've evaluated about 19,000 persons, including about 1500 with anxiety disorder or panic disorder. Hundreds of these patients reported sensitivity to perfumes. Nearly 90 percent of the perfume-sensitive group were overmethylated, and reported multiple chemical and food sensitivities. usually in the absence of seasonal inhalant allergies. Perfume sensitivity is a classic symptom of these high nonepinephrine persons, who usually respond beautifully to folate/B-12 therapy [1 Dec -03] SAMe is likely to cause great worsening of symptoms, including mania, if given to an OVER-methylated person. The incidence of overmethylation in our patient database of 1,500 bipolar cases is about 18%. Bipolar disorder is not a single condition, but a collection of very different biochemical disorders under the same umbrella diagnosis. SAMe works great for truly undermethylated patients, but all hell breaks out if given to someone who is overloaded (genetically) with methyl groups. The right way to do this is to (a) first determine the person's innate methylation tendency & then (b) act accordingly. (Jan 31, 2003) Histadenia - (High Histamine - Under-methylation) Elevated histamine and/or elevated basophils indicate undermethylation. Review of symptoms and medical history can bolster the diagnosis. For example, most undermethylated persons exhibit seasonal allergies, perfectionism, strong wills, slenderness, OCD tendencies, high libido, etc. (Overmethylated persons generally exhibit anxiety, absence of seasonal allergies, presence of food/chemical sensitivities, dry eyes, low perspiration, artistic/music interests/abilities, intolerance to Prozac and other SSRI's, etc.) Low in serotonin, dopamine, and norepinephrine. Conditions associated with undermethylation: Anorexia, Bulemia, shopping/gambling disorders, depression, schizo-affective disorder, delusions, oppositional-defiant disorder, OCD. Many patients with obsessive-compulsive tendencies, "oppositional-defiant disorder," or seasonal depression are under-methylated, which is associated with low serotonin levels. They generally exhibit seasonal allergies and other distinctive symptoms and traits. They have a tendency to be very depressed in calcium, magnesium, methionine, and vitamin B-6 with excessive levels of folic acid. These under-methylated persons can have a positive effect from Paxil, Zoloft, and other serotonin-enhancing medications, although nasty side effects are common. A more natural approach is to directly correct the underlying problem using methionine, calcium, magnesium, and B-6. SAMe, St. John’s Wort, Kava Kava, and inositol (a natural sugar alcohol) are also very useful in treating these individuals. 40-70 is optimum histamine range for mental health considerations. Histamine is an important neurotransmitter which affects human behavior. This syndrome often involves seasonal variations in depression, obsessive-compulsive behavior, inhalant allergies, and frequent headaches. In severe cases involving psychosis, the dominant symptom is usually delusional thinking rather than hallucinations. They tend to speak very little and may sit motionless for extended periods. They may appear outwardly calm, but suffer from extreme internal anxiety. Most OCD patients with both obsessive thoughts and compulsive actions are in this category. Associated with under-methylation, which results in low levels of important neurotransmitters such as serotonin, dopamine and norepinephrine. Treatment focuses on the use of antifolates such as calcium, methionine, SAMe, magnesium, zinc, TMG, omega-3 essential oils, B6, inositol, and A, C and E. The dose of inositol is 500 to 1000mg. Choline is anti-dopaminergic and often makes undermethylated patients worse. Also bad are DMAE, copper and folic acid. Three to six months of nutrient therapy are necessary to correct this chemical imbalance. Symptoms will return if treatment is stopped. Two good labs for whole blood histamine are LabCorp and Quest. Also use a special absolute basophil count as a methlyation marker. The count must be direct and not differential. Alcian blue dye is the preferred staining agent. Best lab for this test is Direct Healthcare Access in Glenview IL 847 299 2440 One thing that is absolutely certain is that methionine and/or SAMe are wonderful for high-histamine (undermethylated) persons. Histadelic (undermethylated) persons thrive on methionine, SAMe, Ca and Mg..... but get much worse if they take folates & B-12 which can increase methyl trapping. The bottom line is that undermethylated persons generally exhibit very elevated folate levels.... and these persons get worse if additional folate is given SAMe is very promising for undermethylated persons and a bad idea for those who suffer from a genetic tendency for overmethylation. I don't particularly like the "allopathic" method you referred to which is simply trial & error. SAMe can do great harm if given to the wrong person. I hate going to funerals. (17 Dec, 2002) The mechanisms of action of SAMe and TMG are quite different. Most of our methyl groups come from dietary methionine. The methionine is converted to SAMe in a reaction with magnesium, ATP, methionine-adenosyl-transferase, and water. SAMe is a relatively unstable carrier of methyl groups and is the primary source of methyl for most reactions in the body. Once the methyl group has been donated, the residual molecule is s-adenosyl-homocysteine which converts to homocysteine. TMG (betaine) is a biochemical which can donate a methyl group to homocysteine, thus converting it back to methionine. The TMG route is secondary to the 5-methyl-tetrahydrofolate/B-12 reaction which the primary route for restoring methionine. Methionine and SAMe supplements directly introduce new methyl groups into the body. TMG can provide a methyl group only to the extent that there is insufficient folate/B-12 to do the job. In some persons, the methylation effect of TMG is very minimal. In addition, persons who are undermethylated have a SAM cycle which is "spinning very slowly", much like a superhighway with little traffic. The answer for them is NOT to more efficiently convert the small amount of homocysteine to methionine (using TMG), but rather to directly introduce more methionine or SAMe into the body. A small percentage of persons with sufficient dietary methionine cannot efficiently produce SAMe --- These persons need supplemental SAMe, and not methionine or TMG and are the exception to the rule. In most other cases, methionine supplements alone are sufficient. TMG is a great way to treat individuals with dangerously high homocysteine levels. TMG can be very useful in augmenting methionine therapy along with B-6/P-5-P , serine, etc. The challenge is to supply enough methyl groups to help the patient, without creating dangerously high levels of homocysteine. Use of TMG is an "insurance policy" against this happening. (Jan 22, 2003) OTHER Pyroluria A stress disorder characterized by pronounced mood swings, temper outbursts, anxious depression. Inability to eat breakfast, absence of dream recall and frequent infections. The biochemical signature of this disorder includes elevated urine kryptopyrroles, a double deficiency of zinc and B-6, and low levels of arachidonic acid. Devastated by stresses including physical injury, emotional trauma, illness, sleep deprivation. Sensitivity to light and loud noises, dry skin, abnormal fat distribution, rage episodes, histrionic behavior. They also have low levels of arachidonic acid. Treatment centers on correcting a double deficiency of B-6, zinc essential fatty acids and augmenting nutrients. It is believed to result from abnormal hemoglobin synthesis which depletes the body of these nutrients. A positive response often occurs within the first seven days of treatment, with 1-2 months usually required for correction of the imbalance. 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.