The Role of Vitamins B3 and Cin the Treatment of Histadelia

Jonathan E. Prousky, B.P.H.E., B.Sc., N.D.;1 David W. Lescheid, B.Sc., N.D. (Cand)2

Suicidal depression, obsessive-compulsive rumination, mental fogginess, disperceptions, and hyperactivity (overarousal) characterize the psychiatric manifestations of hista-delia, a type of schizophrenia.1 The non-psychiatric clinical features of histadelia include: increased salivation, elevated metabolic rate, allergic symptoms, frequent headaches, diminished pain threshold, heightened sexual responsiveness (a greater ability to achieve orgasm), and strong cravings for sugar.2,3 Increased basophils (greater than 50 cells/mm3) and elevated blood histamine levels (greater than 70 ng/ ml) confirm the diagnosis of histadelia.4

The goal of orthomolecular treatment for this disorder is to restore blood hista-mine levels to normal. This can be achieved through dietary modifications (low protein and high fruit/vegetable diet), a combina-tion of various nutrients (calcium, methio-nine, zinc, and manganese), and sometimes the drug phenytoin (Dilantin).5 A low pro-tein diet reduces the amount of ingested L-histidine, which is a precursor to hista-mine. Calcium helps mobilize bodily stores of histamine, and also might increase hista-mine catabolism. Methionine lowers blood histamine by reacting with histamine to form N-methylhistamine, an inert methyl-ated ring structure. Zinc and manganese replenish possible deficiencies, and pheny-toin negates the compulsive behaviors and depression.

It has been proposed that the histadelic patient does not respond “to the classical meganutrient (B3, vitamin C) therapy.”6 This lack of response is confus-ing considering that thousands of schizo-

1.Assistant Professor of Clinical Medicine, The Canadian College of Naturopathic Medicine, 1255 Sheppard Ave. E. Toronto, ON, M2K 1E2 2.Clinical Intern, The Canadian College of Naturopathic Medicine. 1255 Sheppard Ave. E. Toronto, ON, M2K 1E2.

phrenic patients have benefited from taking megadoses of vitamins B3 and C.7 If 20% of all schizophrenics are thought to have histadelia,8 it is possible that favorable therapeutic responses to vitamins B3 and C have occurred among many histadelic pa-tients. The therapeutic potential of vita-mins B3 and C in the treatment of histadelia is clear given the biochemical functions of these vitamins.

Vitamin B3 and Histamine

Both forms of vitamin B3, nicotinic acid (niacin) and nicotinamide (niacina-mide), are necessary to counteract the clini-cal problems associated with high blood histamine. When histamine levels are in ex-cess, the enzyme nicotinamide-adenosine dinucleotidase (NADase) catalyzes the re-moval of a nicotinamide moiety from nico-tinamide-adenosine dinucleotide (NAD) and irreversibly replaces it with a molecule of histamine.9 The net effect of excess hista-mine would be increased production of his-tamine-adenosine dinucleotide (HAD), an inert compound devoid of the energetic prop-erties of NAD. Other conditions with an as-sociated NAD deficiency include alcoholism, drug addiction, violent behaviors, and schizo-phrenia.10

Using niacin to treat histadelia might seem contradictory considering it will aug-ment the release of histamine from basophils and tissue mast cells.11 However, there is evidence that the niacin flush is mediated by the release of prostaglandin D2 (PGD2) from dermal macrophages and not from degranulation of basophil and tis-sue mast cells.12,13 Further, Hoffer suggested that daily intake of niacin gradually lowers total body histamine by chronically deplet-ing storage levels.11 Niacin has a compli-cated mechanism of action that modulates histamine release, lowers total blood hista-mine, and increases the production of PGD2.

The amide form of vitamin B3 (nicotina-mide or niacinamide) does not directly pro-mote the degranulation of histamine contain-ing cells, deplete tissue stores, or increase PGD2 release. Nicotinamide might function primarily by reducing the histaminergic re-sponse to antigenic stimulation. Various in-vestigators have shown that certain foods, especially wheat and milk, can trigger schizo-phrenic-like symptoms in susceptible peo-ple.14-17 Specific protein fractions, derived from wheat and milk, might be responsible for the schizophrenic-like effects.18 Chronic release of histamine, in response to certain foods, might be a potential mechanism by which behavior is severely affected.19 Nicotinamide has been shown in vivo (guinea pigs) to reduce ana-phylactic reactions mediated by antigen in-halation. Antigen-antibody induced hista-mine release can therefore be suppressed by nicotinamide.9 Nicotinamide also has been demonstrated to prevent degranulation of mouse peritoneal mast cells after exposure to compound 40/80, a specific antigen mix-ture composed of aluminum hydroxide and egg albumin.9 Bekier and Maslinski hypoth-esized that nicotinamide might exert its antihistaminic actions in vivo (guinea pigs) by inhibiting the enzyme phosphodiesterase (PDE). Inhibition of PDE would increase cy-clic adenosine-3’, 5’-monophosphate (cAMP) and therefore, relax smooth muscles.20 Fur-ther, in vivo (guinea pigs)9 and in vitro (chopped guinea pig lung)21 studies demon-strated that nicotinamide inhibits the enzyme NADase. Inhibition of NADase enzyme activ-ity reduces HAD formation, an energetically inert molecule possibly implicated in the de-velopment of schizophrenia. The actions that vitamin B3 has upon histamine metabolism are summarized in Table 1 (below).

Histadelia is a clinical syndrome metabolically driven by elevated histamine levels and perhaps provoked by chronic food sensitivities in susceptible people. The follow-ing hypotheses might be proposed: (1) chronic use of nicotinic acid depletes tissue stores of histamine and lowers total blood histamine, (2) nicotinamide attenuates his-tamine release in response to antigen-anti-body interactions, inhibits mast cell degranu-lation, relaxes smooth muscles and prevents the formation of excess of HAD and (3) both forms of vitamin B3 might be essential in correcting the central defect of this disorder

- the NAD deficiency induced by the excess activity of NADase.

Vitamin C and Histamine

The exact biochemical mechanism underlying low plasma ascorbate levels and high blood histamine remains to be eluci-

Table 1. Biochemical interactions between vitamin B3 and histamine.

Substance EvidenceLowers Blood Histamine

Nicotinic Acid anectdotal (humans)depletes storage sites with chronic use

Nicotinamide in vivo (guinea pigs)reduces antigen-mediated anaphylactic reactions and inhibits both PDE and NADase

in vitro reduces histamine degranulation in response to antigen and inhibits NADase Nicotinic acid and theoretical inhibits NADase Nicotinamide

dated. However, in vitro studies have shown that the activity of enzyme histidine decar-boxylase (HDC) increases in a medium deficient in ascorbic acid.22 HDC is the en-zyme that converts L-histidine to hista-mine.23 Another in vitro study demon-strated that ascorbic acid increases hista-mine degradation by promoting the forma-tion of a mono-oxygenated form of N-acetylhistamine (NAH).24 NAH is one of the byproducts of histamine catabolism, and is produced by the action of N-acetylhistamine deacetylase, the rate-lim-iting enzyme in its synthesis.23 Further, it has been suggested that excess histamine binds the copper site of monoamine oxi-dase (MAO). The function of histamine-bound MAO accelerates the oxidation of ascorbate instead of eliminating dopamine and other monoamines.25 This hypothesis would support the link between reduced vi-tamin C levels and schizophrenia, as well as the high dopamine levels potentially linked to this disorder.

Vitamin C also has been shown to lower blood histamine and indirectly aug-ment neutrophil chemotaxis in healthy human subjects.26 Johnston et al demon-strated an association between low plasma ascorbate levels and elevated blood hista-mine in humans.27 Suboticanec et al. deter-mined that schizophrenic patients have lower fasting plasma ascorbate levels com-pared to controls, despite adequate dietary intake of ascorbic acid.28,29 Further, schizo-phrenic patients (in contrast to control subjects) exhibited a greater reduction in the urinary excretion of vitamin C when measured 6-hours after an oral loading dose of ascorbic acid.28,30 These findings suggest that schizophrenia might be char-acterized by impaired ascorbic acid me-tabolism that might lead to increased blood histamine levels. Optimal doses of ascorbic acid might be necessary to combat the ill effects of histadelia. Table 2 (below) sum-marizes the ways in which vitamin C low-ers blood histamine.

Histamine and Schizophrenia

The histadelic-type of schizophrenia is marked by disordered histamine metabo-lism. Kobayashi and Freeman demon-strated that higher amounts of conjugated imidazole acetic acid appear in the urine of schizophrenics.31 Imidazole acetic acid is a breakdown product of histamine ca-tabolism.21 Heleniak and O’Desky hypoth-esize that defects in the histaminergic sys-tem play a primary role in the etiology of schizophrenia.32 It has been suggested that histamine functions as a mast cell stabi-lizer, acting in a paracrine fashion to down regulate its own release.33 In the histadelic

Table 2. Biochemical interactions between vitamin C and histamine.

Substance EvidenceLowers Blood Histamine

Vitamin C in vitrolikely inhibits HDC through correcting deficiency of ascorbic acid, and increases histamine catabolism

in vivo (humans)correcting deficiency lowers blood histamine through an unknown mechanism of action

patient there is probably a defect in the negative feedback circuit that inhibits his-tamine release and/or there might be a problem with the catabolism of histamine. Future case reports and studies should help to clarify the exact defect responsible for the excess histamine.

Genetic studies have been inconclu-sive. Orange et al found an increased inci-dence for the H2R649G allele (histamine type-2 receptor gene; H2 receptor gene) in schizophrenics compared to normal sub-jects.34 However, a follow-up study found no increased allelic variations in the H2 receptor gene amongst schizophrenic pa-tients when compared to controls.35 A clini-cal research review of the H2 receptor an-tagonist drug, Famotidine, demonstrated that it is helpful in the management of schizophrenic symptoms. This suggests that Famotidine does bind H2 receptors and should be considered as an alternative when the usual antipsychotic agents have not been successful.36 Another study failed to demonstrate unique polymorphisms in the histamine N-methyltransferase (HNMT) gene of schizophrenic patients.37 All of the above findings imply that abnor-mal histamine metabolism is linked to schizophrenia; however, no current genetic evidence clearly establishes this link.

Conclusion

Optimal (megadose) amounts of vitamins B3 and C might be necessary treat-ments to correct the impaired histamine metabolism of the histadelic patient. The therapeutic use of these vitamins for histadelia contradicts the “preferred” treat-ment for this disorder as described by the late Carl C. Pfeiffer.5 In vivo and in vitro studies demonstrate that both of these nutrients can normalize blood histamine levels by influencing various biochemical functions. To date, it is not yet established that the histadelic patient is genetically predisposed to defects in the histaminer-gic system. The current evidence does sug-gest, however, that disordered histamine metabolism plays a central role in this spe-cific type of schizophrenia.

References

  1. Pfeiffer CC: Mental and Elemental Nutrients. New Canaan, CT. Keats Publishing, Inc. 1975; 399-400.

  2. Pfeiffer CC: Nutrition and Mental Illness. Rochester, VT. Healing Arts Press. 1987;28-29.

  3. Jackson JA, Riordan HD, Neathery S, et al: His-tamine levels in health and disease. J Orthomol Med, 1998; 13(4): 236-240.

  4. Pfeiffer CC, Mailloux R, Forsythe L: The Schizophrenias: Ours to Conquer. Wichita, KS. Bio-Communication Press. 1970;155.

  5. Pfeiffer CC, Mailloux R, Forsythe L: The Schizophrenias: Ours to Conquer. Wichita, KS. Bio-Communication Press. 1970; 159.

  6. Pfeiffer CC: Nutrition and Mental Illness. Rochester, VT. Healing Arts Press. 1987;30.

  7. Hoffer A: Vitamin B3 & Schizophrenia: Discov-ery, Recovery, Controversy. Kingston, ON, Quarry Press. 1998; 8-22.

    1. Pfeiffer CC: Mental and Elemental Nutrients. New Canaan, CT. Keats Publishing, Inc. 1975;

      2. 401.

  8. Bekier E, Wyczolkowska J, Szyc H, et al: The inhibitory effect of nicotinamide on asthma-like symptoms and eosinophilia in guinea pigs, anaphylactic mast cell degranulation in mice, and histamine release from rate isolated peri-toneal mast cells by compound 48/80. Int Arch Allergy, 1974; 47: 737-748.

  9. Cleary JP: NAD deficiency diseases. J Orthomol Med, 1986; 1(3): 149-157.

  10. Hoffer A: Vitamin B3 & Schizophrenia: Discov-ery, Recovery, Controversy. Kingston, ON, Quarry Press.1998; 100.

  11. Morrow JD, Parsons WG III, Roberts LJ II: Re-lease of markedly increased quantities of pros-taglandin D2 in vivo in humans following the administration of nicotinic acid. Prostaglandins, 1989; 38: 263-74.

  12. Morrow JD, Awad JA, Oates JA, et al: Identifica-tion of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. J Invest Dermatol, 1992; 98: 812-815.

  13. Reichelt K-L, Sagedal E, Landmark J, et al: The effect of gluten-free diet on urinary peptide excretion and clinical state in schizophrenia. J Orthomol Med, 1990; 5(4): 223-239.

15.Singh MM, Kay SR: Wheat gluten as a pathologic factor in schizophrenia. Science, 1976; 191: 401-402.

16. Vlissides DN, Venulet A, Jenner FA: A doubleblind gluten-free/gluten-load controlled trial in a secure ward population. Br J Psychiatry, 1986;

148: 447-452.

  1. Philpott WH: Maladaptive reactions to fre-quently used foods and commonly met chemi-cals as precipitating factors in many chronic physical and chronic emotional illnesses. A Physician’s Handbook on Orthomolecular Medi-cine. 3rd ed. In eds. Williams RJ, Kalita DK. New Canaan, CT. Keats Publishing. 1979;140-150.

  2. Mycroft FJ, Wei ET, Bernardin JE, et al: MIF-like sequences in milk and wheat proteins. Letter to the Editor. N Engl J Med, 1982; 307(14): 895.

    1. Whitford T: The underlying mechanisms of brain allergies. J Orthomol Med, 2000; 15(1): 5-

    2. 14.
  3. Bekier E, Maslinski CZ: Antihistaminic action of nicotinamide. Agents Actions, 1974;4/3:196.

  4. Parrot J-L, Wyczolkowska Y, Santais MC, et al: The action of nicotinamide on the release of histamine. Agents Actions, 1974; 4/3: 202.

  5. Oh C, Nakano K: Reversal by ascorbic acid of suppression by endogenous histamine of rat lymphocyte blastogenesis. J Nutr, 1988; 118(5): 639-644.

  6. Lorenz W, Thon K, Barth H, et al: Metabolism and function of gastric histamine in health and disease. J Clin Gastroenterol, 1983; 5(suppl.1): 37-56.

  7. Uchida K, Mitsui M, Kawakishi S: Mono-oxy-genation of N-acetylhistamine mediated by L-ascorbate. Biochem Biophys Acta, 1989; 991(2): 377-379.

  8. Johnson S: Micronutrient accumulation and de-pletion in schizophrenia, epilepsy, autism and Parkinson’s disease. Med Hypotheses, 2001; 56(5): 641-645.

  9. Johnston CS, Martin LJ, Cai X: Antihistamine effect of supplemental ascorbic acid and neu-trophil chemotaxis. J Am Coll Nutr, 1992; 11(2): 172-176.

  10. Johnston CS, Solomon RE, Corte C: Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults. J Am Coll Nutr, 1996; 15(6): 586-591.

  11. Suboticanec K. Vitamin C status in schizophre-nia. Bibl Nutr Dieta, 1986;38:173-181.

  12. Suboticanec K, Folnegovic-Smalc V, Korbar M, et al: Vitamin C status in chronic schizophre-nia. Biol Psychiat, 1990;28(11):959-966.

  13. Suboticanec K, Folnegovic-Smalc V, Turcin R, et al: Plasma levels and urinary vitamin C ex-cretion in schizophrenic patients. Hum Nutr Clin Nutr, 1986; 40(6): 421-428.

  14. Kobayashi Y, Freeman H: Histamine metabo-lism in schizophrenic and normal subjects. J Neuropsychiat, 1961;3:112.

  1. Heleniak E, O’Desky I: Histamine and prostaglandins in schizophrenia: revisited. Med Hypotheses, 1999; 52(1): 37-42.

  2. Gillson G, Wright JV, DeLack E, et al: Transdermal histamine in multiple sclerosis, part two: a proposed theoretical basis for its use. Alt Med Rev, 2000; 5(3): 224-248.

  3. Orange PR, Heath PR, Wright SR, et al: Indi-viduals with schizophrenia have an increased incidence of the H2R649G allele for the hista-mine H2 receptor gene. Mol Psychiat, 1996; 1(6): 466-469.

  4. Ito C, Morisset S, Krebs MO, et al: Histamine H2 receptor gene variations: lack of association with schizophrenia. Mol Psychiat, 2000; 5(2): 159-164.

  5. Martinez MC: Famotidine in the management of schizophrenia. Ann Pharmacother, 1999; 33(6): 742-747.

  6. Yan L, Szumlanski CL, Rice SR, et al: Histamine N-methyltransferase functional polymorphism: lack of association with schizophrenia. Am J Med Genet, 2000; 96(3): 404-406.