" Just as histamine dominates other neurotransmitters, it also can deregulate the HPA axis by overstimulation of the pituitary and adrenal glands."
Full text:
The Role of Histamine in Mental Illness and its Attenuation with Vitamin C – Part III
Chapter 5: Conclusions, Implications and Recommendations for Further Research
Conclusions and Implications:
The role of histamine in mental illness has been theorized about for several decades, but both the conventional and alternative medical fields have been very slow to respect histamine’s influence in mental health. In addition, the vast majority of conventional and alternative practitioners do not realize that vitamin C has potent antihistamine effects, which can be beneficial in both physical and mental health. Conventional medicine uses pharmaceutical antihistamines to treat histamine-related physical complaints, and sometimes mental ones as well. As mentioned earlier, pharmaceutical antihistamines have several side effects, including many that worsen mental health. It is lamentable that the vast majority of alternative practitioners are ignorant of vitamin C’s antihistamine effects. It is the purpose of this dissertation to convey vitamin C’s antihistamine effects, especially as it pertains to treating various forms of mental illness.
The evidence for vitamin C’s positive impact on mental health is compelling. Vitamin C can act as a mild antidepressant via boosting cAMP levels. Low cAMP levels are associated with depression. Vitamin C also helps produce norepinephrine, which, like cAMP, is often low in depression. In fact, cAMP is downstream of the norepinephrine pathway, which is the pathway that many pharmaceutical antidepressants use to boost mood. Vitamin C also hydroxylates dopamine to help form norepinephrine (Goodman, et al., 1996).
Vitamin C, when used in large doses, can potentially reduce anxiety (Balch & Balch, 1997). As mentioned previously, the brain constantly strives to keep the vitamin C levels constant, no matter how low the levels are in the rest of the body. So, the question arises: how can low or high vitamin C levels affect mental health, assuming that it is at a constant concentration in the brain? A plausible explanation is the following: the total vitamin C pool in the body may become more oxidized than reduced. Recall that only oxidized vitamin C enters the brain, where it is then reduced. If there are not sufficient reducing agents in the brain, then the vitamin C will remain oxidized, and therefore most of its properties rendered useless. Reduced vitamin C modulates dopamine levels in the brain, and can thus act as a natural antipsychotic by lowering high dopamine levels. It also helps secrete oxytocin, a pleasure hormone, thus improving mood. As mentioned previously, “ascorbate promotes myelin formation” (Rice, 2000, p. 214). Vitamin C also inhibits release of the stress hormone cortisol, which in excess for prolonged periods can precipitate depression. It also helps protect the brain from drug-induced neurotoxicity, presumably by its antioxidant effects.
However, by far the most important positive effect on mental health that vitamin C has is its antihistamine effect. This is because, as mentioned before, histamine has several detrimental effects on mental health. Administration of histamine into animal brains reinforced fear memory (Blandina, et al., 2004). It is well known that histamine plays a major role in allergic reactions, and allergic people are significantly more likely to suffer from depression (Firshein, 1996; Ossofsky, 1976). Histamine itself can directly cause behavioral depression (Arrigo-Reina & Chiechio, 1998).
As mentioned previously, histamine either directly or indirectly influences all other major neurotransmitters, often via inhibition of neurotransmitter release (Brown, Stevens, & Haas, 2001), thus theoretically causing anxiety, depression, or both. The anxiety may be caused by histamine’s inhibition of GABA, which slows nerve transmission. The depression may be caused by inhibition of the ‘antidepressant’ neurotransmitters serotonin and norepinephrine. However, histamine can also release norepinephrine (Bugajski, 1984), thus potentially causing anxiety or mania. Stress often releases histamine, which in turn will help release the HPA axis stress hormones. It is known that chronic HPA activation is associated with depression and brain alterations. There is also evidence that histamine activates the calcium pathway more than the DAG pathway (Sarri, Picatoste, & Claro, 1995). There is abundant evidence that the DAG pathway is antidepressant-like, and the calcium pathway may cause depression.
Besides its antihistamine effect, there are multiple sources of evidence to suggest that humans should supplement with vitamin C. Dr. Linus Pauling, a two-time Nobel Prize winner, believes that adult humans need between two to nine grams of vitamin C daily (Haas, 1992). Animals who can synthesize vitamin C do so at 45-300 times the adult human RDA, which is about 0.9 mg/kg/day (60-90 mg/day) (Levine, 1985). For a 150 pound human, this would extrapolate to about 12 grams per day, if humans synthesized their own vitamin C. Vitamin C blood and tissue levels decline with age (Lieberman & Bruning, 1997), which is an additional reason to supplement. If vitamin C is taken as a supplement, then other supplementation should be considered, since vitamin C needs calcium, magnesium, and bioflavonoids to help its own assimilation (Balch & Balch, 1997).
Recommendations for Further Research:
Since vitamin C and histamine are involved in both physical and mental processes, this leads to the question of psychosomatic issues with both molecules. Recall that both molecules are also involved in the immune response and pro- or anti-allergic responses. There are three possible links between psychic state and somatic allergy. First is that allergies are produced by psychological stress. Second is that psychological stress is produced by allergies. Third is that allergic exposure can produce both psychic and somatic responses. This third link has been proven in a double-blind study (King, 1981). As mentioned earlier, allergy-mediated histamine release is associated with various mental reactions.
There have been various theories on the molecular basis of mental illness for several decades. The first theory is called the monoamine theory, formed in the 1950’s and 1960’s. It proposes that abnormal brain function is directly dependent on fluctuating monoamine levels (serotonin, norepinephrine, dopamine, GABA). Interestingly, histamine was not included in the original monoamine theory, probably due to the lack of research at the time regarding its mental health effects. At that time, doctors would most often give only antidepressants to depressed patients, and benzodiazepins (ex. Xanax, Valium) to anxious people. The second theory is the comorbid theory, which dominated psychiatric philosophy in the 1990’s. It was formed after the realization that drugs such as Prozac could singlehandedly reduce both depression and anxiety. The third is the subsyndromal theory, which evolved from the discovery that the vast majority of anxious people have some depression, and vice versa. The philosophy of the subsyndromal theory is basically in-between the monoamine and comorbid theories.
The discovery that histamine can inhibit all other major neurotransmitters suggests taking another look at the original monoamine hypothesis of mental illness. It is known that dopamine tends to be high in psychosis, norepinephrine high in mania, and serotonin low in depression. It could be postulated that psychotics have a dopaminergic-dominated neurotransmitter system, bipolars a norepinephrine-dominated neurotransmitter system, and depressives a serotonin-dominated neurotransmitter system. The fourth major monoamine, histamine, may very well be dominant in atopic (allergic) people. People with histaminergic-dominant neurotransmitter systems could have a very wide variety of mental illnesses, since histamine affects the release of all major neurotransmitters. The biochemical characterization of the histaminergic person may therefore be of interest to practitioners in order to help that person physically and mentally. This characterization leads to the topic of metabolic typing, described below.
In the emerging nutritional science of metabolic typing, people are asked a series of questions to determine what type of biochemistry they have. Some people are slow oxidizers and tend to be sympathetic nervous system dominants. Those people do better on carbohydrates. Others are fast oxidizers and tend to be parasympathetic nervous system dominants. These people do better with more fat and protein in their diet. Too many carbohydrates for a fast oxidizer can bring a lot of physical and mental problems. Since histamine is a stimulatory molecule, it may hasten oxidation, and histaminergic types may want to consider limiting carbohydrates.
There is some evidence to suggest that histamine is involved in creating the parasympathetic dominant biochemistry in a person. The parasympathetic branch of the CNS is responsible for decreased heart rate and increased digestive secretions, both of which are also caused by histamine release. Also, physical tendencies of parasympathetic dominants include allergies and excessive appetite (Wolcott & Fahey, 2002). Histamine is a major cause of allergies and its stimulatory effect on digestion can result in excessive appetite.
Besides its antihistamine effect, vitamin C can help a person’s biochemistry in other, more subtle ways. Vitamin C can be purchased as straight ascorbic acid, or the pH neutral calcium ascorbate or sodium ascorbate. For people who are sympathetic dominants, straight ascorbic acid should be tried, since those types of people may not have sufficient hydrochloric acid secretions. The loosely bound hydrogen from the ascorbic acids hydroxyl group will dissociate in the stomach and help digest protein. Ascorbic acid may also be helpful to balance the blood pH of people with metabolic alkalosis.
Conversely, parasympathetics, who tend to have robust hydrochloric acid production, should try calcium ascorbate, since the ascorbate will accept excess hydrogen ions in the stomach. Calcium ascorbate taken in large doses may help neutralize acid reflux. Calcium is also good for parasympathetics, since it slows down oxidation (Wolcott and Fahey, 2002). Calcium ascorbate may help balance the blood pH of people who have metabolic acidosis.
Other future research may concentrate on how megadosing with vitamin C affects mental health quantitatively. There has already been research proving that vitamin C intake enhances mood (Brody, 2002; Balch & Balch, 1997). So far, there has not been a large study to see if vitamin C alone can significantly reduce depression or anxiety, either in conventional or alternative medicine. There are two main clinical scales to measure depression and anxiety—the Hamilton depression scale and the Hamilton anxiety scale. It would be of interest to see if vitamin C alone could significantly reduce depression and/or anxiety.
Since different people have different biochemistry, the question arises of how much vitamin C is needed daily by a person for physical and mental health. One of the best ways to test how much vitamin C a person needs is to have them do an ascorbic acid flush. This can be done with both ascorbic acid and calcium/sodium ascorbate. The protocol can be varied, but it usually consists of a person taking 1-2 grams of vitamin C every hour until bowel tolerance occurs (diarrhea). The grams of vitamin C are counted and recorded. The final gram(s) that cause bowel tolerance are usually multiplied by 50-80%, and that is the baseline daily dose that the person should take from then on. For example, if 18 grams causes bowel tolerance, than 9-16 grams is the daily baseline amount. If the person is under an unusual amount of stress, or has a viral infection, the baseline can be raised until bowel tolerance occurs at a higher level than before. Again, the new temporary bowel tolerance is lowered a certain percentage until the stressor abates.
Summary:
The contents of this dissertation have introduced a multidimensional model for the attenuation of histamine-related mental illness via vitamin C supplementation. Both histamine and vitamin C affect the human body on multiple levels. Histamine plays many different roles in the body, including neuromodulation, neurotransmission, allergic mediator, inflammatory mediator, and gastric acid secretion stimulator. When histamine levels are in the normal range, the above processes are usually in equilibrium and functioning optimally. It is when histamine levels become too low or high that trouble can arise. One of the roles of vitamin C in the body is to modulate histamine levels; if histamine levels are low, vitamin C administration will cause small amounts of histamine to be released. When histamine levels are abnormally high, vitamin C acts as an antihistamine, destroying excess histamine and thus bringing this chemical down to normal physiological levels.
In addition to its antihistamine effect, vitamin C has many other actions on the body. Like histamine, vitamin C is also both a neuromodulator and an immunomodulator. In fact, based on the information earlier in this dissertation, it is not an exaggeration to state that vitamin C is histamine’s counterpart and molecular ‘watchdog’. Unfortunately for humans, vitamin C cannot be synthesized in the body, so it must be supplemented either in food or nutritional supplements. If humans could synthesize vitamin C, a 150 pound person would make roughly 12 grams of vitamin C daily. That’s 133-200 times the US RDA (recommended daily allowance) of vitamin C. This statistic underscores the fact that there is a huge difference between the RDA of vitamin C designed to prevent rare diseases, and the optimal amount to sustain physical and mental health.
Sub-optimal amounts of vitamin C in the blood and tissues can allow histamine to rise to dangerous levels. Histamine competes with other neurotransmitters, and excess histamine can end up dominating and inhibiting other neurotransmitters. This can lead to anxiety and/or depression. Histamine sometimes releases norepinephrine and dopamine, and these two neurotransmitters in excess can precipitate mania and psychosis, respectively. Histamine may also be involved in ADD (Passani, Bacciottini, Mannaioni, & Blandina, 2000). Stress releases histamine, which then in turn releases various stress hormones that can result in serious bodily harm if the stress is chronic. Just as histamine dominates other neurotransmitters, it also can deregulate the HPA axis by overstimulation of the pituitary and adrenal glands.
The molecule cyclic AMP (cAMP) is an extremely important regulator of metabolism. Robust levels allow the maintenance of both physical and mental health. Low levels can result in asthma, depression, and possibly even cancer. Histamine lowers cAMP levels, by a mechanism that is not completely elucidated; it may have to do with the calcium pathway antagonizing the cAMP pathway. Vitamin C boosts cAMP levels by at least three methods: directly degrading histamine, synergism with cAMP producers, and inhibiting the enzyme (phosphodiesterase) that degrades cAMP. In this way it can attenuate, prevent, or even reverse asthma, depression, and cancer. Vitamin C also helps reverse asthma by slowing down synthesis of the inflammatory mediators arachidonic acid (AA) and PGF2a. cAMP also inhibits histamine release (Mohsenin & Dubois, 1987).
It has been shown in this dissertation that vitamin C is very beneficial for mental health in many different ways. Vitamin C benefits mental health both with its antihistamine effects and in numerous other ways as well. It is very unfortunate that humans cannot synthesize their own vitamin C. Animals who synthesize their own vitamin C develop cancer much less than humans. Yet the RDA for vitamin C is a paltry 60-90 mg/day, just enough to prevent certain diseases that are very rare in developed countries. The time will come when vitamin C is recommended by both doctors and nutritionists in doses that are appropriate to a person’s weight—about eight grams for every 100 pounds, as suggested by the two-time Nobel Prize winner Linus Pauling.
References
Abbas, A., Lichtman, A., & Pober, J. (2000). Cellular and molecular immunology (4th ed.). New York: W.B. Saunders Company.
Abdulla, Y., & Hamadah, K. (1970). 3’,5’-cyclic adenosine monophosphate in depression and mania. Lancet, 1, 378-381.
Agus, D., Gambhir, S., Pardridge, W., Spielholz, C., Baselga, J., Vera J., et al., (1997). Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. Journal of Clinical Investigation, 100, 2842-2848.
Anderson, K., Means, R., Huang, Q-H., Kemp, B., & Goldstein, E. (1998). Components of a calmodulin-dependent protein kinase cascade: molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase beta. Journal of Biological Chemistry, 273, 31880-31889.
Aprison, M., Takahashi, R., & Tachiki, K. (1978). Hypersensitive serotonergic receptors involved in clinical depression—a theory. Neuropharmacology and Behavior. New York: Plenum Press.
Arora, R., & Meltzer, H. (1989). Increased serotonin2 (5-HT2) receptor binding as measured by 3H-lysergic acid diethylamide (3H-LSD) in the blood platelets of depressed patients. Life Sciences, 44, 725-734.
Arrigo-Reina, R. & Chiechio, S. (1998). Evidence of a key role for histamine from mast cells in the analgesic effect of Clomipramine in rats. Inflammation Research, 47, 44-48.
Axelrod, J., & Reisine, T. (1984). Stress hormones: their interaction and regulation. Science, 224, 452-459.
Balch, J., & Balch, P. (1997). Prescription for nutritional healing, 2nd Edition. Garden City Park: Avery Publishing Group.
Banhegyi, G., Braun, L., Csala, M., Puskas, F., & Mandl, J. (1997). Ascorbate metabolism and its regulation in animals. Free Radical Biology & Medicine, 23, 793-803.
Bielkiewicz-Vollrath, B., Carpenter, J., Schulz, R., & Cook, D. (1987). Early production of 1,4,5-inositol trisphosphate and 1,3,4,5-inositol tetrakisphosphate by histamine and carbachol in ileal smooth muscle. Molecular Pharmacology, 31, 513-522.
Bito, H., Deisseroth, K., & Tsien R. (1996). CREB phosphorylation and dephosphorylation: a Ca2±and stimulus duration-dependent switch for hippocampal gene expression. Cell, 87, 1203-1214.
Blandina, P., Efoudebe, M., Cenni, G., Mannaioni, P., & Passani, M. (2004). Acetylcholine, histamine, and cognition: two sides of the same coin. Learning & Memory, 11, 1-8.
Boeing, H., & Rausch, E. (1996). Ascorbic acid and chronic diseases: how strong is the evidence? Subcellular Biochemistry, 25, 117-136.
Bongers, G., Leurs, R., Robertson, J. & Raber, J. (2004). Role of H3-receptor-mediated signaling in anxiety and cognition in wild-type and Apoe-/- mice. Neuropsychopharmacology, 29, 441-449.
Brody, S. (2002). High-dose ascorbic acid increases intercourse frequency and improves mood: a randomized controlled clinical trial. Biological Psychiatry, 52, 371-374.
Brody, S., Preut, R., Schommer, K., & Schurmeyer, T. (2002). A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress. Psychopharmacology, 159, 319-324.
Brown, A., Mallinger, A., & Renbaum, L. (1993). Elevated platelet membrane phosphatidylinositol-4,5-bisphosphate in bipolar mania. American Journal of Psychiatry, 150, 1252-1254.
Brown, R., Stevens, D., & Haas, H. (2001). The physiology of brain histamine. Progress in Neurobiology, 63, 637-672.
Bugajski, J., & Gadek, A. (1983). Central H1- and H2-histaminergic stimulation of pituitary-adrenocortical response under stress in rats. Neuroendocrinology, 36, 424-430.
Bugajski, J. (1984). Central metabolic and pituitary adrenocortical stimulatory action of histamine and clonidine. Polish Journal of Pharmacology and Pharmacy, 36, 159-176.
Bussing, R., Halfon, N., Benjamin B., & Wells, K. (1995). Prevalence of behavior problems in U.S. children with asthma. Archives of Pediatrics & Adolescent Medicine, 149, 565-572.
Calam, R., Gregg, L., Simpson, B., Morris, J., Woodcock, A., et al. (2003). Childhood asthma, behavior problems, and family functioning. Journal of Allergy and Clinical Immunology, 112, 499-504.
Cameron, E., & Pauling, L. (1993). Cancer and vitamin c. Philadelphia: Camino Books.
Cantu, T., & Korek, J. (1991). Central nervous system reactions to histamine-2 receptor blockers. Annals of Internal Medicine, 114, 1027-1034.
Carr, A., & Frei, B. (1999). Does vitamin C act as a pro-oxidant under physiological conditions? Journal of the Federation of American Societies for Experimental Biology, 13, 1007-1024.
Cathcart, R. (1986). The vitamin C treatment of allergy and the normally unprimed state of antibodies. Medical Hypotheses, 21, 307-21.
Chen, G., Hasanat, K., Bebchuk, J., Moore, G., Glitz, D., et al. (1999). Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants. Psychosomatic Medicine, 61, 599-617.
Chen, K., Suh, J., Carr, A., Morrow, J., Zeind, J., et al. (2000). Vitamin C suppresses oxidative lipid damage in vivo, even in the presence of iron overload. American Journal of Physiology Endocrinology and Metabolism, 279, E1406-1412.
Cheung, W. (1970). Cyclic 3’, 5’-nucleotide phosphodiesterase. Demonstration of an activator. Biochemical and Biophysical Research Communications, 38, 533-538.
Chiavegatto, S., Nasello, A., & Bernardi, M. (1998). Histamine and spontaneous motor activity: biphasic changes, receptors involved and participation of the striatal dopamine system. Life Sciences, 62, 1875-1888.
Chrousos, G. (2000). The stress response and immune function: clinical implications. Annals New York Academy of Sciences, 917, 39-67.
Clemetson, C. (1999). The key role of histamine in development of atherosclerosis and coronary heart disease. Medical Hypotheses, 52, 1-8.
De Chaffoy de Courcelles, D., Leysen, J., De Clerck, F., Van Belle, H., & Janssen, P. (1985). Evidence that phospholipid turnover is the signal transducing system coupled to serotonin-S2 receptor sites. Journal of Biological Chemistry, 260, 7603-7608.
De Kloet, E., Sybesma, H., & Reul, H. (1986). Selective control by corticosterone of serotonin1 receptor capacity in raphe-hippocampal system. Neuroendocrinology, 42, 513-521.
Dinndorf, P., McCabe, M., & Frierdich, S. (1998). Risk of abuse of diphenhydramine in children and adolescents with chronic illnesses. Journal of Pediatrics, 133, 293-295.
Edelman, E. (1998). Natural healing for schizophrenia and other mental disorders. Eugene: Borage Books.
Edelman, N. (1997). American lung association: family guide to asthma and allergies. New York: Time Life Media.
Feinstein, A. (1996). Healing with vitamins. Emmaus: Rodale Books, Inc.
Fernandez-Novoa, L., & Cacabelos, R. (2001). Histamine function in brain disorders. Behavioral Brain Research, 124, 213-233.
Firshein, R. (1996). Reversing asthma. New York: Warner Books, Inc.
Fried, R. (1999). Breathe well, be well. New York: John Wiley & Sons, Inc.
Friedman, E., Hoau, Y., Lavinson, D., Connell, T., Singh, H. (1993). Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biological Psychiatry, 33, 520-525.
Galosi, R., Lenard, L., Knoche, A., Haas, H., Huston, J., et al. (2001). Dopaminergic effects of histamine administration in the nucleus accumbens and the impact of H1-receptor blockade. Neuropharmacology, 40, 624-633.
Ginter, E. (1980). What is truly the maximum body pool size of ascorbic acid in man? American Journal of Clinical Nutrition, 33, 538-539.
Ghosh, A., Carnahan, J., & Greenberg, M. (1994). Requirement for BDNF in activity-dependent survival of cortical neurons. Science, 263, 1618-1623.
Glick, S., & Crane, L. (1978). Opiate-like and abstinence-like effects of intracerebral histamine administration in rats. Nature, 273, 547-549.
Goodman, A., Harman, J., Limbird, L., Molinoff, P., Ruddon, R., et al. (1996). The Pharmacological Basis of Therapeutics, 9th Edition. New York: McGraw Hill.
Greengard, P., Nairn, A., Girault, J., Ouimet, C., Snyder, et al. (1998). The DARPP-32/protein phosphatase-1 cascade: a model for signal integration. Brain Research Reviews, 1998, 26, 274-284.
Greenwood, J. (1991). Mechanisms of blood-brain barrier breakdown. Neuroradiology, 33, 95-100.
Gruenwald, R. (1993). Ascorbic acid in the brain. Brain Research Reviews, 18, 123-133.
Gutteridge, J. & Halliwell, B. (1996). Antioxidants in nutrition, health, and disease. Oxford: Oxford University Press.
Haas, E. (1992). Staying healthy with nutrition. Berkeley: Celestial Arts Publishing.
Hagiwara, M., Brindle, P., Harootunian, A., Armstrong, R., Rivier, et al. (1993). Coupling of hormonal stimulation and transcription via the cyclic AMP-responsive factor CREB is rate limited by nuclear entry of protein kinase A. Molecular and Cellular Biology, 13, 4852-4859.
Halpert, A., Olmstead, M., & Beninger, R. (2002). Mechanisms and abuse liability of the anti-histamine dimenhydrinate. Neuroscience & Biobehavioral Reviews, 26, 61-67.
Hasenohrl, R., Weth, K., & Huston, J. (1999). Intraventricular infusion of the histamine H(1) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Experimental Brain Research, 128, 435-440.
Hatta, S., Ozawa, H., Saito, T., & Ohshika, H. (1995). Participation of tubulin in the stimulatory regulation of adenylyl cyclase in rat cerebral cortex membranes. Journal of Neurochemistry, 64, 1343-1350.
Hediger, M. (2002). New view at C. Nature Medicine, 8, 445-446.
Heleniak, E., & O’Desky, I. (1999). Histamine and prostaglandins in schizophrenia: revisited. Medical Hypotheses, 52, 37-42.
Hitomi, K., & Tsukagoshi, N. (1996). Role of ascorbic acid in modulation of gene expression. Subcellular Biochemistry, 25, 41-56.
Hoffer, A. & Walker, M. (1978). Putting it all together: the new orthomolecular nutrition. New Canaan: Keats Publishing, Inc.
Hook, S., & Means, A. (2001). Ca2+ /CaM-dependent kinases: from activation to function. Annual Review of Pharmacology and Toxicology, 41, 471-505.
Horrobin, D. (1996). Ascorbic acid and prostaglandin synthesis. Subcellular Biochemistry, 25, 109-115.
Horstra, C., Desai, P., Thurmond, R., & Fung-Leung, W. (2003). Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. Journal of Pharmacology and Experimental Therapeutics, 305, 1212-1221.
Hoshi, M., Akiyama, T., Shinohara, Y., Miyata, Y., Ogawara, H., et al. (1988). Protein-kinase-C-catalyzed phosphorylation of the microtubule-binding domain of microtubule-associated protein 2 inhibits its ability to induce tubulin polymerization. European Journal of Biochemistry, 174, 225-230.
Hurwitz, E., & Morgenstern, H. (2001). Immediate and long term effects of immune stimulation: hypothesis linking the immune response to subsequent physical and psychological well being. Medical Hypotheses, 56, 620-624.
Hyman, C., Juhasz, M., Jackson, C., Wright, P., Ip, N., and Lindsay, R. (1994). Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. Journal of Neuroscience, 14, 335-347.
Ito, C. (2000). The role of brain histamine in acute and chronic stresses. Biomedicine & Pharmacotherapy, 54, 263-267.
Jacob, R. (1996). Three eras of vitamin C discovery. Subcellular Biochemistry, 25, 1-15.
Jacobs, E., Yamatodani, A., & Timmerman, H. (2000). Is histamine the final neurotransmitter in the entrainment of circadian rhythms in mammals? TiPS, 21, 293-298.
Jameson, L., Frey, T., Zeeberg, B., Dalldorf, F., & Caplow, M. (1980). Inhibition of microtubule assembly by phosphorylation of microtubule-associated proteins. Biochemistry, 19, 2472-2479.
Janson, M. (2000). Dr. janson’s new vitamin revolution. New York: Avery Books.
Jensen, R. (2002). The failures of american medicine. Victoria: Trafford Publishing.
Johnson, E., Kamilaris, T., Chrousos, G., & Gold, P. (1992). Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis. Neuroscience & Biobehavioral Reviews, 16, 115-130.
Johnston, C., Martin, L, & Cai, X. (1992). Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis. Journal of the American College of Nutrition, 11, 172-176.
Johnston, C., Retrum, K., & Srilakshmi, J. (1992). Antihistamine effects and complications of supplemental vitamin C. Journal of the American Dietetic Association, 92, 988-989.
Johnston, C. (1996). Antihistamine action of ascorbic acid. Subcellular Biochemistry, 25, 189-213.
Kagaya, A., & Yamawaki, S. (1998). Immunological aspects of mood disorders: interaction between cytokines and intracellular calcium signaling. In: Signal transduction in affective disorders. Tokyo: Springer-Verlag.
Kalivas, P. (1982). Histamine-induced arousal in the conscious and pentobarbital-pretreated rat. Journal of Pharmacology and Experimental Therapeutics, 222, 37-42.
Kallner, A. (1987). Requirement of vitamin C based on metabolic studies. Annals New York Academy of Sciences, 496, 418-423.
Kamei, C., & Tasaka, K. (1993). Effect of histamine on memory retrieval in old rats. Biological & Pharmaceutical Bulletin, 16, 128-132.
Katsuki, H. (1996). Vitamin C and nervous tissue: in vivo and in vitro aspects. Subcellular Biochemistry, 25, 293-311.
Katzung, B. (1998). Basic and clinical pharmacology, 7th Ed. New York: McGraw Hill.
Kilpelainen, M., Koskenvuo, M., Helenius, H., & Terho, E. (2002). Stressful life events promote the manifestation of asthma and atopic diseases. Clinical & Experimental Allergy, 32, 256-263.
King, D. (1981). Can allergic reactions provoke psychological symptoms? A double-blind test. Biological Psychiatry, 16, 3-19.
Kiyatkin, E., & Rebec, G. (1998). Ascorbate modulates glutamate-induced excitations of striatal neurons. Brain Research, 812, 14-22.
Klee, C., Ren, H., Wang, X. (1998). Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. Journal of Biological Chemistry, 273, 13367-13370.
Knigge, U., & Wargberg, J. (1991). Neuroendocrine functions of histamine. Agents Actions Supplemental, 33, 29-53.
Knoche, A., Yokoyama, H., Ponomarenko, A., Frisch, C. Huston, J., & Haas, H. (2003). High-frequency oscillation in the hippocampus of the behaving rat and its modulation by the histaminergic system. Hippocampus, 13, 273-280.
Koenig, J. & Elmadfa, I., (1996). Ascorbic acid, transport and availability. Subcellular Biochemistry, 25, 136-155.
Komindr, S., Nichoalds, G., & Kitabchi, A. (1987). Bimodal effects of megadose vitamin C on adrenal steroid production in man: an in vivo study. Annals New York Academy of Sciences, 496, 487-490.
Koob, G. (1999). Stress, corticotropin-releasing factor, and drug addiction. Annals New York Academy of Sciences, 897, 27-45.
Kurian, P., Chandler, J., Patel, R., & Crews, F. (1992). Receptor coupling to phosphoinositide signals. In: Neurobiology of Essential Fatty Acids. New York: Plenum Press.
Kusumi, I., Koyama, T., & Yamashita, I. (1991). Effect of various factors on serotonin-induced Ca2+ response in human platelets. Life Sciences, 48, 2405-2412.
Kusumi, I., & Koyama, T. (1998). Serotonin-2A receptor function in affective disorders. In: Signal Transduction in Affective Disorders. Tokyo: Springer-Verlag.
Lader, M., & Scotto, J-C. (1998). A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder. Psychopharmacology, 139, 402-406.
Lakoski, J., & Aghajanian, G. (1983). Effects of histamine, H1- and H2-receptor antagonists on the activity of serotonergic neurons in the dorsal raphe nucleus. Journal of Pharmacology and Experimental Therapeutics, 227, 517-523.
Leurs, R., Remko, Bakker, R., Timmerman, H., & de Esch, I. (2005). The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nature Reviews Drug Discovery, 4, 107-120.
Levine, M., & Morita, K. (1985). Ascorbic acid in endocrine systems. Vitamins and Hormones, 42, 1-65.
Levine, M., & Hartzell, W. (1987). Ascorbic acid: the concept of optimum requirements. Annals New York Academy of Sciences, 496, 424-444.
Lewin, B. (1994). Genes v. New York: Oxford University Press.
Lieberman, S., & Bruning, N. (1997). The real vitamin & mineral book, 2nd Ed… Honesdale: Paragon Press.
Lintunen, M., Raatesalmi, K., Sallmen, T., Anichtchik, O., Karlstedt, K., et al. (2002). Low brain histamine content affects ethanol-induced motor impairment. Neurobiology of Disease, 9, 94-105.
Lisman, J. (1994). The CaM kinase II hypothesis for the storage of synaptic memory. Trends in Neurosciences, 17, 406-412.
Maes, M., De Ruyter, M., Hobin, P., & Suy, E. (1987). Relationship between the dexamethasone suppression test and the L-tryptophan/competing amino acids ratio in depression. Psychiatry Research, 21, 323-335.
Mamounas, L., Blue, M., Siuciak, J., & Altar, C. (1995). BDNF promotes the survival and sprouting of serotonergic axons in the rat brain. Journal of Neuroscience, 15, 7929-7939.
Mark, V., & Mark, J. (1989). Brain Power. Boston: Houghton Mifflin Company.
Martin, P. (1997). The healing mind. New York: Thomas Dunne Books.
Matsushita, M., & Nairn, A. (1999). Inhibition of the Ca2+/Calmodulin-dependent protein kinase I cascade by cAMP-dependent protein kinase. Journal of Biological Chemistry, 274, 10086-10093.
May, J. (2002). Recycling of vitamin C by mammalian thioredoxin reductase. Methods in Enzymology, 347, 327-332.
Mazurkiewicz-Kwilecki, I. (1983). Brain histamine-plasma corticosterone interactions. Life Sciences, 32, 1099-1106.
McDonald, E., Mann, A., & Thomas, H. (1987). Interferons as mediators of psychiatric morbidity: an investigation in a trial of recombinant a-interferon in hepatitis-B carriers. Lancet, 21, 1175-1178.
Menkes, D., Rasenick, M., Wheeler, M., & Bitensky, M. (1983). Guanosine triphosphate activation of brain adenylyl cyclase: enhancement by long-term antidepressant treatment. Science, 129, 65-67.
Meyers, D., Maloley, P., & Weeks, D. (1996). Safety of antioxidant vitamins. Archives of Internal Medicine, 13, 925-935.
Mohsenin, V., & Dubois, A. (1987). Vitamin C and airways. Annals New York Academy of Sciences, 496, 260-267.
Mrazek, D., Schuman, W., & Klinnert, M. (1998). Early asthma onset: risk of emotional and behavioral difficulties. Journal of Child Psychology and Psychiatry, 39, 247-254.
Nandi, B., Subramanian, N., Majumder, A., & Chatterjee, I. (1974). Effect of ascorbic acid on detoxification of histamine under stress conditions. Biochemical Pharmacology, 23, 643-647.
Nibuya, M., Nestler, E., & Duman, R. (1996). Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. Journal of Neuroscience, 16, 2365-2372.
Nishiga, M., Fujii, Y., Konishi, M., Hossen, M., & Chiaki, K. (2003). Effects of second-generation histamine H1 receptor antagonists on the active avoidance response in rats. Clinical and Experimental Pharmacology & Physiology, 30, 60-63.
Nishikimi, M., & Yagi, K. (1996). Biochemistry and molecular biology of ascorbic acid biosynthesis. Subcellular Biochemistry, 25, 17-39.
Nishizuka, Y. (1986). Studies and perspectives of protein kinase C. Science, 233, 305-312.
Nualart, F., Rivas, C., Montecinos, V., Godoy, A., Guaiquil, V., Golde, D., et al. (2003). Recycling of vitamin C by a bystander effect. Journal of Biological Chemistry, 278, 10128-10133.
Ossofsky, H. (1976). Affective and atopic disorder and cyclic AMP. Comprehensive Psychiatry, 17, 335-346.
Paleologos, M., Cumming, R., & Lazarus, R. (1998). Cohort study of vitamin C intake and cognitive impairment. American Journal of Epidemiology, 148, 45-50.
Parle, M., & Dhingra, D. (2003). Ascorbic acid: a promising memory-enhancer in mice. Journal of Pharmacological Sciences, 93, 129-135.
Parmentier, R., Ohtsu, H., Djebbara-Hannas, Z., Valatx J., Watanabe, T., et al. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. (2002). Journal of Neuroscience, 22, 7695-7711.
Passani, M., Bacciottini, L., Mannaioni, P., & Blandina, P. (2000). Central histaminergic system and cognition. Neuroscience & Biobehavioral Reviews, 24, 107-113.
Passani, M., Line, J-S., Hancock, A., Crochet, S., & Blandina, P. (2004). The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends in Pharmacological Sciences, 25, 618-625.
Peitsaro, N., Kaslin, J., Anichtchik, O., & Panula, P. (2003). Modulation of the histaminergic system and behaviour by alpha-fluoromethylhistidine in zebrafish. Journal of Neurochemistry, 86, 432-441.
Perrig, W., Perrig, P., & Stahelin, H. (1997). The relation between antioxidants and memory performance in the old and very old. Journal of the American Geriatrics Society, 45, 718-724.
Petrie, W. & Ban, J. (1985). Vitamins in psychiatry: do they have a role? Drugs, 30, 58-65.
Pfeiffer, C. (1987). Nutrition and mental illness. Rochester: Healing Arts Press.
Pilc, A., Rogoz, Z., & Skuza, G. (1982). Histidine-induced bizarre behaviour in rats: the possible involvement of central cholinergic system. Neuropharmacology, 21, 781-785.
Popoli, M., Brunello, N., Perez, J., & Racagni, G. (2000). Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs. Journal of Neurochemistry, 74, 21-33.
Prast, H., Argyriou, A., & Philippu, A. (1996). Histaminergic neurons facilitate social memory in rats. Brain Research, 734, 316-318.
Raman, I., Tong, G., & Jahr, C. (1996). b-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. Neuron, 16, 415-421.
Reader’s Digest Association. (1999). The healing power of vitamins, minerals, and herbs. Pleasantville: Reader’s Digest Association.
Reavley, N. (1998). The new encyclopedia of vitamins, minerals, supplements, and herbs. New York: Bookman Press.
Rebec, G., & Pierce, R. (1994). A vitamin as a neuromodulator: ascorbate release into the extracellular fluid of the brain regulates dopaminergic and glutamatergic transmission. Progress in Neurobiology, 43, 537-565.
Rebec, G., & Wang, Z. (2001). Behavioral activation in rats requires endogenous ascorbate release in striatum. Journal of Neuroscience, 21, 668-675.
Rebec, G., Barton, S., Marseilles, A., & Collins, K. (2003). Ascorbate treatment attenuates the Huntington behavioral phenotype in mice. Neuroreport, 14, 1263-1265.
Repka-Ramirez, M., & Baraniuk, J. (2002). Histamine in health and disease. Clinical Allergy and Immunology, 17, 1-25.
Rice, M. (2000). Ascorbate regulation and its neuroprotective role in the brain. Trends in Neuroscience, 23, 209-216.
Rivers, J. (1987). Safety of high-level vitamin C ingestion. Annals New York Academy of Sciences, 496, 445-454.
Rogers, M., Bloomingdale, K., Murawski, B., Soter, N., Reich, P., et al. (1986). Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosomatic Medicine, 48, 437-447.
Rose, R. (1988). Transport of ascorbic acid and other water soluble vitamins. Biochemica et Biophysica Acta, 947, 335-366.
Sakata, T., & Yoshimatsu, H. (1995). Homeostatic maintenance regulated by hypothalamic neuronal histamine. Methods of Finding in Experimental and Clinical Pharmacology, 17SC, 51-56.
Santos, N., Huston, J., Brandao, M. (2001). Escape behavior under tonic inhibitory control of histamine H(2)-receptor mediated mechanisms in the midbrain tectum. Behavioural Brain Research, 124, 167-175.
Sarri, E., Picatoste, F., & Claro, E. (1995). Neurotransmitter-specific profiles of inositol phosphates in rat brain cortex: relation to the mode of receptor activation of phosphoinositide phospholipase C. Journal of Pharmacology and Experimental Therapeutics, 272, 77-84.
Schwaninger, M., Blume, R., Kruger, M., Lux, G., Oetjen, E., et al. (1995). Involvement of the Ca2±dependent phosphatase calcineurin in gene transcription that is stimulated by cAMP through cAMP response elements. Journal of Biological Chemistry, 270, 8860-8866.
Shankaran, M., Yamamoto, B., & Gudelsky, G. (2001). Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT. Synapse, 40, 55-64.
Sharma, S., & Wilson, C. (1980). The cellular interaction of ascorbic acid with histamine, cyclic nucleotides and prostaglandins in the immediate hypersensitivity reaction. International Journal of Vitamin and Nutrition Research, 50, 163-70.
Shelton, R., Mainer, D., & Sulser, F. (1996). cAMP-dependent protein kinase activity in major depression. American Journal of Psychiatry, 153, 1037-1042.
Shenolikar, S., & Nairn, A. (1991). Protein phosphatases: recent progress. Advances in Second Messenger Phosphoprotein Research, 23, 1-121.
Shimizu, M., Nishida, A., Fukuda, H., Saito, H., & Yamawaki, S. (1994). Inhibitory effect of imipramine on depolarization-induced increases in intracellular Ca2+ of rat cortical neurons. European Journal of Pharmacology, 268, 65-71.
Silver, P., Sigg, E., & Moyer, J. (1986). Antidepressants and protein kinases: inhibition of Ca2±regulated myosin phosphorylation by fluoxetine and iprindole. European Journal of Pharmacology, 121, 65-71.
Sloboda, R., Rudolph, S., Rosenbaum, J., & Greengard, P. (1975). Cyclic AMP-dependent endogenous phosphorylation of a microtubule-associated protein. Proceedings of the National Academy of Sciences USA, 72, 177-181.
Smith, M., Makino, S., Kvetnansky, R., & Post, R. (1995). Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. Journal of Neuroscience, 15, 1768-1777.
Smythies, J. (1998). Every Person’s Guide to Antioxidants. London: Rutgers University.
Snodgrass, S. (1992). Vitamin neurotoxicity. Molecular Neurobiology, 92, 41-73.
Stabel, S., & Parker, P. (1991). Protein kinase C. Pharmacology & Therapeutics, 51, 71-95.
Steinman, L. (2004). Elaborate interactions between the immune and nervous systems. Nature Immunology, 5, 575-581.
Stevenson, J., & ETAC study group. (2003). Relationship between behavior and asthma in children with atopic dermatitis. Psychosomatic Medicine, 65, 971-975.
Subramanian, N. (1977). On the brain ascorbic acid and its importance in metabolism of biogenic amines. Life Sciences, 20, 1479-1484.
Subramanian, N. Nandi, B., Majumber, K., & Chatterjee, I. (1974). Effect of ascorbic acid on detoxification of histamine in rats and guinea pigs under drug treated conditions. Biochemical Pharmacology, 23, 637-641.
Taglialatela, M., Timmerman, H., & Annunziato, L. (2000). Cardiotoxic potential and CNS effects of first-generation antihistamines. TiPS, 21, 52-56.
Takahashi, K., Suwa, H., Ishikawa, T., & Kotani, H. (2002). Targeted disruption of H3 receptors results in changes in brain histamine tone leading to an obese phenotype. Journal of Clinical Investigation, 110, 1791-1799.
Thomas, T. & Zemp, J. (1977). Inhibition of dopamine-sensitive adenylate cyclase from rat brain striatal homogenates by ascorbic acid. Journal of Neurochemistry, 1977, 663-665.
Tisdale, M. (1975). Inhibition of cyclic adenosine 3’-5’-monophosphate from Walker carcinoma by ascorbic and dehydroascorbic acids. Biochemical and Biophysical Research Communications, 62, 877-882.
Tolbert, L., Thomas, T., Middaugh, L., and Zemp, J. (1979). Effect of ascorbic acid on neurochemical, behavioral, and physiological systems mediated by catecholamines. Life Sciences, 25, 2189-2195.
Tong, G., Shepherd, D., & Jahr, C. (1995). Synaptic desensitization of NMDA receptors by calcineurin. Science, 267, 1510-1512.
Traxer, O., Huet, B., Poindexter, J., Pak, C., & Pearle, M. (2003). Effect of ascorbic acid consumption on urinary stone risk formers. Journal of Urology, 170, 397-401.
Traynelis, S., & Wahl, P. (1997). Control of rat GluR6 glutamate receptor open probability by protein kinase A and calcineurin. Journal of Physiology, 503, 513-531.
Tuomisto, J., & Mannisto, P. (1985). Neurotransmitter regulation of anterior pituitary hormones. Pharmacological Reviews, 37, 249-332.
Tuomisto, L. (1994). Regulation of feeding behavior, with special reference to histamine. Journal of Physiology and Pharmacology, 45, 469-477.
Van Sweden, B., & Kamphuisen, H. (1984). Cimetidine neurotoxicity. EEG and behaviour aspects. European Neurology, 23, 300-305.
Vayda, W. (1994). Attack asthma. Port Melbourne: Lothian Books.
Victor, M., & Ropper, A. (2001). Adams and victor’s principles of neurology, 7th Ed. New York: McGraw-Hill.
Wachtel, H. (1982). Characteristic behavioral alterations in rats induced by rolipram and other selective adenosine cyclic 3’,5’-monophosphate phosphodiesterase inhibitors. Psychopharmacology, 77, 309-316.
Wachtel, H. (1990). The second-messenger dysbalance hypothesis of affective disorders. Pharmacopsychiatry, 23, 27-32.
Wada, H., Inagaki, N., Itowi, N., & Yamatodani, A. (1991). Histaminergic neuron system in the brain: distribution and possible functions. Brain Research Bulletin, 27, 367-370.
Wada, H., Inagaki, N., Yamatodani, A., & Watanabe, T. (1991). Is the histaminergic system a regulatory center for whole-brain activity? TiNS, 14, 415-418.
Walaas, S., & Greengard, P. (1991). Protein phosphorylation and neuronal function. Pharmacological Reviews, 43, 299-349.
Washko, P., Rotrosen, D., & Levine, M. (1991). Ascorbic acid in human neutrophils. American Journal of Clinical Nutrition, 54 (6-Suppl), 1221S-1227S.
Weinstein, A. (1987). Asthma: The complete guide to self-management of asthma and allergies for patients and their families. New York: Fawcett Crest.
Willems, E., Knigge, U. Jorgensen, H., Kjaer, A., & Warberg, J. (1999). Effect of selective blockade of catecholaminergic alpha and beta receptors on histamine-induced release of corticotrophin and prolactin. Neuroendocrinology, 69, 309-315.
Wilson, B., Shannon, M., & Stang, C. (2000). Nurses Drug Guide: 2000. Stamford: Appleton and Lange.
Wilson, C. (1982). Appetite for vitamin C: its relationship to cellular energy potential. International Journal for Vitamin and Nutrition Research Supplemental, 23, 173-185.
Winder, D., Mansuy, I., Osman, M., Moallem, T., & Kandel, E. (1998). Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin. Cell, 92, 25-37.
Wolcott, W., & Fahey, T. (2002). The metabolic typing diet. New York: Broadway Books.
Wray, B. (1998). Taking charge of asthma: a lifetime strategy. New York: John Wiley & Sons, Inc.
Xu, D., & Wells, W. (1996). Alpha-Lipoic acid dependent regeneration of ascorbic acid from dehydroascorbic acid in rat liver mitochondria. Journal of Bioenergetics and Biomembranes, 28, 77-85.
Yanai, K., Son. L., Endou, M., Sakurai, E., Nakagawasai, O., et al. (1998a). Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience, 87, 479-487.
Yanai, K., Son, L., Endou, M., Sakurai, E., & Watanabe, T. (1998b). Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization. Life Sciences, 62, 1607-1610.
Young, L., Li, P., Kish, S., Siu, K., Kamble, A., et al. (1993). Cerebral cortex Gsa protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorders. Journal of Neurochemistry, 61, 890-898.
Zafra, F., Lindholm, D., Castren, E., Hartikka, J., & Thoenen, H. (1992). Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. Journal of Neuroscience, 12, 4793-4799.
Zanotti, S., Mori, S., Radaelli, R., Perez, J., Racagni, G., et al. (1998). Modifications in brain cAMP- and calcium/calmodulin-dependent protein kinases induced by treatment with S-adenosylmethionine. Neuropharmacology, 37, 1081-1089.
About the author
Dr. Jensen is both a consultant and author in the BioMedical and Nutrition fields. He has previously written a book on both topics, The Failures of American Medicine, published in 2002. Dr. Jensen has also written a doctoral dissertation on how Vitamin C can reduce stress and allergies via its antihistamine effect. He has worked in a broad range of BioMedical fields, such as gene regulation, cancer research, and HIV vaccine development. However, Dr. Jensen eventually decided that helping people more directly would be more rewarding for everyone involved. He has since helped clients with dozens of different ailments. Dr. Jensen is a practitioner in the field of Metabolic Typing, which characterizes different biochemistries among people based on certain physical and behavioral traits they have.
