" 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.
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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.
…na the results interest me more in a way…which is the sad state of our situation. 
