Mast Cells Travel To The Brain

[Travis]

Mast cells travel to the brain and have been estimated to be the major source of brain histamine in people who have them. The range varies considerably: histologists have counted thousands in some people, and zero in others. These can be induced by immunogenic peptides derived from food, and also can be induced by ionizing radiation. Histamine is neurotransmitter proper. Normal brain histamine is created not from mast cells, but by the tuberomammillary nucleus—a brain structure which can be seen as analogous to the serotonergic raphe nucleus; and like the raphe nucleus, the tuberomammillary nucleus sends centimetre‐long projections throughout.

Brain histamine has consistently been shown to reduce learning in rats. Brain histamine is a stimulant, a property not necessarily in contradiction to its effects on learning. While it's true that other stimulants—such as nicotine, acetylcholine, and glutamate—promote learning, I can't think of a fundamental reason why a stimulant must promote memory consolidation (especially considering the weight of evidence which suggests otherwise):

Persinger, Michael A. "Mast cells in the brain: possibilities for physiological psychology." Physiological Psychology (1977)​

Mast cells have unique properties which allow localization, and are counted on the microscope by histologists. It would be—of course—impossible to count them all yet histologists ostensibly have the patience, discipline, and posture to count to over one thousand:

'Dropp's (1976, personal communication) latest investigations involved normal brains from 103 human subjects between 1 and 98 years of age. MCs were found only in the infundibulum, pineal body, area postrema, and supraoptic crest; four of the individuals demonstrated MCs within the subfornical organ while another three subjects showed MCs attached to choroid plexuses within the ventricles. Again large ranges in cell numbers were encountered. MCs within the adult pineal body ranged from only a few to 49,000, while those in the infundibulum ranged from 0 to 7,000.' ―Persinger​

'The laboratory rat demonstrates a similar marked intraspecies variation. Total brain MCs ranged between 333 and 4,358 in 10 hooded rats and between 632 and 1,205 in 3 albino rats.' ―Persinger​

'Dropp (1972, 1976) reported between 0 and 1,500 total MC numbers within the brains of squirrel monkeys, but found no brain MCs within five mulatta monkeys; three chimpanzees displayed 8,600, 15,470 and 69,570 total brain MCs. Thirteen cat brains analyzed by Dropp (1974) displayed total MCs ranging from 144 to 203,226.' ―Persinger​

Imagine the histologists relief upon seeing a brain with no mast cells. What is good for the histologist is good for the subject—that is to say before, when they were still alive.

Total mast cell numbers exhibit great interpersonal variation, and does psychology. There has been a convincing histaminergic theory of schizophrenia proposed (Heleniak, 1999), risk ratios of ~4 have been found between celiac disease and schizophrenia (Kalaydjian, 2005), mast cells in the celiac intestine have been found elevated approximately threefold over controls (Strobel, 1983), and histamine has actually been detected the brain of schizophrenics at levels 2.6 that of controls (Prell, 1995). Such findings might suggest that it's actually the histamine that is doing this, and not oft‐speculated gluten exorphin also perennially found elevated in the cerebospinal fluid of patients diagnosed with same condition (Dohan, 1988). But this conflicting theory only strengthens the histaminergic one, since gluten exorphins in the brain are both indicative of current wheat consumption and also the inability of the subject to completely hydrolyze the proline‐rich peptides found therein—both prerequisites for an immunogenic reaction to gluten.

'A report by Hadjivassiliou et al. (15) showed that 57% of patients with neurological dysfunction of unknown cause had serological evidence of gluten sensitivity in contrast to the control rate of only 12%.' ―Kalaydjian​

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Strobel, S. "Human intestinal mucosal mast cells: expanded population in untreated coeliac disease." Gut (1983) [right image]
Prell, George D. "Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms." Schizophrenia research (1995) [left image]
​

Mast cells travel to the brain a fact which has been proven in two separate rat studies—at minimum. The way this had been proven was through the use of a green fluorescent dye to stain mast cells ex vivo—using chloromethylfluorescein diacetate, which is incorporated into the cell and trapped—with these same labeled green cells being then injected afterwords into a living, and rather furry, rat. Mast cells also contain tryptophan which absorbs blue light strongly, resulting a red reflection when viewed under many lighting conditions. Bombarding the cell with blue, or near ultraviolet, light results in dim tryptophan (since most blue light is absorbed) but the characteristic green of chloromethylfluorescein emitting at 520λ is apparent. The superposition of the two images or course makes yellow; but more importantly, this proves that mast cells migrate into the brain:

Silverman, Ann-Judith. "Mast cells migrate from blood to brain." Journal of Neuroscience (2000)​

In the year 1985 Robert C. Goldschmidt counted mast cells in the rat brain, and had also determined the histamine content of the same brains. His experiment provided the data necessary to correlate mast cells and brain histamine. He drew two distinctions, and had made two separate correlations: thalmic histamine vs mast cells, and whole brain histamine vs mast cells.

'These results are direct biochemical evidence for a contribution by MCs to brain HA levels, and indicate that thalamic MCs contribute up to 90% of the HA in thalamus, and up to 50% of whole brain HA levels.' ―Goldschmidt​

​

'The significant correlations between MC numbers and thalamic HA levels (Fig. 2) also provide a method to estimate directly the amount of brain HA contributed by MCs. Thus, without making any assumptions about other stores of thalamic HA, the y-intercepts of the regression lines of Fig. 2 are suggestive of the mean thalamic HA levels in the absence of MCs (6.8 and 8.5 ng for males and females, respectively). With these values for non‐MC histamine, the ranges of thalamic HA values found (Fig. 2) suggest that thalamic MCs contribute a mean of 81% (0-92%) and 54% (0-82%) of the thalamic HA in males and females, respectively. Similarly, the slopes of these regression lines provide estimates of the mean HA content per MC, i.e., 2.5 and 1.3 pg/cell, for males and females, respectively.' ―Goldschmidt
​

Also found by Goldschmidt was that range of values, going from zero to thousands. At 2.5 picograms histamine per mast cell, this can contribute up to 90% of total brain histamine in some rats. The correlation between mast cells and brain histamine was very good, what you'd rightly expect from more mast cells—migrating immunogenic cells known specifically for releasing histamine, much more than they are known for anything else.

'Thalamic HA content was significantly correlated with the estimated thalamic MC numbers both in males (r = 0.843) and in females (r = 0.678).' ―Goldschmidt

​

'Individual levels ranged over more than an order of magnitude in both sexes (males: 89–1, 138 ng/g; females: 60–596 ng/g). Whole brain levels were 58 ± 3 ng/g in males (33–89 ng/g) and 54 ± 3 ng/g in females (37–84 ng/g, Table I), not significantly different' ―Goldschmidt​

Mast cells are migratory cells, induced by both by immunogenic stimulation and radiation (Ibrahim, 1973). These have been shown capable of migrating to the brain where they can contribute up to 90% of total histamine. Of course, none of this would matter if histamine was totally benign—but it's not!

Goldschmidt, Robert C. "Rat brain mast cells: contribution to brain histamine levels." Journal of neurochemistry (1985)​

Histamine decreases learning in various rat models measured in various ways, differing both in method of histaminergic manipulation and mnemonic metric. The simplest and straightforward is, of course, raising histamine directly; this can be done either by intracranial injection or the serological delivery of amino acid histidine via injection or ingestion; histamine synthesis from serum histadine follows Fernstrom‐like serotonin/tryptophan kinetics, having appreciable brain uptake while also being liable to the influence competing amino acids—a different set in the case of histidine (Taylor, 1972; Schwarz, 1971).

'The intraperitoneal administration of L-histidine in a dose of 1000 mg/kg increased threefold the whole brain levels of histamine in the mouse. This increase was evident in all brain regions except the medulla oblongata-pons.' ―Taylor

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'Administration of L-histidine at the rate of 500 mg/kg induced an increase of nearly 50 per cent in the level of histamine in rat brain which lasted several hours.' ―Schwarz
​

Although protein ratios would be expected to alter brain histidine levels, the production capacity of mast cells would likely overshadow subtle dietary manipulations. Worrying about the His/Σ(cAA) ratio while having mast cells present in the brain would be tantamount to worrying about Joey's dilemma with Phoebe—from the television program Friends—while you're house is on fire. Perhaps those on a totally hypoimmunogenic diet could worry about such things, but considering how vitally important histidine is it probably shouldn't be greatly diminished. Histidine is necessary to chelate zinc and transport it throughout the body, is used as a structural component for newly‐synthesized proteins, and also becomes urocanic acid—an ultraviolet light‐absorbing molecule of the skin which protects against sun damage.

In the most direct type of experiment, histamine is applied directly to the brain via cannula (Eidi, 2003). The use of control rats eliminates the possibility that trauma has anything to do with this, since the same surgery is given to both; control rats were also administered saline in this study. As a result of direct histamine application and passive avoidance electric foot‐shock trials, it had been determined that histamine is a detriment to learning:

'Further analysis showed that post-training injections of histamine or scopolamine decreased memory retention, and lower doses of the two drugs, which did not elicit any response by themselves, showed inhibition of memory retention.' ―Eidi​

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'Our data indicate that the memory improvement induced by acetylcholine or nicotine can be impaired by histamine.
​

Cimetidine is the classic histamine antagonist, and this too was used. Nicotine and acetylcholine are nearly functionally synonymous, and work to the same end on the nicotinic acetylcholine receptor. These two drugs have long been proven to facilitate things like word recall, reaction time, and attention. The drugs scopolamine (used) and atropine (not used) are the classic muscarinic receptor antagonists. Perhaps most noteworthy is the fact that cimetidine, a histamine antagonist, increased learning.

'The present data show that scopolamine, the muscarinic receptor antagonist, potentiates the histamine-induced decrease of memory retention, while the histamine receptor antagonists, pyrilamine and cimetidine, increased the acetylcholine- or nicotine-induced enhancement, but attenuated the inhibitory response induced by scopolamine.' ―Eidi​

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'Administration of histamine (5–20 μg/rat) reduced, but the histamine H₁ receptor antagonist, pyrilamine (10–50 μg/rat), and the histamine H₂ receptor antagonist, cimetidine (1–50 μg/rat), increased memory retention in rats.' ―Eidi​

Histadine antagonizes both nicotine and acetylcholine; the converse is also true. This could be the reason why schizophrenics smoke more often than the general population (de Leon, 2005); they could be using nicotine as a device to counteract gluten‐induced mast cell histamine. The odds ratio between schizophrenia and smoking was found to be 5.9×, similar to the ~4× risk ratios between schizophrenia and gluten (and the ~3× elevated intestinal mast cells in celiacs). I do remember—over ten years ago after not having eaten gluten for months—I had found myself to be nearly chain‐smoking Nat Sherman MCDs in an attempt to ward‐off the lobotomizing effects I felt impinging on my brain which had incurred after eating wheatbread during an acute money‐deficiency. Perhaps it was the exorphins, but perhaps the histamine. Gluten peptides have been shown, like cortisol, to release histamine from mast cells as well as induce them.

Eidi, Maryam. "Effects of histamine and cholinergic systems on memory retention of passive avoidance learning in rats." European journal of pharmacology (2003)
de Leon, Jose. "A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors." Schizophrenia research (2005)​

 

[aguilaroja]

Mast cells travel to the brain and have been estimated to be the major source of brain histamine in people who have them. The range varies considerably...
Cimetidine is the classic histamine antagonist, and this too was used. ... Perhaps most noteworthy is the fact that cimetidine, a histamine antagonist, increased learning.

There’s certainly many lines of evidence for histamine’s role in brain impairment. @haidut has multiple posts describing beneficial effects of the H2-blocker faomotidine. Famotidine is in the same class of anti-histamines as Cimetidine, with rationale in the @haidut posts for preferring famotidine.

https://www.ncbi.nlm.nih.gov/pubmed/23764683
“…the PANSS (Positive and Negative Syndrome Scale) Total score and the General subscore as well as the CGI showed significantly (P < 0.05) greater change in the famotidine group than in the placebo group. No significant adverse effects were observed.”

Stroke induces histamine accumulation and mast cell degranulation in the neonatal rat brain. - PubMed - NCBI
In mast cells, histamine immunoreactivity is detected at 2, 6 and 12 h after ischemia, whereas it disappears at 24 h, when a concomitant degranulation of mast cells is observed. Taken together, these data suggest that the recruitment of cerebral mast cells releasing histamine may contribute to ischemia-induced neuronal death in the immature brain.

Mast cell stabilization limits hypoxic-ischemic brain damage in the immature rat. - PubMed - NCBI
The cromolyn treatment inhibited MC [mast cell] migration into the CNS (p < 0.05) and limited brain damage more than 50% (p < 0.01) vs. saline controls.

 

[Travis]

The effects of histadine on memory is certainly not a unique finding. Other experiments have observed the same general effect; this is very consistent, and I've yet to see an exception. Besides applying histamine directly, there are other ways to predictable alter the histamine levels. In the late '70s a very specific drug had been developed, α-fluoromethylhistadine, which is also able to achieve this. Alpha-fluoromethylhistadine inhibits histadine decarboxylase, an enzyme which does exactly as stated: it decarboxylates histidine into histamine. Alpha-fluoromethylhistadine is a high-affinity ligand and suicide inhibitor which completely disables said enzyme until more is synthesized, all the while having very little effect on anything else. Data from a 1980 Parisian study demonstrates this:

'Histamine decarboxylase activity was reduced by about 70% in both regions even at the low dose of 10 mg/kg of the (±) stereoisomer, corresponding to 5 mg/kg of the active form. After a dose of 20 mg/kg, the enzyme activity was nearly destroyed in these two tissues.' ―Garbarg​

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'Considering the dose of inhibitor required to obtain the maximal in vivo effect (Table 2), (+)-α-FMH appears to be 20-30 times more potent than brocresine or α-hydrazino histidine (Taylor and Snyder, 1971; Schwartz et al., 1972), two competitive inhibitors of HD which, in addition, lack selectivity. (+)-α-FMH is also more effective than a-chloromethylhistidine, another ‘suicide’ inhibitor of HD as shown by the less complete and shorterlasting inhibition of the enzyme in the stomach of rats treated with the latter agent (Lippert et al., 1979).' ―Garbarg​

He cites Schwarz because he's the veritable Fernstrom of brain histadine research; but more importantly, he proves that α-fluoromethylhistadine is a reliable way to lower brain histamine. Drugs like this make noninvasive experimental histamine manipulation possible, and this very drug has been used on rats sent through the radial arm maze—perhaps the most sophisticated method for gauging memory in the rodent.

The results are in concord with the study on histamine and cimetidine: Lowering histamine in the rat brain using a specific inhibitor of histadine decarboxylase improves performance in the radial arm maze:

'FMH does not necessarily reduce histamine levels in the hippocampus, becausecentral histaminergic neurons have scarce projections in the hippocampus of rats.' ―Sakai​

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'In conclusion, histamine depletion by FMH caused enhancements of maze study for 11 days without locomotor changes. We advocate that long-term histamine depletion influenced amino acid levels and improved maze performance on day 6, but the mechanism of amino acid changes is unknown. Further studies would provide more information on the role of central histamine.' ―Sakai​

You can see performance starting to equilibrate as the drug wears off and new enzymes are created (left image). Measurements taken six days later show roughly a 50% reduction in brain histamine, with very little effect on the other neurotransmitters measured (right image).

Garbarg, M. "Inhibition of Histamine Synthesis in Brain by α‐Fluoromethylhistidine, a New Irreversible Inhibitor: In Vitro and In Vivo Studies." Journal of neurochemistry (1980)
Sakai, Naruhiko. "Depletion of brain histamine induced by α-fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino acid levels." Life sciences (1998)​

The use of receptor agonists, receptor antagonists, and enzyme inhibitors is not the only way to manipulate histamine levels. There is yet another, more brutal way to achieve this end. Because the tuberomammillary nucleus is centralized, like the serotonergic raphe, destruction of the nucleus inhibits histamine throughout the entire brain. This has been done; the blueprints were already in place from the routine ablation of the raphe nuclei performed when investigating effects of serotonin. Experiments done in this manner, perhaps surprisingly, also show an increase in learning. This says quite a bit about histamine, when literal brain damage can increase learning. This is similar to the semantic double negative or the logical double negation (~(~A)=A); eliminating a negative (histamine) makes a positive.

'As depicted in Fig. 2, the TM-lesion group showed a higher performance level when compared to the control group in both long-term retention sessions,' ―Segura-Torres​

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'In summary, a unilateral tuberomammillary lesion administered 24 h before the acquisition session enhanced long-term memory.' ―Segura-Torres​

Besides cimetidine and pyrilamine (Eidi, 2003), the histamine receptor antagonist chlorpheniramine has also shown capable of improving the memory of rodents (Frisch, 2007). These are consistent findings, and histamine appears worse than serotonin in this regard. Histamine has an undeniable negative effect on memory, perhaps making cimetidine a candidate for a memory‐enhancing drug.

Segura-Torres, Pilar. "Tuberomammillary nucleus lesion facilitates two-way active avoidance retention in rats." Behavioural brain research (1996)​

Histamine is released as a result of parasitic infection and resistant food peptides. Perhaps for this reason, its effects were never 'meant' to be beneficial. Some researchers consider histamine a punisher, a term used in contradistinction to the term 'reinforcer.' Opiates reinforce good behavior (such as growing poppies), and histamine punishes both the grain user and inhabitants of parasite‐endemic areas.

'In contrast to the HA antagonists, histamine is an effective punisher. Goldberg (1980) showed that IV histamine suppressed the behaviour on which it was contingent. Pretreatment with diphenhydramine reversed this effect,' ―White​

'When choosing between cocaine alone and cocaine followed immediately by histamine, preference increased with histamine dose from indifference to >80% choice of cocaine alone.' ―Woolverton & Green ​

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'Finally, the neuronal histamine system appears to act as a punisher, preventing the reinforcement of behaviours which led to the dangerous system in the first place (Section 8.3).' ―Brown​

'This could be prevented by pretreatment with an H₁ but not an H₂ antagonist. Thus, as with peripherally administered histamine, the punishing effects appear to be mediated via H₁ receptors.' ―White​

If histamine can be seen as a 'punisher,' than so can cortisol—a steroid long‐known to degranulate mast cells. In this way, a human or animal with brain mast cells could become adverse to stressful conditions. They could even perhaps be afraid of violence—but almost certainly punished for it—almost as in Burgess' science fiction novel A Clockwork Orange.

Brain mast cells don't seem conducive for maintaining mental poise during times of stress; nobody want's to feel nonplussed or at times of confrontation, or emergency.

Brown, Ritchie E. "The physiology of brain histamine." Progress in neurobiology (2001)
White, Jason M. "Behavioural effects of histamine and its antagonists: a review." Psychopharmacology (1988)
Woolverton, William L. "Suppression of cocaine self-administration in monkeys: effects of delayed punishment." Psychopharmacology (2012)​

As in the case of schizophrenia, autism has also been associated with wheat. Autism has also been correlated with casein, which also has an indigestible proline–glutamine repeat (though not nearly as bad as gluten, in terms of percent total protein). Noteworthy is that histamine is also antinocipeptive, making an additional way—besides exorphins—to logically explain the self‐harm seen in recipients of autism diagnosis. And like schizophrenia, the exorphins measured in the cerebospinal fluid of the 'autistic' represent: (1) This prior consumption of the parent protein, be it casein or gliadin, and: (2) The inability to completely hydrolize the offending peptide. Wherever you have a seven amino acid food peptide in the brain, you likely also have elevated histamine—at least somewhere. Most plant proteins—and even eggs and beef—break down completely. For these reasons the positive studies concerning wheat, dairy, and autism strengthen the histamininergic theory of autism. Some of the best evidence comes from studies on a histamine receptor (H₃) antagonism (Baronio, 2014). However, it's clear to The Writer that casein does have μ‐opiate‐like effects that could also be significant. I don't feel that it's necessary to have one cause for autism or schizophrenia since they are diagnosed based on subjective metrics and subject to the assessor's biases. These conditions aren't like real, frank diseases like pellagra and cancer; diagnosing these diseases follow an unambiguous yes/no rule—immediately discernible. Pseudo‐diseases like autism fall on a spectrum—admittedly.

'The Control mice spent significantly more time exploring the novel mouse 1 than the novel object.' ―Baronio​

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'In the present study, VPA mice treated with CPX displayed a reduced repetitive behavior in the marble burying test. Stereotypy and behavior rigidity are widely known as core and defining features of ASD.' ―Baronio​

'In the 80’s, the use of L-histidine, a precursor of brain histamine, modified the methamphetamine (MET)-induced stereotypy in mice [39].' ―Baronio​

I'm fairly certain that I know what schizophrenia feels like; I'm also fairly certain that it comes from seed storage proteins found in wheat, rye, barley, and oats when absorbed as peptides over ~10 amino acids long. And with the very strong risk ratios reported above, I think there is also good epidemiological evidence for this (and the 2.6× hard, analytical, chemical determination of elevated histamine in schizophrenics).

Niacin has traditionally been used to treat schizophrenia since Abram Hoffer had pioneered its use. It causes flushing, and so does histamine. I don't think it's a stretch to think that it works on histamine receptors, especially considering the molecular similarity between the two.

'The data presented here indicate that both receptors are involved [H₁, H₂] in the vascular action of histamine and that histamine is the principal mediator of flushing in this condition.' ―Roberts​

And it's far simpler that Hoffer & Osmond's explanation, which rely on roundabout ceruloplasmin copper and zinc kinetics (their explanations can be found here). Niacinamide also has been prescribed for schizophrenia, yet does not cause a flush—but histamine has three separate receptors, all three with different actions and binding propensities.

Baronio, Diego. "Effects of an H₃R antagonist on the animal model of autism induced by prenatal exposure to valproic acid." PLoS One (2015)
Roberts, L. Jackson. "Blockade of the flush associated with metastatic gastric carcinoid by combined histamine H1 and H2 receptor antagonists: evidence for an important role of H2 receptors in human vasculature." New England Journal of Medicine (1979)​

 

[Travis]

There’s certainly many lines of evidence for histamine’s role in brain impairment. @haidut has multiple posts describing beneficial effects of the H2-blocker faomotidine. Famotidine is in the same class of anti-histamines as Cimetidine, with rationale in the @haidut posts for preferring famotidine.

I never knew it was so bad. I think the mast cells in the brain makes the best case between food and psychosis since they can elevate a neurotransmitter considerably. It's rare to see an increase in a neurotransmitter of over 100% baseline; histamine can do this—and then some.

If I recall correctly cimetidine it's a pretty safe drug.

 

[Koveras]

I never knew it was so bad. I think the mast cells in the brain makes the best case between food and psychosis since they can elevate a neurotransmitter considerably. It's rare to see an increase in a neurotransmitter of over 100% baseline; histamine can do this—and then some.

If I recall correctly cimetidine it's a pretty safe drug.

I think some of the risks around cimetidine related to it's ability to increase prolactin

• Rojdmark, S. (1983). Prolactin release in man: influence of cimetidine, thyrotrophin-releasing hormone and acute hypercalcaemia. Acta Endocrinol (Copenh), 102(4), 481-485.

Also interesting to note that cimetidine inhibits diamine oxidase (DAO, aka. histaminase) which is partly responsible for the metabolism and inactivation of histamine

• Finazzi-Agro, A., Floris, G., Fadda, M. B., & Crifo, C. (1979). Inhibition of diamine oxidase by antihistaminic agents and related drugs. Agents Actions, 9(3), 244-247.
• Wantke, F., Hemmer, W., Focke, M., Stackl, W., Gotz, M., & Jarisch, R. (2001). Are adverse effects of sildenafil also caused by inhibition of diamine oxidase? Urol Int, 67(1), 59-61. doi:10.1159/000050946

“Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation.”

“The main enzyme for metabolism of ingested histamine is diamine oxidase (DAO).”​

And decreased DAO and subsequently increased histamine being related to a number of intestinal issues

“An impaired histamine degradation based on a reduced DAO activity and the resulting excess of histamine may cause numerous symptoms mimicking an allergic reaction. “

“Ingestion of histamine-rich food, alcohol, or drugs that release histamine or block DAO may provoke diarrhea, headache, congestion of the nose, asthmatoid wheezing, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in these patients.”​

• Enko, D., Kriegshauser, G., Halwachs-Baumann, G., Mangge, H., & Schnedl, W. J. (2017). Serum diamine oxidase activity is associated with lactose malabsorption phenotypic variation. Clin Biochem, 50(1-2), 50-53. doi:10.1016/j.clinbiochem.2016.08.019
• Enko, D., Meinitzer, A., Mangge, H., Kriegshauser, G., Halwachs-Baumann, G., Reininghaus, E. Z., . . . Schnedl, W. J. (2016). Concomitant Prevalence of Low Serum Diamine Oxidase Activity and Carbohydrate Malabsorption. Can J Gastroenterol Hepatol, 2016, 4893501. doi:10.1155/2016/4893501
• Hoffmann, K. M., Gruber, E., Deutschmann, A., Jahnel, J., & Hauer, A. C. (2013). Histamine intolerance in children with chronic abdominal pain. Arch Dis Child, 98(10), 832-833. doi:10.1136/archdischild-2013-305024
• Jarisch, R., & Wantke, F. (1996). Wine and headache. Int Arch Allergy Immunol, 110(1), 7-12.
• Ji, Y., Sakata, Y., & Tso, P. (2011). Nutrient-induced inflammation in the intestine. Curr Opin Clin Nutr Metab Care, 14(4), 315-321. doi:10.1097/MCO.0b013e3283476e74
• Kovacova-Hanuskova, E., Buday, T., Gavliakova, S., & Plevkova, J. (2015). Histamine, histamine intoxication and intolerance. Allergol Immunopathol (Madr), 43(5), 498-506. doi:10.1016/j.aller.2015.05.001
• Maintz, L., & Novak, N. (2007). Histamine and histamine intolerance. Am J Clin Nutr, 85(5), 1185-1196.
• Manzotti, G., Breda, D., Di Gioacchino, M., & Burastero, S. E. (2016). Serum diamine oxidase activity in patients with histamine intolerance. Int J Immunopathol Pharmacol, 29(1), 105-111. doi:10.1177/0394632015617170
• Music, E., Korosec, P., Silar, M., Adamic, K., Kosnik, M., & Rijavec, M. (2013). Serum diamine oxidase activity as a diagnostic test for histamine intolerance. Wien Klin Wochenschr, 125(9-10), 239-243. doi:10.1007/s00508-013-0354-y
• Reilly, M. A., & Schayer, R. W. (1970). In vivo studies on histamine catabolism and its inhibition. Br J Pharmacol, 38(3), 478-489.
• Rosell-Camps, A., Zibetti, S., Perez-Esteban, G., Vila-Vidal, M., Ferres-Ramis, L., & Garcia-Teresa-Garcia, E. (2013). Histamine intolerance as a cause of chronic digestive complaints in pediatric patients. Rev Esp Enferm Dig, 105(4), 201-206.

Some other points of interest:

• Serotonin inhibits DAO and thus may increase histamine levels
• Histamine increases the synthesis of estrogen (participating in a loop where estrogen increases the synthesis of serotonin).
• Estrogen can also augment the action of histamine, possibly through serotonin as mentioned above and also potentially through the augmentation of nitric oxide signalling
• Long chain fats, such as polyunsaturated fats, activate mast cells and increase the secretion of histamine (and likely serotonin as well)
• Part of this effect may be due to the role fats have on increasing the absorption of endotoxin
• Endotoxin activates the enzyme histamine decarboxylase, which increases the formation of histamine
• The formation and degranulation of mast cells is increased in hypoxia, and hypoxia in intestinal cells may be brought about partially by effects of endotoxin and serotonin on energy metabolism

“A further matter of interest is the competitive inhibition of diamine oxidase by serotonine and tryptamine, typical substrates of mitochondrial monoamine oxidase. “

“Various drugs were tested as inhibitors of diamine oxidase on the basis of chemical relationships to the enzyme substrates. It was found that serotonine tryptamine and phenformin are good competitive inhibitors while cimetidine and pheniprazine are non-competitive inhibitors. “

“Histamine has been shown to stimulate, in a dose- dependent manner, the synthesis of estradiol via H1R “

“Thus, histamine may augment dysmenorrhea by increasing estrogen concentrations. And, in reverse, estrogen can influence histamine action. A significant increase in weal and flare size in response to histamine has been observed to correspond to ovulation and peak estrogen concentrations. In pregnancy, DAO is produced at very high concentrations by the placenta, and its concentration may become 500 times that when the woman is not pregnant. This increased DAO production in pregnant women may be the reason why, in women with food intolerance, remissions frequently occur during pregnancy”

“The gut microbiota affects intestinal permeability and mucosal mast cell (MMCs) responses. Activation of MMCs has been associated with absorption of dietary fat.”

“The intestinal microbiota appears to activate MMCs following the ingestion of fat in rats—this contributes to fat-induced intestinal permeability.”

“There is increasing evidence linking gut local inflammatory events with the intake of nutrients. Our recent studies, using the conscious lymph fistula rat model, demonstrate that fat absorption activates the intestinal mucosal mast cells. This is accompanied by a dramatic increase in the lymphatic release of mast cell mediators including histamine, rat mucosal mast cell protease II (RMCPII), as well as the lipid mediator prostaglandin D2 (PGD2).”

“Studies in our laboratory have shown that DAO secretion into intestinal lymph significantly increases during active fat absorption. Lymphatic histamine and DAO both peak at the same time during fat absorption, suggesting a close relationship between the two. It is tempting to speculate that DAO is released during fat absorption to safeguard against the deleterious effect of the excessive histamine secretion during fat absorption. The increased release of histamine and DAO is specific to fat feeding and is not shared by carbohydrate or protein feeding.“

“Pretreatment of mice with endotoxin or with Freund's adjuvant, irritants known to cause activation of histidine decarboxylase, failed to affect histamine catabolism”

“Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked reduction in mucosal oxygen concentrations.”

“During active inflammation, resident macrophages and dendritic cells (DCs) become activated and produce proinflammatory cytokines and chemokines that trigger Tcell differentiation and the recruitment of inflammatory cells from the peripheral blood into the mucosa. The infiltrated immune cells consume a large amount of the local oxygen in the mucosa and submucosa. At the same time, the oxygen supply from the bloodstream is decreased during inflammation as a result of microvascular occlusion and thrombosis. The resulting imbalance between oxygen consumption and supply renders the inflamed intestinal mucosa severely hypoxic.”​

DAO requires several nutritional cofactors such as Vitamin B6, Vitamin C, and copper

“Diamine oxidase (E.C. 1.4.3.6) is a copper enzyme “

“In addition, histamine degradation can be supported by the administration of vitamin C and vitamin B-6, which leads to an increase in DAO activity.”​

 

[Travis]

“The intestinal microbiota appears to activate MMCs following the ingestion of fat in rats—this contributes to fat-induced intestinal permeability.”

Could this be explained by the fact that histamine is a vasodilator? I know that it releases prostaglandin D₂, but I'm unsure which one interacts with the muscle on the vessel wall. If I had to bet, I would say histamine by counteracting serotonin; but so far there is no realistic theory on muscle contraction so it might take some effort to figure out exactly what is doing what.

 

[ddjd]

@Travis I was wondering if I could run this by you. I've had hair loss for years, but it's diffuse, so gradually thinning all over rather than just standard mpb.

Through peats work I've pinpointed that Adrenaline causes the shedding.

I know high histamine and high Serotonin are intimately involved too, I think because they both signal the release of Adrenaline. I know Serotonin antagonists (I'm still trying to work out which receptors exactly) stop my hair loss. And H1 antagonists stop my hair loss.

So anything that blunts Adrenaline, antagonises h1 receptor or antagonises Serotonin receptors stops my hair loss for 6-12 hours.

What I can't work out is what's the root cause of all of this. I know the gut is source of all my problems.

But specifically what do you think it could be? Is it mast cell related? DAO?

Any thoughts you might have much appreciated.

 

[Travis]

@Travis Through peats work I've pinpointed that Adrenaline causes the shedding.

Are you sure about that? The old experiments I had read showed that adrenaline is actually essential for hair growth.

After total adrenalectomy, complete hair loss is observed in animals. When the adrenal cortex is removed, then the animal generally grows thicker hair.

The older experiments I had read indicated that products of the adrenal cortex—such as cortisol—caused hair loss while that of the adrenal medulla (i.e. adrenaline) were required for hair growth . . . in sheep. I'm fairly certain that if you'd look on sci‐hub.cc you'd find indication of adrenaline promoting hair growth, or at least being necessary to maintain it.

 

[Travis]

@Travis I was wondering if I could run this by you. I've had hair loss for years, but it's diffuse, so gradually thinning all over rather than just standard mpb.

Through peats work I've pinpointed that Adrenaline causes the shedding.

I know high histamine and high Serotonin are intimately involved too, I think because they both signal the release of Adrenaline. I know Serotonin antagonists (I'm still trying to work out which receptors exactly) stop my hair loss. And H1 antagonists stop my hair loss.

So anything that blunts Adrenaline, antagonises h1 receptor or antagonises Serotonin receptors stops my hair loss for 6-12 hours.

What I can't work out is what's the root cause of all of this. I know the gut is source of all my problems.

But specifically what do you think it could be? Is it mast cell related? DAO?

Any thoughts you might have much appreciated.

Are you eating any immunogenic proteins, such as those found in wheat and oats? These can release interferon-γ and interferon-6 shown to induce phospholipase A₂ and cyclooxygenase‐2, respectively. These two enzymes, when working in tandem, powerfully increase all prostaglandins.

Immune activation has been shown to cause diffuse thinning. I think the phospholipase A₂ upregulated mice had diffuse thinning . .

click to embiggen

I found some interferon-γ mice. When the gene for interferon-γ is spliced next to a certain keratin gene, it is expressed only in the skin.
Above are such mice, with excessive interferon-γ being produced in the skin.

So on the practical level, the main causes appear to be: immunogenic food proteins (interferon-γ), salt imbalance (aldoseterone), linoleic acid (prostaglandin precursor), and stress (cortisol). Both cortisol and aldosterone are ligands for the mineralocorticoid receptor, known to transcribe the prostaglandin D synthase enzyme. All of the above act to increase the levels of prostaglandin D₂ on the skin in some manner.

It is important to avoid the immunogenic peptides derived form grains due to the strength of correlation between prostaglandin D₂ and hair loss.

Carroll, Joseph M.. "Transgenic mice expressing IFN-γ in the epidermis have eczema, hair hypopigmentation, and hair loss." Journal of investigative dermatology (1997)​

 

[peep]

@Travis
Is there really something like "histAdine" ?
HistidineDeCarboxylation, α-fluoromethylhistidine. Its all histidine like the amino acid histidine.

Because histadine would be a drug like loratadine for me.
And I found a lot of websites and articles using "histadine" too. But I always thought they mixed up histamine and histidine.

 

[Travis]

@Travis
Is there really something like "histAdine" ?
HistidineDeCarboxylation, α-fluoromethylhistidine. Its all histidine like the amino acid histidine.

Because histadine would be a drug like loratadine for me.
And I found a lot of websites and articles using "histadine" too. But I always thought they mixed up histamine and histidine.

They are close:

histidine − CO₂ = histamine​

The carboxyl groups of some amino acids are cleaved in the brain, and this carboxyl group becomes carbon dioxide and is floated away. The amino acid histidine can be viewed as the histamine prodrug, and large doses of histidine have been determined to increase brain histamine. It is unfortunate that the two words are so similar, and we should be glad that this is uncommon. Tryptophan becomes serotonin upon decarboxylation (−CO₂) and tyrosine becomes dopamine after decarboxylation (− CO₂) and hydroxylation (+ OH).

Histamine has a great range in the brains of people, so experimenting with it would only make you schizophrenic at worst (who've been found to have ~5× higher brain histamine than controls).

I'm done eating oats and grains, even in when they are free. I used to eat them like once a year, but since I never eat food like that I eat large amounts when I actually do. The raw vegan belly is small, but can stretch appreciably (think of the bulge inside of snakes after they eat a mouse). The neurological effects after eating grains, if the body responds to them, can last weeks since mast cells can travel to the brain—experimentally proven to do so, where they can contribute up to 90% of brain histamine (in rats at least).

 

[managing]

Cimetidine reduces stomach acid, which seems like a bad idea.

Also, are cimetidine/famotidene sedating like other H2 antagonists?

 

[peep]

They are close:

histidine − CO₂ = histamine
The carboxyl groups of some amino acids are cleaved in the brain, and this carboxyl group becomes carbon dioxide and is floated away. The amino acid histidine can be viewed as the histamine prodrug, and large doses of histidine have been determined to increase brain histamine. It is unfortunate that the two words are so similar, and we should be glad that this is uncommon. Tryptophan becomes serotonin upon decarboxylation (−CO₂) and tyrosine becomes dopamine after decarboxylation (− CO₂) and hydroxylation (+ OH).

Histamine has a great range in the brains of people, so experimenting with it would only make you schizophrenic at worst (who've been found to have ~5× higher brain histamine than controls).

I'm done eating oats and grains, even in when they are free. I used to eat them like once a year, but since I never eat food like that I eat large amounts when I actually do. The raw vegan belly is small, but can stretch appreciably (think of the bulge inside of snakes after they eat a mouse). The neurological effects after eating grains, if the body responds to them, can last weeks since mast cells can travel to the brain—experimentally proven to do so, where they can contribute up to 90% of brain histamine (in rats at least).

I think you did not get what I mean Look at the spelling.

You change from histIdine to histAdine. The amino acid is histIdine. NOT HistAdine. (Its i not a)
I know that there is Histamine. But no Histadine.

 

[tfcjesse]

Are you eating any immunogenic proteins, such as those found in wheat and oats? These can release interferon-γ and interferon-6 shown to induce phospholipase A₂ and cyclooxygenase‐2, respectively. These two enzymes, when working in tandem, powerfully increase all prostaglandins.

Immune activation has been shown to cause diffuse thinning. I think the phospholipase A₂ upregulated mice had diffuse thinning . .

View attachment 7759 click to embiggen

I found some interferon-γ mice. When the gene for interferon-γ is spliced next to a certain keratin gene, it is expressed only in the skin.
Above are such mice, with excessive interferon-γ being produced in the skin.

So on the practical level, the main causes appear to be: immunogenic food proteins (interferon-γ), salt imbalance (aldoseterone), linoleic acid (prostaglandin precursor), and stress (cortisol). Both cortisol and aldosterone are ligands for the mineralocorticoid receptor, known to transcribe the prostaglandin D synthase enzyme. All of the above act to increase the levels of prostaglandin D₂ on the skin in some manner.

It is important to avoid the immunogenic peptides derived form grains due to the strength of correlation between prostaglandin D₂ and hair loss.

Carroll, Joseph M.. "Transgenic mice expressing IFN-γ in the epidermis have eczema, hair hypopigmentation, and hair loss." Journal of investigative dermatology (1997)​

Does rice contain immunogenic proteins? Also, have you written any on correcting a salt imbalance?

What's your perspective on fish oil in this manner? Does the prostaglandin inhibiting effect outweigh the anti-thyroid effects?

I wonder if any one here has guinea pigged topical cyclosporine (or whichever was found to be most practical)..

 

[Travis]

I think you did not get what I mean Look at the spelling.

You change from histIdine to histAdine. The amino acid is histIdine. NOT HistAdine. (Its i not a)
I know that there is Histamine. But no Histadine.

Oh my god. That is especially confusing. Why did they name a drug histadine which has no resemblance to either histamine or histidine? It's almost like they were trying to get Google hits or something.. . .

Does rice contain immunogenic proteins? Also, have you written any on correcting a salt imbalance?

What's your perspective on fish oil in this manner? Does the prostaglandin inhibiting effect outweigh the anti-thyroid effects?

I wonder if any one here has guinea pigged topical cyclosporine (or whichever was found to be most practical)..

I think rice is pretty safe, but oleic acid also inhibits cyclooxygenase with only one unsaturated bond. I think olives would be a safer thing to eat than fish, and olive oil safer than fish oil.

Vitamin A can be made from β-catotene. I think this is safer since the enzyme required to do so is silenced by high retinoic acid levels, preventing overload. The ingestion of β-catotene goes through one extra regulatory loop than the ingestion of retinol.

Rice has a very safe protein. It is a bit low in lysine, but I'd think that'd be fine if you eat other foods (like you of course would).

Cyclosporine is expensive. It is a large cyclic protein and the production of which is relatively space and time consuming. It appears to selectively bind the cyclophilins, small transcription factors within the cell. I think it could have been the eponymous cyclophilin‐40 that's the main target. This binding event inhibits the cyclophilin's ability to transcribe γ-interferon, and doesn't seem to have many side-effects besides those on the kidney. I think these side-effects could perhaps be prevented if they are understood, and appear to have something to do with nitric oxide. I think cyclosporine would be interesting to toy around with, but this molecule is expensive and relatively hard‐to‐find.

I think perhaps salt imbalance can be corrected by avoiding fluctuations and consuming enough potassium. I know that sodium predictably lowers aldosterone in the short term, but know little about long‐term effects—or whether or not the kidneys are desensitized, leading to an increase and a new steady-state level. I think to get a fair idea of Na⁺/K⁺ homestasis one would have to read about renin, something I haven't read much about.

 

[haidut]

If I recall correctly cimetidine it's a pretty safe drug

In human studies it raises prolactin and also causes pneumonia in hospital patients for some reason.

 

[Travis]

But does it have any toxicity besides it's obvious histaminergic effects? Or to state it in another way, are the side‐effects any worse than other H₂ antagonists?

 

[haidut]

But does it have any toxicity besides it's obvious histaminergic effects? Or to state it in another way, are the side‐effects any worse than other H₂ antagonists?

I think it also disturbs steroid metabolism. I can't recall how exactly but I think it interferes with thyroid function and suppresses gonadal synthesis of steroids in males. Have not seen similar data on famotidine, which could be simply because it has not been studied yet.

 

[Travis]

But is it worse than histamine? (lol)

 

[aguilaroja]

In human studies it raises prolactin and also causes pneumonia in hospital patients for some reason.

But does it have any toxicity besides it's obvious histaminergic effects? Or to state it in another way, are the side‐effects any worse than other H₂ antagonists?

Yes, Cimetidine was the first H2-blocker. Ranitidine and famotidine followed. They are all OTC now in many places. Usually, I am pretty skeptical of nuances between “me-too” individual selections in the same drug family, invented by pharma-marketers for the purposes of selling their brand. But Cimetidine (Tagament) really was worse. Physicians were pushed by sales reps, but the later products were a better choice.

Anecdotally, there was a spectrum of Cimetidine endocrine issues including gynecomastia (including under-reported variations), impaired libido, menstrual & erectile disturbances. Confusion, spaciness, and fatigue also happened often. There were much less of these problems with the other members of the H2-blocker group. @haidut and others have discussed the problems with PPI’s. In the H2-antagonist group, choosing something different from Cimetidine (Tagament) would be my recommendation.

H2 antagonist - Wikipedia