The Clinical and Psychopathological Implications in the Forms of Hyperhistaminosis

The present work analyzes the clinical and psychopathological implications of hyperhistaminosis, starting from the general consideration that, despite the recent scarcity of research on the subject under examination, the correlation of hyperhistaminosis with different physical and psychic pathologies emerges and the direct relationship between body and mind and how these are interconnected. Hyperhistaminosis besides being involved in immune, neurodegenerative, systemic vascular, cardiac, pulmonary, hepatic, kidney and

The effect of histamine, which accompanies vasodilation, is to alter the balance between the liquid component of the blood and the water contained in the connective tissue: the result is an accumulation of liquids in the connective tissue that causes edema.
Edema can be a serious risk if it occurs in the throat or bronchi.
A second exposure to the allergen can have very violent effects because in that case, IgE antibodies (immunoglobulins) are already present on the mast cell [7].
The effects of histamine [1,[8][9][10]  Guanylate-cyclase has a heme group in its structure that receives NO and is also soluble at the cytoplasmic level. is not yet clear. They are mainly found in bone marrow, spleen, eosinophils, mast cells, neutrophils, and T-helper lymphocytes.
The effects are to modulate the activation of the immune response.
These receptors also inhibit adenylatocyclase via a Gi. They can also mate with a G-zero (G0), which regulates potassium channels and the activation of MAP-kinases via PKC. It has been reported that they can also activate G proteins present exclusively in marrow cells, G15 and G16, through which they can act on the mobilization of calcium from intracellular deposits ( Figure 3). Most histamine release is non-synaptic but neuronal histamine may also be capable of fast neurotransmission; for example, histamine increases chlorine ion conductance in the thalamus through its H2 receptors or an ion channel and this implies that, like serotonin, histamine can activate both second messenger receptors and ligand-controlled ion channels [1].
Histaminergic neurons can also regulate and be regulated by cycles. It is on this basis that the side effects of certain anti-allergic drugs (drowsiness) are explained, thanks to the antagonism they have towards the H1 receptors in the brain. Another effect also mediated by H1 receptors is the suppression of convulsive activity [9].
At the hypothalamic level histamine is a regulator of other functions, such as the release of vasopressin, oxytocin, prolactin, ACTH, and beta-endorphin. It also regulates hunger and thirst: an increase in histamine suppresses these two sensations, while H1 receptor antagonists act on the ventromedial hypothalamus to stimulate appetite. At the pituitary level, it seems that both H1 and H2 receptors are implicated in the regulation of local hormones.
In the experimental animal, histamine, after microinjection in certain areas of the brain, is also an effective suppressor of painful responses, an effect that seems to be mainly mediated by H2 receptors. Outside the brain, the presence of H1 and H3 receptors on certain types of sensory nerves promote prophlogistic/nociceptive and antiphlogistic/nociceptive responses, respectively. Neuronal histamine is also a mediator of the condition known as kinetosis;

Monoamine Oxidase Inhibitors and the Role in Neurological and Psychopathological Conditions
Monoamine oxidase inhibitors (MAO-I) are a class of drugs that can reduce or block the activity of monoamine oxidases, the enzymes that oxidatively metabolize monoamines. Monoamines include numerous endogenous substances such as some neurotransmitters (such as serotonin and catecholamines such as adrenaline, noradrenaline, melatonin, and dopamine) and exogenous compounds (such as tyramine and some drugs) [11]. The different drugs may be more or less selective towards one of the two isoforms (e.g. MAOA are mainly inhibited by clorgyline while MAOB is selectively inhibited by selegiline) or lack selectivity (as in the case of phenelzine or tranylcypromine). The compounds that irreversibly inhibit MAO-A, the form that preferentially degrades serotonin and tyramine, are those with the greatest potential for interaction with foods containing tyramine (cured foods such as sausages and some cheeses), which can result in hypertensive crises, and serotonergic agents (such as some antidepressants), which can result in serotonergic syndrome, which in some cases are fatal. These restrictions do not apply to selective MAO-B inhibitors, reversible and transdermal formulations that skip liver metabolism and do not require dietary restrictions [12].
The inhibition of the degradation of neurotransmitters [12,13], which are important in the regulation of mood tone, leads to their increase in the central nervous system: this mechanism is responsible for the antidepressant and anxiolytic effect of MAO-I.

Clinical Conditions Resulting from Hyperhistaminosis
Significant changes in the histaminergic system have been found in some neurological disorders such as multiple sclerosis, Wernicke's alcoholic encephalopathy, Alzheimer's disease, Parkinson's disease, and Down syndrome [16]. Whether derived from mast cells or neurons, histamine can participate in these processes by controlling vascular permeability and the blood-brain barrier to peripheral immune cells [5]. The ability of histamine to enhance NMDA-dependent responses could explain some of its neurotoxic effects found in toxic encephalopathies, especially those from alcohol and chronic hepatopathies (ammoniopathies), but also some genetic conditions such as histidinemia, where histamine synthesis receives severe imbalances [17].
But without a doubt, the most common condition [18] is  if IgE production is lower, it is possible to speak of a hyper-IgE induced by the high amount of histamine circulating in the serum [20].
Immunoglobulin E (IgE) are antibodies produced by the immune system in response to a stimulus perceived as a threat. itching. Whenever the allergy sufferer is exposed to allergens to which he or she has become sensitized during the first exposure, IgE is produced rapidly, increasing until the allergic reaction is triggered. The severity of the reaction and the symptoms associated with it can range from localized redness and itching of the skin to respiratory failure, vomiting, diarrhea, and, in some cases, lifethreatening anaphylactic shock. The severity of the reaction varies from person to person, episode to episode and may worsen over time [7].

The Psychopathological Implications in Hyper histamine Hypotheses
Although histamine molecules are found in both the body and the brain, they do not cross the blood-brain barrier; however, histamine intolerance can still affect mental health [36]. Histamine also acts as an important neurotransmitter in the brain, where it helps regulate stress response, alertness, sexual function, sleepwake cycles, attention, learning, and memory. Although there are no direct correlations and studies with representative samples that specifically demonstrate the formal link between histamine intolerance and mood disorders, people with histamine intolerance commonly report symptoms of easy fatigue, hypersensitivity to heat, anxiety, panic, phobia, and insomnia. We know that histamine is not able to cross the blood-brain barrier, however, it can interfere with other hormones that affect the nervous system, such as catecholamines; even adrenaline does not cross the blood-brain barrier, but in the body, it can trigger symptoms of panic, heart in the throat, anxiety, nausea, sweating, insomnia, shortness of breath, tremors, and other typical symptoms.
Another interesting hypothesis is the correlation with estrogen, which can interfere with testosterone, affecting plasma levels: once inside the brain, estrogen stimulates the release of histamine, thus creating another vicious circle, more histamine, more estrogen, and more histamine. In the brain, histamine is not degraded by the enzyme DAO (as it is not expressed in the brain) but by the enzyme HNMT, which belongs to the class of transferases. HNMT catalyzes the movement of a methyl group from SAM, which is of bad histamine metabolism. The release of histamine from the brain regulates leptin, which in turn regulates satiety and obesity.
Histamine also seems to be strongly related to insulin resistance.
The H1R receptor promotes a brain excitement that often results in anxiety and underlying nervousness. Histamine regulates pain perception, H1R receptor activation increases pain perception, while H2R receptor activation decreases it. Since itching follows the same pathways as pain, the sensation of itching is also modulated by the activation of histamine receptors in the brain. It is quite common for people intolerant to histamine to suffer from fibromyalgia or diffuse pain that is difficult to explain. Histamine influences the release of serotonin and dopamine, so it is related to depression. Histamine influences blood pressure and heart rate, becoming a risk factor for heart disease as well. Add another factor, some people present polymorphisms to an enzyme fundamental in the synthesis of GABA, the main NeuroT with inhibitory effect on the central nervous system, this leads to a decrease in GABA production, with the alteration of the GABA/Glutamate ratio and consequently influences the basal activation state of the central nervous system. If we add the effects of the alteration of this mechanism to the hyperactivation by excess histamine, we find the exacerbation of the physical and psychic symptomatology connected to these phenomena [37].
In food [38], histamine is never alone, it is always accompanied by a considerable amount of other biogenic amines. This makes the symptoms and diagnosis of histamine intolerance complicated and sometimes rather unpredictable. Putrescine and Cadaverine in food can cause problems by interfering with AED activity, making it more difficult for us to degrade histamine in our intestines.
This can increase the level of histamine to which we are exposed.
The higher the level of putrescine and cadaverine in a food, the higher the actual level of histamine. Tyramine is degraded not by the AED, but by a different enzyme called monoamine oxidase (MAO). Tyramine is therefore known to cause problems in people taking antiquated antidepressants called "MAO-inhibitors", which block the destruction of tyramine. If tyramine accumulates, severe headaches and dangerous high blood pressure can occur. Here there is another important link, subjects with polymorphisms on MAO A and MAO B, are exposed to an altered effect of histamine, both for the symbiotic effect with other amines that are not degraded effectively and for the effect on the humoral tone due to the incorrect degradation of neurotransmitters; in fact, we have already seen how monoamine oxidase inhibitors have been found effective in psychiatric treatment [39] of panic disorder, even when associated with agoraphobia or social phobia, in the treatment of dysthymia, atypical depression, major depression, and bipolar depression, in suicidal risk, treatment of generalized anxiety, aggressive behavioral disorders, bulimia, obsessive-compulsive disorder, post-traumatic stress disorder, personality avoidance disorder, and borderline personality disorder [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54].

Conclusion
Even if recent research confirms only the data already acquired in the literature, without any particular relevant news, the correlation of hyperhistaminosis with various physical and mental pathologies emerges, to the point of deserving more attention in the future.
More and more emerges the direct relationship between body and mind and how these are interconnected. Hyperhistaminosis, besides being involved in immune, neurodegenerative, systemic vascular, cardiac, pulmonary, hepatic, kidney and skin diseases, is directly connected to a large part of mood disorders, depression, obsessive disorder, phobias, and various personality disorders, even if it is not yet clear whether the role of histamine is the main factor or cause that exacerbates the symptoms, also taking into account the neurobiological and genetic correlates related to the forms of hyperhistaminosis.