The role of histamine in the nervous system is largely overlooked, despite the nervous system being an important source of histamine, which accounts for a wide ranging symptoms.

Histamine  Receptors

Histamine has four known receptors, name H1R, H2R, H3R and H4R. The first three are present widely in the brain. H4R is not.

  • H1R excites neurons in the brain, and is mainly responsible for arousal and wakening. This is why H1R anti-histamines that cross the blood brain barrier (which is not all of them) have a sedation effect on the brain.
  • H2R also excites neurons in the brain and is mainly responsible for perception, learning, pain, reward, and neuro-plasticity of the brain. This is why H2R histamines that cross the blood brain barrier affects a person’s perception of pain.
  • H3R is inhibitory and controls the release of neurotransmitters, including histamine, from the brain neurons. H3R drugs, along with methylation, are seen as a promising target to address histamine dysregulation in the brain.

Histamine Production

Histamine produced in the body does not pass the blood brain barrier. Instead, the brain itself produces histamines from histadine in the blood stream.

Histamine is then stored inside specific cells - histaminergic neurons, where it is released upon stimulation.

Both H3R and other neurotransmitters, (mostly glutamate, GABA, acetylcholine, catecholamines, and serotonin) which coat the surface of the histaminergic neurons, can promote histamine release (excitatory), or blocking of histamine release (inhibitory).

Histamine Methylation

Excess histamine in the brain is primarily inactivated by methylation by either histamine n-methyltransferase (HNMT), and then by  monoamine oxidase - B (MAO-B). Mutations in these genes are thought to contribute to dysregulation of histamine in the nervous system.

Diamine Oxidase (DAO), the main methylator in the gut, is not present in the brain, although it is believed that the vascular system drains histamine not metabolised by HNMT or MAO-B, back into the body where DAO may play a further role.

Histamine in the Brain

Histamine is synthesised in the brain in the hypothalamus, in a specific area known as the tuberomamillary nucleus (TMN), where it acts as a signalling messenger (or neurotransmitter).

The hypothalamus is the area of the brain that overseas the metabolic processes of the body found in the central nervous system.  Whilst the TMN may store the histamine it does not determine the individual symptoms.

The histaminergic neurons act as neurotransmitters, sending their signals throughout the central nervous system, from the spinal cord, brain stem, cerebellum, vestibular nuclei, basal ganglia, amygdala, hippocampus and cerebral cortex.

It is these target sites, with their own executive responsibilities, which determine the type of symptoms, a histamine intolerant individual will experience.

Scientifically Proven Roles of Histamine in The Nervous System

Considerable evidence suggests that histamine is part of the body's evolutionary protective system designed to respond to danger.

The body is aroused, energy conserved, and pain and reward learning disabled, to focus solely on responding to the danger. When the histamine system is dysregulated the body acts like there is danger when there is not, and can result in the following symptoms, all of which have histamine as their root cause:

1. Adrenal Fatigue

H3R regulates the sympathetic nervous system, through the adrenal glands, and plays a role in the release of hormones under stress. Histamine activates the release of corticosterone through the activation of the hypothalamus-adrenal axis by H1R. Adrenal fatigue is quite common with histamine intolerance.

2. Estrogen

Histamine plays a role in the release of the luteinizing hormones responsible for ovulation in women and testosterone in men. Histamine and estrogen also have a symbiotic relationship. Histamines release estrogen, and estrogen releases histamines. This often results in histamine intolerance getting worse immediately prior to menstruation and in peri-menopause.

3. Thyroid Issues

The thyroid plays a vital role in energy metabolism. Histamine also controls the release of thyroid (TSH) hormones. H2R decreases TRH release, and TSH plasma levels.

4. Appetite

There is strong evidence that brain histamine regulates appetite. H3R antagonists suppress food intake, decrease body weight, and triglycerides, and H1R antagonists stimulate appetite. Weight issues (either difficulty gaining, or difficulty losing) are quite common with histamine intolerance.

5. Stress

Histamine is involved in the regulation of the body’s functions, and any physiologically stress (e.g. dehydration, prolonged fasting, loss of blood, severe infection), results in the release of histamines.

Similarly, when emotionally stressed, histamine mediates the release of hormones, and other neurotransmitters (e.g. norepinephrine or noradrenaline), as part of the stress response.

6. Insomnia

Histamines, through HR1 activation, regulate sleep, either causing insomnia or hypersomnia. Histamine levels vary with the sleep wake cycle, H1R antagonists and H3R antagonists are helpful in hypersomnia, while the opposite drugs are helpful in insomnia. Insomnia, when triggered, is arguably the most dominant symptom with histamine intolerance.

7. Addiction & Compulsiveness

Histamine also plays a role in addiction and compulsive disorders, mostly through H2R's role in modulation of learning, memory, pleasure, and aversion.

Many addictive substances (sugar, alcohol, benzodiazepines, cannabis, and illicit drugs) appear to interfere with TMN's histamine activity. Withdrawal can also cause hyper-arousal, pain, psychosis, and/or delirium. An HNMT mutation has been linked to alcoholism.

Compulsive eating in anorexia nervosa, bulimia, or binge-eating is also thought to relate to H2R's effects on brain reward systems. H3R drugs are clinically tested for application in eating disorders.

8. Metabolic Syndrome

The brain's histamine system regulates the hormone, leptin, which regulates saiety and obesity. It is known that histamine levels can influence obesity, insulin resistance, diabetes, and high cholesterol. H1R antagonists induce severe weight gain. H3R antagonists have been developed to counteract body weight gain. Interestingly, chewing your food well induces activation of histamine neurons, which in turn suppress food intake through H1R activation.

9. Anxiety

H1R is known to produce anxiety and signal a danger response. It is quite common for people with histamine intolerance to report feeling "free-floating anxiety" without situational anxiety. H1R anti-histamines are known to reduce excitatory effects in the brain. H3R blockers impairs the memory of fear, and avoidance, whilst H3R retains the memory.

10. Pain Perception

Histamine mediates itching, and modulates pain or myalgia, through similar mechanisms. Both are extremely common symptoms of histamine intolerance.

Histamine promotes analgesic effects through H2R and hyperalgesic effects (more pain) through H1R. However, overall, increasing l-histadine, HNMT inhibitors, or blocking H3R will have analgesic effects. H3R is a promising target in pain therapy.

11. Depression

It is speculated that histamine may play a role in depression. Certainly, histamine mediates the stress-induced release of noradrenaline and seratonin in the brain.

Many antidepressants have H1R and H2R blocking activities. Insomnia is a key symptom of depression. Sleep deprevation has anti-depressive effects. The sleep- wake cycle is known to be regulated by histamine. Sleep deprivation is also known to have anti-depressive affects. There is a strong inter-action between histamine, and other neuro-transmitters associated with depression, in particular seratonin.

12. Cardiovascular Issues

Histamine increases blood pressure,  and decreases heart rate, often resulting in tachycardia. Both H1 and H2 are involved.

13. Motion Sickness

Histamine also plays a role in motion sickness and vomiting. Anti-histamines are an effective treatment.


Histamine neurons are deeply involved in basic brain and body functions. If you have histamine intolerance, with an HNMT mutation, then it is often not necessary to look beyond histamine dysregulation as the cause of many symptoms.

Many people with histamine intolerance find their symptoms follow a clear histamine related pattern. So for example, I sleep like a baby, unless my histamine intake is high. Its generally my first sign that somethings slipped through my histamine radar.

My adrenals are fragile, and I have to pay attention, to my routine. I have to stick to a fairly regimented sleep, rest, and waking up routine. Also whilst my weight is generally stable I can have extreme and rapid weight gain when on anti-histamines.

Methylation and HR3 medications represent a promising solution in the future. There are currently no HR3 medications available commercially.

Additional Reading
Helmut L. Haas, Olga A. Sergeeva, Oliver Selbach, Histamine in the Nervous System, Physiological ReviewsJul 2008,88(3)1183-1241;DOI:10.1152


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