Histamine And The Nervous System

December 23, 2014  |  Blog, Histamine Intolerance

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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  • Kath Tonkin

    Wow that is really interesting. Thanks. I recently embarked on a low histamine diet to try to reduce my chronic migraines, I also have a low thyroid, issues with estrogen, adrenal fatigue, weight gain, depression. This means they are all related. I need to read more of your stuff because I need to balance my histamine regulation and get my life back.

    • Hi Kathy welcome to the brave new world of histamines! Getting a diagnosis has given control over my life again. Migraines are also often linked to tyramine. I hope you find the answers you are looking for and welcome!

  • Nicolas N

    Hi Alison, thank you very much for all this precious content on your website. I am histamine intolerant, with systemic candida overgrowth, thyroid and other hormonal issues, leaky gut, and many food intolerances (IgG). The doctors I see seem to handle the different problems, except from histamine intolerance, that they don’t seem to know well. I have many of the nervous system related symptoms that you describe, and early arousal with ringing ears is one on the first signs when I eat too much histamine. After reading your post, I have one question : if histamine produced in the body does not pass the blood brain barrier, how can you explain that food-related histamine intolerance can trigger brain histamine related symptoms ? Thank you again.

    • Hi Nicolas. Thankyou! You are not alone. I hope you continue to find my site content of service.

  • Mary

    Whats treatment

    • Hi Mary thanks for dropping by. What do you mean? Can you let me know a little more about your question?

  • jb

    Question for you…for methylation, I’m taking B12/folic acid, however, I find I feel much worse when doing so, but I feel more ‘histamine-y’ when not taking it. Would it make sense to push through the crappy feeling that feels like overmethylation, or make more sense to back off and work on something else. To be clear, I barely know if this is even an intelligent question, but I’m trying to learn. I did know, just from how my body behaves off and on histamine, that it affects my adrenals and estrogen, as well. Thank you!

    • I dont believe in ‘pushing through”. Work on your adrenals. Nothing sensible can be achieved without supporting them as the HPA is the spoke in the centre of the wheel. These are HIGHLY implicated in mast cell issues. You need a test that shows 4x cortisol, melatonin, DHEA, and estrogen, testosterone, progesterone etc.

      • jb

        I’ve had a 28 day and 24 hour test done recently. I’m high cortisol all day, and low DHEA, low testosterone, low progesterone. I believe I was low melatonin, too, but I’d have to check.

      • jb

        Thanks for your response!

  • Marina Pirzad-Swain

    Hi Alison, could you tell me why certain foods cause insomnia? could you explain the chemical process of foods causing insomnia in the body? ie.night sade vegetables cause me insomnia, milk kefir and saurkraut and others….

    • Hi Marina I cant give personal advice to people who are not my clients. You are welcome to make an appointment. One explanation is likely to be a mixture of foods, and chemicals, with cortisol responding.

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  • Jessamyn Butler Âû

    Hello Alison! I just stumbled upon your blog, and I am intrigued. I am suffering (true to the word’s meaning, too) from severe chronic pain, as well as a puzzling issue: I keep falling asleep. I have a very regimented sleep/wake schedule, but I have these very regular episodes where I am overcome by the urge to sleep–regardless of what I am doing!! (Driving, talking with someone, etc…) I seek out safety and am in immediate sleep–for exactly 55 minutes. I wake and all is well until 3 hours later, and the same happens. Could this be connected somehow?

  • Carolyn Lowe

    Hello Alison, so can taking Gaba increase histamine in the body? I have prescribed Gaba to support a leaky brain and gut… I wake up wired at around 1am but could this increase a histamine response or is it to support? Thank you…

    • Hi Carolyn thankyou for your question. I cannot comment on your own situation.

      Histamine is a neurotransmitter and the neurotransmitter pathway is similar to the adrenal pathway. It is highly important that neurotransmitters are in balance which is why I tend to supplement co-factors only. Also they are highly susceptible to depletion due to stressors in the body with gut issues being one such stressor.

      Typically when you have a gut issue melatonin is depleted as 70% of melatonin is made in the gut. You need melatonin to balance cortisol. Also gut bugs are active at night leading to the release of cortisol which can wake you. I tend to start here. I trust that is of assistance.

  • chellethesouthernbelle

    Hi Alison, I am looking for information about Dematographia…My daughter was diagnosed with that some time ago, and we have noticed it seems to be stress related, however I recently found out that she had been using a drug when it first began about 4 yrs ago…so I am not sure if it’s not a reaction to drugs…. she was using something called molly, I have no idea what it is, but she discontinued using that and still has dermatographia episodes and was totally drug free and clean for several months and the episodes continue to happen, where her skin burns and itches and one little touch can result in severe swelling and reddened areas, she also experiences restless leg syndrome at the same time as well…She normally treats it with an antihistamine OTC, and it seems that generic allegra works best for her without making her sleepy. But after reading this article I’m wondering if all of this somehow connects and her drug use, impulsiveness etc has not been and ongoing health issue for years and it all plays together…She is currently in rehab and drug free now but due to the stressful environment of being away from her family, her children, she’s experiencing dermatographia episodes and is wanting to take an allergy medication…what do you suggest if you don’t mind answering my question.

  • Bonnie Jacobus

    Do you have to do genetic testing to learn all of this if allergy related? I’m not comfortable with it.

    • Hi bronnie it is absolutely not necessary to do genetic testing. Even if you do genetic testing you still need to look at the expression of the genes. The tests I do look at what is actually going on . Genes are instructions. They may not be being used. It’s the expression that we are interested in.

      • Bonnie Jacobus

        What exactly do you mean by expression?

        • Just because you have a genetic mutation does not mean that it is relevant. We need to know whether it is that gene which is actually misfiring and causing the issue. This is done via testing to determine at which part the wiring is “miscommunicating”. That is what I mean by expression.

  • elanor

    Thank you for sharing all this information Alison Vickery. This really is helpful to me. I would like to read more about point 2. Estrogen and point 7. Addiction & Compulsiveness, both in relation with histamine. I want to ask you if you could share the literature where those two point are based on. A link to the the specific articles would be enough. Thank you in advance!

    • HI elanor
      the information came from the article cited below. You are welcome to download the article and refer to the references. In relation to estrogen I am currently writing a book which should be available shortly and which has extensive references. If you google the research is readily available.

  • Thank you so much for such amazing information. I have extreme stress and extreme adrenal fatigue and HIGH Histamine in the brain. I am noticing adrenal support and B vitamins (methylated and subligual) with 5htp helps (Gaba too)