The role of histamine in the nervous system is largely overlooked, despite the nervous system being an essential source of histamine.
It is histamine generated by the nervous system, of which the autonomic nervous system is part, which accounts for histamine’s wide-ranging symptoms throughout the body.
The Nervous System
The nervous system has two parts the central nervous system – within the brain and spinal cord, and the peripheral nervous system – outside of the brain.
The peripheral nervous system:
Connects the central nervous system to the organs, limbs, and skin.
Allows the brain and spinal cord to receive and send information to other body areas.
Carries sensory and motor information to and from the central nervous system.
Regulates involuntary body functions like heartbeat and breathing.
Sends histamine signals.
Histamine and The Nervous System
Histamine is part of the body’s evolutionary protective system to respond to danger or the cell danger response.
Histamine regulates the body’s functions, and any physiological 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.
The body is aroused, energy conserved, and pain and reward learning disabled by the nervous system to enable the body to focus solely on responding to the danger.
The histamine system usually is tightly regulated.
However, if the stressors exceed the nervous system’s ability to process the stress at that time, the nervous system can become dysregulated.
The nervous system (and histamine release under its control) acts like there is a danger when there is none.
Histamine and the Brain
Histamine produced in the body does not pass the blood-brain barrier.
Instead, the brain produces histamines from histidine in the bloodstream and deactivates any excess via methylation.
Histamine is then stored inside neurons, where it is released upon stimulation.
Histamine in the brain acts as neurotransmitters, sending signals throughout the central nervous system, where the autonomic nervous system delivers histamine to targeted areas.
These target sites determine the type of symptoms a histamine intolerant individual will experience.
Histamine  Receptors
Histamine has four known receptors named 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 awakening. 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 the brain’s perception, learning, pain, reward, and neuroplasticity. This is why H2R histamines cross the blood-brain barrier and affect 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.
H4R is excitatory and controls the release of neutrophils from the bone marrow and white blood cells. It is not found within the brain. Instead, it communicates with the brain via the nervous system.
Therefore, these histamine receptors, H1, H2, and H3, play a vital response in assessing danger. They then communicate via the nervous system, the H4 receptor, and the immune system.
Histamine Symptoms
Wide-ranging symptoms characterize histamine intolerance.
This is due to the effects of histamine signaling from H1, H2, and H3 receptors to H4 receptors throughout the body, via the nervous system.
Common histamine symptoms are:
1. Adrenal Fatigue
H3R regulates the sympathetic nervous system through the adrenal glands and plays a role in releasing hormones under stress. Histamine activates the release of corticosterone through the activation of the hypothalamus-adrenal axis by H1R. Adrenal fatigue is common with histamine intolerance.
2. Estrogen Dominance
Histamine plays a role in releasing 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 release histamines. This often worsens histamine intolerance immediately before 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. Cardiovascular Issues
Histamine increases blood pressure and decreases heart rate, often resulting in tachycardia. Both H1 and H2 are involved.
5. 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 of histamine intolerance.
6. Depression
It is speculated that histamine may play a role in depression. Indeed, histamine mediates the stress-induced release of noradrenaline and serotonin in the brain.
Many antidepressants have H1R and H2R blocking activities. Insomnia is a crucial symptom of depression. Sleep deprivation has anti-depressive effects. The sleep-wake cycle is known to be regulated by histamine. Sleep deprivation is also known to have anti-depressive effects. There is a strong interaction between histamine and other neurotransmitters associated with depression, particularly serotonin.
7. Anxiety
H1R is known to produce anxiety and signal danger. It is common for people with histamine intolerance to report feeling “free-floating anxiety” without situational anxiety. H1R antihistamines are known to reduce excitatory effects in the brain. H3R blockers impair the memory of fear and avoidance, while H3R retains the memory.
8. Addiction & Compulsiveness
Histamine also plays a role in addiction and compulsive disorders, mainly through H2R’s role in modulating 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 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.
9. Metabolic Syndrome
The brain’s histamine system regulates the hormone leptin, which regulates satiety 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.
10. Appetite Control
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 shared with histamine intolerance.
11. 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, increasing l-histidine, HNMT inhibitors, or blocking H3R will have analgesic effects. H3R is a promising target in pain therapy.
12. Motion Sickness
Histamine also plays a role in motion sickness and vomiting. Anti-histamines are an effective treatment.
Conclusion
Histamine neurons are deeply involved in essential brain and body functions.
With histamine intolerance, symptoms are far-ranging, reflecting the reach of the nervous system.
You can learn more in my FREE Course, The Roadmap To Resolution of Histamine Intolerance and Mast Cell Activation.
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