How does histamine affect anxiety?

Anxiety disorders

How does histamine affect anxiety?

You have probably felt anxious many times in your life. You likely very familiar with that fear and worry that precedes an important exam, a job interview, a trip, etc. 

Anxiety is a natural process that our bodies developed to face danger and to control the response to threatening stimuli throughout human evolution. 

However, when this fear stops being temporary and sporadic, and become a constant problem, it deserves further attention. 

Sometimes, this fear doesn´t go away, on the contrary, it gets worse. People with anxiety disorders experience symptoms that can interfere with their daily activities such as job performance, school work, and relationships. This can have serious consequences for their quality of life. 

There are several types of anxiety disorders. The most common are:

  • Generalized anxiety disorder
    People with generalized anxiety disorder feel anxious most of the time. They worry about several things at the same time, such as health, work, relationships, studies, etc.
  • Symptoms include: feeling restless or on the edge, fatigue, difficulty concentrating, irritability, muscle tension, sleep problems. 
  • Panic disorder
    People with panic disorder experience sudden periods of intense fear that come on quickly and reach their peak within minutes. Attacks can occur unexpectedly or can be brought on by a trigger, such as a feared object or situation. These folks may also worry about the next attack, making them avoid certain places and situations.
  • Symptoms include: heart palpitations, sweating, shaking, shortness of breath, and the feeling of being out of control. 
  • Phobia-related disorder
    Phobias are intense fears or aversions to specific objects or situations. This fear is often out of proportion to the actual danger. 
  •  Social anxiety
    People with social anxiety may avoid certain social situations because they fear being judged, and feeling embarrassed. 
  • Separation anxiety
    It´s the fear of being separated from people you are attached to. 

What are some of the causes of anxiety?

Anxiety is caused by both genetic and environmental factors. Some of the most common risk factors are:

  • Personality traits and shyness
  • Exposure to stressful or traumatic situations 
  • History of anxiety in the family
  • Health conditions 
  • Use of stimulants such as caffeine
  • The use of medications or drugs

Treatment of anxiety

Treatment of anxiety disorders often involves medication, behavioral therapy, or a combination of both. Among the pharmacological interventions are antidepressants, buspirone, and benzodiazepines. Phenibut is a more of an over-the-counter dietary supplement option that has been recommended by some natural doctors – it’s a form of GABA and has been used more commonly in Russia. 


Histamine is a biological substance chemically classified as an amine, an organic molecule based on the structure of ammonia (NH3). 

Histamine is synthesized and released by different human cells, such as basophils, mastocytes, lymphocytes, and histaminergic neurons. It is stored in granules in these cells. Once released from its granules, histamine mediates numerous physiological reactions in the body. It acts through the activation of 4 types of receptors (H1R, H2R, H3R, and H4R):

  • in the contraction of smooth muscle tissues of the lungs, uterus, and stomach
  • the dilation of blood vessels, which increases permeability and lowers blood pressure
  • the stimulation of gastric acid secretion in the stomach
  • and the acceleration of heart rate
  • Histamine also serves as a neurotransmitter and modulator, carrying chemical messages between nerve cells
  • It also plays an important role in the sleep-wake cycle, promoting wakefulness
  • in the regulation of food intake
  • in motivation and goal-directed behavior (alcoholism, for example). 

Histamine is essential in inflammation and allergic responses. When a tissue is injured, mast cells release histamine, this makes the blood vessels to dilate, and increase its permeability, so that fluids and immune cells can migrate to the injury site promoting its healing. 

In allergic reactions, mast cells also release histamine. Antibodies that are bound to the mast cells bind to antigens to inactivate them. The release of histamines causes the symptoms you experience during an allergic reaction, such as runny nose, watery eyes, constriction of bronchi, and tissue swelling.

The role of histamine in anxiety

We discussed the role of histamine in inflammation and allergies, but what does it have to do with anxiety?

We have seen that mast cells contain granules of histamine. These cells are found in the brain, and they contain numerous mediators that are released in response to a variety of conditions, such as stress.

The role of histamine and histamine receptors in anxiety is not yet entirely clear. One study using animal models showed that mice without mast cells had greater anxiety-like behavior than the ones who had normal mast cells. In the same study, they blocked the mast cells activation in mices’ brains and noticed an increase in anxiety-like behavior. This mast cell deficiency caused a reduction in the levels of histamine in the mices’ brains (Nautiyal et al., 2008).

This may explain why people with food allergies, asthma, and irritable bowel syndrome (all mast cell-related conditions) tend to have higher levels of anxiety. In fact, medication used to treat these conditions, known as anti-histamine drugs, can affect the patient´s mood. 

In a research study, 92 patients with chronic pruritus (itchy skin) were treated with 2 types of anti-histamines. Classical anti-histamines produced a higher impact on a patient´s quality of sleep and mood-related disorders, such as anxiety than new-generation anti-histamines that are less permeable to the brain (Ozdemir et al., 2014).

The anti-histamine hydroxyzine is an H1R antagonist that has been used in the treatment of anxiety. Receptor antagonists are ligands that block a biological response when they bind to a receptor. 

A review including 39 studies and 884 patients showed that hydroxyzine is effective in the treatment of generalized anxiety disorder, and its safeness and tolerability was comparable to the other anxiolytics. However, it induced more sleepiness, thus it´s not recommended as a first-line treatment (Guaiana et al., 2010). 

Moreover, people with a generalized anxiety disorder (GAD) have a relatively increased pro-inflammatory response and decreased anti-inflammatory response when compared to the healthy volunteers. The authors found that patients with GAD had higher levels of pro-inflammatory cytokines (proteins used in the cell to cell communication) IFN-y and TNF-a, but lower levels of the anti-inflammatory IL-10. They suggested that an impairment of the tryptophan degrading enzyme leads to the degradation of serotonin in patients with GAD (Hou et al., 2017).

One study using an antagonist of the histamine H3 receptor thioperamide showed that blockade of this receptor increases anxiety-like behavior and locomotor activity in mice (Mohsen et al., 2014).

The H3R receptor is known to modulate the activity of other histamine receptors H1R and H2R. H3R blockade stimulates histamine release from histamine neurons, inducing the anxiety-like behavior.

L-histidine and anxiety

L-histidine is an essential amino acid, which is used to make the proteins of our body. Histidine is present in most protein-rich foods such as meat, fish, eggs, soy, whole grains, beans, and nuts.

Histamine is synthesized from L-histidine in the presence of the enzyme histidine decarboxylase, found in the histamine neurons.

One study demonstrated that the insufficient intake of histidine due to a non-balanced diet reduced the brain histamine content, leading to anxiety-like behaviors in mice (Yoshikawa et al., 2014). 

Appropriate dietary intake of histidine is crucial, both during development and throughout life. Deficiencies in histidine, as well as genetic defects in histidine metabolism, can cause problems in various systems of the body.

Important reminder

Anxiety is a serious condition that can affect your overall well-being. The causes are not fully understood yet, but it involves both genetic and environmental factors. Treatment is usually based on the use of medications, and behavioral therapy. 

It has been shown that histamine plays an important role in anxiety, but further research in humans is needed to clarify the extension of this role. 

To learn more about specific genetic variant SNPs (single nucleotide polymorphisms) in regards to anxiety and its mechanism of action – particularly GAD SNPs, check out our article on Treating Anxiety Naturally and Recognizing Its Mechanism of Action within the Body.

Seek medical help if you´re experiencing any of the symptoms mentioned in this article. 


Nautiyal, Katherine M., et al. "Brain mast cells link the immune system to anxiety-like behavior." Proceedings of the National Academy of Sciences 105.46 (2008): 18053-18057.

Ozdemir, Pinar Guzel, et al. "Assessment of the effects of antihistamine drugs on mood, sleep quality, sleepiness, and dream anxiety." International journal of psychiatry in clinical practice 18.3 (2014): 161-168.

Guaiana, Giuseppe, Corrado Barbui, and Andrea Cipriani. "Hydroxyzine for generalised anxiety disorder." Cochrane Database of Systematic Reviews 12 (2010).

Yoshikawa, Takeo, et al. "Insufficient intake of L-histidine reduces brain histamine and causes anxiety-like behaviors in male mice." The Journal of nutrition 144.10 (2014): 1637-1641.

Hou, Ruihua, et al. "Peripheral inflammatory cytokines and immune balance in Generalised Anxiety Disorder: Case-controlled study." Brain, behavior, and immunity 62 (2017): 212-218.

Mohsen, Attayeb, et al. "Mechanism of the histamine H3 receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice." Neuropharmacology 81 (2014): 188-194.

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