The Connection Between Histamine and Anxiety

The Connection Between Histamine and Anxiety

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - BSN, RN

Medical Reviewer:

Kari Asadorian - BSN, RN
Jamie Hope - Methyl-Life® Founder

Edited By:

Jamie Hope - Methyl-Life® Founder
Last updated:

What is histamine intolerance?

Histamine intolerance occurs when the body can't break down histamine as quickly as it accumulates. Normally, histamine is broken down by two major pathways in the body. The methylation pathway involves histamine N-methyltransferase (HNMT) converting histamine into N-methylhistamine, while the oxidative deamination pathway involves diamine oxidase (DAO) converting histamine from food into imidazole acetic acid (IAA).4


The methylation pathway requires the availability of S-adenosyl-l-methionine (SAMe), and the oxidative deamination pathway requires the presence of DAO. Factors like certain medications or genetic mutations can reduce both SAMe and DAO, impairing the breakdown of histamine.5 This leads to a buildup of histamine in the blood which may trigger symptoms similar to allergic reactions. For example, around 20% of Europeans take medications that lower DAO activity, increasing their risk of histamine intolerance.6
 

Histamine and its receptors were originally thought to affect mainly the immune and gastrointestinal systems, but research has also linked it to cognitive health and mental illness.

Symptoms of histamine intolerance7

  • Respiratory system: runny nose, nasal inflammation and congestion, sneezing
  • Gastrointestinal system: bloating, gas, diarrhea, abdominal pain, constipation, nausea, vomiting
  • Skin: itching, flushing, rash, swelling
  • Nervous system: headache/migraine, dizziness, fatigue, nervousness, insomnia, anxiety, depression

How is histamine related to mental health?

There are four histamine receptors in the central nervous system (CNS) and histamine plays an important role as a neurotransmitter in the brain. These receptors help regulate many brain functions that are linked to nervous system conditions.8


H1 drives allergic responses and wakefulness, H2 regulates gastric acid and alertness, H3 modulates neurotransmitters and sleep, and H4 influences immunity and inflammation.9

The histamine receptor H3R is concentrated in important areas of the brain, including the cerebral cortex, striatum, and hippocampus. H3R influences brain activity by controlling histamine production and release or by regulating other neurotransmitters. This affects behaviors such as pain sensitivity, movement, memory, eating, sleep patterns, anxiety, and thinking.10


Acute stress increases brain histamine turnover, especially in the diencephalon, which can lead to feelings of anxiety. In addition, chronic restraint stress has been shown to increase the histamine turnovers in the nucleus accumbens and striatum, parts of the brain associated with motivation and behavior.11


H3R antagonists (which block H3R) have been shown to improve mood and cognition. These effects may partly involve another receptor, H4R, which is connected to anxiety, depression, and appetite regulation. Research on animals has found that reducing H4R activity can cause depression-like symptoms while using H3R antagonists can help alleviate them.12


Histaminergic neurons located in the hypothalamus produce and release histamine. These neurons extend their fibers directly to the bed nucleus of the stria terminalis (BNST), a brain region involved in regulating stress and anxiety responses. This means the hypothalamus can influence the activity of the BNST by delivering histamine directly to it, which has been linked to stress-induced anxiety.13 Blocking or reducing H1 and H2 receptor activity in the BNST is shown to reduce anxiety, while infusions of histamine into this region can cause it.

Neurotransmitters and microbiome

Gut bacteria can produce both pro- and anti-inflammatory metabolites, including histamine.14 

Bacterial overgrowth in the gut can lead to increased production of histamine and inflammatory cytokines, which can damage the intestinal mucosal barrier and epithelial function.15 Bacterial endotoxins in the body also cause inflammation.


Recent research has found that chronic, low-grade inflammation can disrupt the brain blood barrier and cause dysfunction in specific cells in the CNS. This affects brain function by altering the balance of GABA and glutamate in the brain, reducing the number of dopaminergic neurons, and also by disrupting the breakdown of tryptophan.16 Both GABA and tryptophan help to regulate mood and maintain a sense of calm, while glutamate triggers excitability.17

How to get histamine and stress levels under control

  • A low-histamine diet
    A low-histamine diet is currently the most advised strategy to prevent symptoms of histamine intolerance, such as anxiety.18 Diet is also key to supporting healthy gut function and managing histamine levels. Minimizing the intake of foods high in histamine can help to maintain healthy histamine levels in the body, which may help to reduce inflammation.
    High histamine foods include fermented products such as processed meats (deli meats, salami, jerky, sausage), aged cheeses, sauerkraut, kimchi, and some soy foods. Shellfish, oily fish, walnuts, beans, chocolate, food additives, and alcoholic beverages are also high in histamine.

  • Stress management
    Managing stress levels can also help to reduce anxiety associated with histamine. Yoga, meditation, and general daily exercise have valuable benefits for reducing the effects of stress and supporting overall wellbeing.

  • Support GABA
    GABA is a calming neurotransmitter that helps to reduce feelings of anxiety and support relaxation. GABA levels can be improved with regular exercise, mind-body practices (such as yoga and diaphragmatic breathing) and supplementing with GABA itself. 
    GABA and histamine are made in the same brain cells (histamine neurons) and some research has suggested that GABA can act as a chemical ‘brake’ against histamine, helping to reduce wakefulness and overactivity.19 

Does high histamine cause anxiety?

High histamine levels may trigger an allergic response in the body, leading to physical symptoms such as a rash and itching as well as psychological symptoms such as anxiety, stress, and panic.20

Does histamine intolerance cause anxiety?

Histamine intolerance can activate histamine receptors in the nervous system, leading to psychological symptoms such as anxiety, headache/migraine, nervousness, sleep disturbances, panic, and depression.21 Histamine intolerance occurs when the body is unable to break down histamine properly, which can cause a buildup of histamine.

Does anxiety lead to a histamine release?

Some studies show that during acute stress, histamine turnover increases in specific brain regions, such as the diencephalon. This part of the brain regulates many bodily functions, including sensory processing, motor control, and the endocrine system. The increase in histamine to this region may be linked to anxiety symptoms.22

What does histamine do in the body?

Histamine is a natural compound in the body involved in inflammatory and immune responses. It plays a regulatory role in the gut and acts as a neurotransmitter.1

Histamine is a key mediator of allergic reactions but also in autoimmune conditions, regulating stomach acid secretion, and the production of blood cells (hematopoiesis). It is concentrated in cells involved in immune responses, including the lungs, basophils, and mast cells. It is a vasoactive agent, which means it influences blood vessels, bronchial smooth muscles, and nerve fibers.2
 

When activated, histamine can trigger allergic responses and gastric acid secretion via its receptors. Symptoms during allergic or inflammatory reactions may include swelling, redness, bronchial constriction, and itching.


Histamine in the brain is also involved with psychological functions including arousal, cognition, and appetite.3

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  • High-Dose L Methylfolate 15 Mg for Natural Mood Support²
  • 3rd-Party Tested for Purity, Potency & Safety
  • 90 Vegan, Non-GMO, Chewable Mint Tablets

Frequently Asked Questions about histamine and anxiety

What does histamine do in mental health?

Histamine receptors are present in the central nervous system (CNS) and histamine plays an important role as a neurotransmitter in the brain. These receptors help regulate many brain functions that are linked to nervous system conditions.23 Histamine plays a significant role in wakefulness, appetite, thinking, and alertness, all of which are affected in mental health disorders.24 In people with histamine intolerance, receptors in the nervous system may trigger symptoms such as headache/migraine, dizziness, fatigue, nervousness, insomnia, anxiety, and depression. Increased mast cell activation has been linked to heightened anxiety-like behaviors.25

How to flush histamine out of your body?

Minimizing your intake of high histamine foods can help to reduce histamine levels and prevent accumulation. Avoid foods like processed meats, fermented foods, alcoholic beverages, and foods containing artificial additives. Supporting your body’s detoxification pathways may assist with histamine removal. Drink plenty of water every day and exercise regularly. Supplementing with DAO may also help your body to metabolize histamine more efficiently.

What happens when your body has too much histamine?

Excess histamine can cause histamine intolerance, which may trigger an allergic-type reaction. A histamine reaction can lead to symptoms such as nasal inflammation and congestion, sneezing, bloating, gas, nausea, vomiting, itching, anxiety, headaches or migraine, fatigue, and nervousness.

How do you know if you are sensitive to histamine?

Sensitivity to histamine may mean that you experience an allergic reaction when you eat foods high in histamine, such as fermented/pickled foods, aged cheeses, processed meat products, shellfish, beans, some nuts, cocoa-based foods, and alcoholic beverages.

References

  1. Ghiath Alnouri, Nicholas Cha, Robert T. Sataloff; "Histamine Sensitivity: An Uncommon Recognized Cause of Living Laryngopharyngeal Reflux Symptoms and Signs—A Case Report"; Ear, Nose & Throat Journal; 2022

    https://journals.sagepub.com/doi/10.1177/0145561320951071

  2. Raj H. Patel, Shamim S. Mohiuddin; "Biochemistry, Histamine"; StatPearls [Internet]; 2023 May

    https://www.ncbi.nlm.nih.gov/books/NBK557790

  3. Li Cheng, Jiaying Liu, Zhong Chen; "The Histaminergic System in Neuropsychiatric Disorders"; Biomolecules; 2021 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8467868/

  4. HNMT histamine N-methyltransferase [Homo sapiens (human)]; Gene ID: 3176; 2025 Jan

    https://www.ncbi.nlm.nih.gov/gene/3176

  5. Yulia O Shulpekova, Vladimir M Nechaev, Irina R Popova, Tatiana A Deeva, Arthur T Kopylov, Kristina A Malsagova, Anna L Kaysheva, Vladimir T Ivashkin; "Food Intolerance: The Role of Histamine"; Nutrients; 2021 Sep

    https://pubmed.ncbi.nlm.nih.gov/34579083/

  6. Yulia O Shulpekova, Vladimir M Nechaev, Irina R Popova, Tatiana A Deeva, Arthur T Kopylov, Kristina A Malsagova, Anna L Kaysheva, Vladimir T Ivashkin; "Food Intolerance: The Role of Histamine"; Nutrients; 2021 Sep

    https://pubmed.ncbi.nlm.nih.gov/34579083/

  7. Sylwia Smolinska, Ewa Winiarska, Anna Globinska, Marek Jutel; "Histamine: A Mediator of Intestinal Disorders—A Review"; Metabolites; 2022 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9610630/

  8. Helmut L. Haas, Olga A. Sergeeva, Oliver Selbach; "Histamine in the Nervous System"; American Physiological Society - Physiological Review; 2008 Jul

    https://journals.physiology.org/doi/full/10.1152/physrev.00043.2007

  9. Elden Berla Thangam, Ebenezer Angel Jemima, Himadri Singh, Mirza Saqib Baig, Mahejibin Khan, Clinton B Mathias, Martin K Church, Rohit Saluja; "The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets"; Frontiers in Immunology; 2018 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6099187

  10. Erich H Schneider, Detlef Neumann, Roland Seifert; "Modulation of behavior by the histaminergic system: lessons from HDC-, H3R- and H4R-deficient mice"; Neuroscience and Biobehavioral Reviews; 2014 Nov

    https://pubmed.ncbi.nlm.nih.gov/25102165/

  11. C. Ito; "The role of brain histamine in acute and chronic stresses"; Biomedicine & Pharmacotherapy Vol. 54, Iss. 5, Pg. 263-267; 2000 Jun

    https://www.sciencedirect.com/science/article/abs/pii/S0753332200800694

  12. Ajeet Kumar, Shalini Dogra, Chandan Sona, Deepmala Umrao, Mamunur Rashid, Sandeep K Singh, Muhammad Wahajuddin, Prem N Yadav; "Chronic histamine 3 receptor antagonism alleviates depression like conditions in mice via modulation of brain-derived neurotrophic factor and hypothalamus-pituitary adrenal axis"; Psychoneuroendocrinology; 2019 Mar

    https://pubmed.ncbi.nlm.nih.gov/30458370/

  13. Bin Li, Leilei Chang, Qian-Xing Zhuang; "Histamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety"; Journal of Affective Disorders; 2023 Aug

    https://pubmed.ncbi.nlm.nih.gov/37201895/

  14. Benoit Pugin, Weronika Barcik, Patrick Westermann, Anja Heider, Marcin Wawrzyniak, Peter Hellings, Cezmi A. Akdis, Liam O’Mahony; "A wide diversity of bacteria from the human gut produces and degrades biogenic amines"; Microbial Ecology in Health and Disease Vol. 28 Iss. 1; 2017 Jul

    https://www.tandfonline.com/doi/full/10.1080/16512235.2017.1353881

  15. Anny-Claude Luissint, Charles A Parkos, Asma Nusrat; "Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair"; Gastroenterology; 2016 Oct

    https://pubmed.ncbi.nlm.nih.gov/27436072/

  16. Jakub Wasiak, Oliwia Gawlik-Kotelnicka; "Intestinal permeability and its significance in psychiatric disorders - A narrative review and future perspectives"; Behavioral Brain Research; 2023 Jun

    https://pubmed.ncbi.nlm.nih.gov/37121278/

  17. Mary J. Allen, Sarah Sabir, Sandeep Sharma; "GABA Receptor"; StatPearls [Internet].; 2023 Feb

    https://www.ncbi.nlm.nih.gov/books/NBK526124/

  18. Sònia Sánchez-Pérez, Oriol Comas-Basté, M Teresa Veciana-Nogués, M Luz Latorre-Moratalla, M Carmen Vidal-Carou; "Low-Histamine Diets: Is the Exclusion of Foods Justified by Their Histamine Content?"; Nutrients; 2021 Apr

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8143338/

  19. Xiao Yu, Zhiwen Ye, Catriona M. Houston, Anna Y. Zecharia, Ying Ma, Zhe Zhang, David S. Uygun, Susan Parker, Alexei L. Vyssotski, Raquel Yustos, Nicholas P. Franks, Stephen G. Brickley, William Wisden; "Wakefulness Is Governed by GABA and Histamine Cotransmission"; Neuron, Vol. 87, Iss. 1, pg. 164-178; 2015 Jul

    https://www.sciencedirect.com/science/article/pii/S0896627315005164

  20. Sylwia Smolinska, Ewa Winiarska, Anna Globinska, Marek Jutel; "Histamine: A Mediator of Intestinal Disorders—A Review"; Metabolites; 2022 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9610630/

  21. Sylwia Smolinska, Ewa Winiarska, Anna Globinska, Marek Jutel; "Histamine: A Mediator of Intestinal Disorders—A Review"; Metabolites; 2022 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9610630/

  22. C. Ito; "The role of brain histamine in acute and chronic stresses"; Biomedicine & Pharmacotherapy Vol. 54, Iss. 5, Pg. 263-267; 2000 Jun

    https://pubmed.ncbi.nlm.nih.gov/10917464

  23. Helmut L. Haas, Olga A. Sergeeva, Oliver Selbach; "Histamine in the Nervous System"; American Physiological Society - Physiological Review; 2008 Jul

    https://journals.physiology.org/doi/full/10.1152/physrev.00043.2007

  24. Li Cheng, Jiaying Liu, Zhong Chen; "The Histaminergic System in Neuropsychiatric Disorders"; Biomolecules; 2021 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8467868/

  25. Leonard B Weinstock, Renee M Nelson, Svetlana Blitshteyn; "Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series"; Journal of Personalized Medicine; 2023 Oct

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10672129/

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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