Symptom's Associated with Abnormal Histamine Levels

From brainmatrix

Notes of relevance for functional medicine[edit]

  • Histamine intolerance can occur in those with an impaired ability to metabolize ingested histamine due to reduced diamine oxidase activity.1,2However, diagnosis of histamine intolerance can be difficult, and some experts believe its existence is undersestimated.3,4 Relevant challenges include a wide variability in symptoms and symptom combinations and a lack of reproducibility of symptoms.5,6
  • The European Food Safety Authority (EFSA) has warned about the health risks associated with consuming foods with high levels of biogenic amines (particularly certain fish), and clinical guidelines have been developed to help address the challenge.1,5
  • Research into food safety related to histamine suggests that there are methods for processing raw materials to control the presence of biogenic amines and that refrigeration is one beneficial strategy.7
  • The table below is from Comas-Baste, 2020, adapted from: Bover-Cid, S.; Latorre-Moratalla, M.L.; Veciana-Nogués, M.T.; Vidal-Carou, M.C. Processing Contaminants: Biogenic Amines. In Encyclopedia of Food Safety; Elsevier: Amsterdam, The Netherlands, 2014; Volume 2, pp. 381–391. ISBN 9780123786128. Foods that contain particularly high levels of histamines include several dairy products, canned fish, cured meat, fermented products like dry-fermented sausages.

Histamine content in different food categories, part 1.png

Histamine content in different food categories, part 2.png

Affective Disorders and Mood[edit]

Changes in the neurotransmission of histamine have been observed in patients with mood disorders including depression and schizophrenia.8,9 Elevated levels of histamine metabolites are found in the cerebrospinal fluid of patients with schizophrenia.10 Higher levels of histamine release and turnover is thought to be associated with the disease.10–12 Histamine has also been shown to influence aggressive behavior.13


Learning and memory. Histamine plays a role in learning and memory.14,15 Specifically, H3 receptor signaling supports the acquisition and storage of both short-term and long-term memories.16

Mental fatigue. Histamine has been implicated in cognitive test performance following acute exercise. For instance, research into the relationship suggests that the binding of histamine to H1 receptors may contribute to reductions in mental fatigue that accompany exercise.17

Cognitive disorders

  • Attention Deficit Hyperactivity Disorder. Evidence is growing that links histamine dysfunction to attention deficit hyperactivity disorder (ADHD).11
  • Alzheimer’s Disease. Changes in the neurotransmission of histamine have been observed in cognitive disorders like Alzheimer’s disease.8,9


Eating behavior. Histamine is linked to appetite and body weight, which was recognized when first generation antipsychotics and antidepressants that antagonized H1 receptors stimulated appetite and led to weight gain.8 Subsequent research revealed that these effects occur due to the modulatory effect of histamine on leptin. Several studies also suggest that food intake decreases in response to histamine due to its actions on H1 receptors in the ventromedial hypothalamus or paraventricular nucleus.18

Motivation. Brain histamine appears to contribute to exploratory behavior and motivation, particularly as they relate to appetitive and consummatory behaviors, which may help explain why histamine is implicated in nutrition and eating disorders.8,9,14,19

Apathy. In accordance with the role of histamine in motivation, apathy can occur in response to histamine dysfunction.19 Avoidance responses have been shown preclinically to be reduced through H1 activity.13

Compulsivity disorders. Lowered levels of histamine are associated with disorders that involve compulsivity such as obsessive-compulsive disorder (OCD) and Tourette’s syndrome.11 Animal studies that have investigated the effects of histamine depletion suggest that histamine may be involved in tic-phenomenology.14

Substance abuse. There is evidence that histamine may play a role in the consumption of alcohol and other substances of abuse, as well as in other potentially addictive behaviors.8,9,13,16

Sleep. Histamine in the brain promotes wakefulness.8,16,19 The initial recognition of this link occurred when first generation antihistamines led to unwanted side effects of sedation.8 While antihistamines have been shown to increase daytime sleepiness, they have also been shown to improve nocturnal sleep quality.20 At the same time, changes in the neurotransmission of histamine have also been observed in people with sleep disorders.8,9

Based on these observations, antihistamines have begun to be used to treat insomnia.21 Research has shown that over-the-counter antihistamines may provide effective short-term treatment for insomnia in young adults but that these patients develop a tolerance quickly.22 Histamine receptor antagonists have also been shown to improve sleep maintenance.23

Physical Symptoms[edit]

Immunity. Histamine plays a role in immunity across several clinical contexts and has been shown to mediate certain autoimmune conditions.24

  • Skin conditions and itching. Histamine is known to induce itch, though the underlying mechanism is not entirely clear.25 What is known is that mast cells release histamine in response to inflamed tissues or allergens, and the resulting excitation of unmyelinated C-fibers appears to induce itch.25–27 Histamine release from basophils that occurs in response to circulating IgG autoantibodies leads to angioedema and chronic urticaria.25,28 In cases of urticaria, histamine H2 receptor antagonists are often used.28

Histamine is a critical modulator of inflammation in the brain as well as the rest of the body.11,24 With respect to skin conditions, the swelling that occurs in response to histamine likely contributes to allergic dermatitis.29

  • Allergy. Histamine modulates allergic reactions.24 The release of histamine in response to allergens accounts for symptoms of allergic rhinitis. Rhinorrhea results from activation of histamine and eicosanoids. Antihistamines are therefore used to treat allergic reactions and allergic rhinitis.21
  • Cancer. Histamine appears to be involved in interactions between tumor cells and infiltrating immune cells that allow malignant cells to evade the immune system.24

Obesity. In addition to its effects on appetite, histamine can lead to weight gain and obesity through its influence on metabolism.8 Specifically, histamine increases lipolysis, which there is some evidence to suggest may be mitigated through blockade of H3 receptors.

Nausea and vomiting. Stimulation of H1 receptors in the brainstem induces vomiting, as do intracerebroventricular injections.31–34 Antihistamines may be indicated for nausea and vomiting, especially in cases of motion sickness and vertigo.21

Vertigo. Antihistamines are the largest class of agents that are used to treat the symptoms of vestibular vertigo.35 Recent research suggests that antihistamines that antagonize the H4 receptor appear to hold promise for treating peripheral vertigo.35

Pain. Histamine is implicated in the modulation of pain.14,15 There is evidence that both H3 and H4 receptors are involved in neuropathic pain.15 Histamine appears to support nociception in the peripheral nervous system and antinociception in the central nervous system.15,30

Movement. Preclinical research has shown that moderate doses of certain H1 antagonists can influence psychomotor performance.13 Evidence has recently emerged linking histamine to degenerative disorders like multiple sclerosis and Parkinson’s disease.8,9,16 Antihistamines are sometimes used in Parkinsonism.21

Temperature changes. Histamine is involved in thermoregulation.14

Sexual function. H2 antagonists have been shown preclinically to depress sexual function.13


1. Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla M, Vidal-Carou MDC. Histamine intolerance: The current state of the art. Biomolecules. 2020;10(8):1-26. doi:10.3390/BIOM10081181

2. Pinzer TC, Tietz E, Waldmann E, Schink M, Neurath MF, Zopf Y. Circadian profiling reveals higher histamine plasma levels and lower diamine oxidase serum activities in 24% of patients with suspected histamine intolerance compared to food allergy and controls. Allergy. 2018;73(4):949. doi:10.1111/ALL.13361

3. Komericki P, Klein G, Reider N, et al. Histamine intolerance: Lack of reproducibility of single symptoms by oral provocation with histamine: A randomised, double-blind, placebo-controlled cross-over study. Wiener Klinische Wochenschrift. 2011;123(1-2):15-20. doi:10.1007/s00508-010-1506-y

4. Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85(5):1185-1196. doi:10.1093/AJCN/85.5.1185

5. Reese I, Ballmer-Weber B, Beyer K, et al. Guideline on management of suspected adverse reactions to ingested histamine: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergology and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA) as well as the Swiss Society for Allergology and Immunology (SGAI) and the Austrian Society for Allergology and Immunology (ÖGAI). Allergologie Select. 2021;5(01):305. doi:10.5414/ALX02269E

6. Schnedl WJ, Lackner S, Enko D, Schenk M, Holasek SJ, Mangge H. Evaluation of symptoms and symptom combinations in histamine intolerance. Intest Res. 2019;17(3):427-733. doi:10.5217/IR.2018.00152

7. Durak-Dados A, Michalski M, Osek J. Histamine and other biogenic amines in food. Journal of Veterinary Research. 2020;64(2):281. doi:10.2478/JVETRES-2020-0029

8. Nuutinen S, Panula P. Histamine in neurotransmission and brain diseases. Adv Exp Med Biol. 2010;709:95-107. doi:10.1007/978-1-4419-8056-4_10

9. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241. doi:10.1152/PHYSREV.00043.2007

10. Prell GD, Green JP, Kaufmann CA, et al. Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms. Schizophr Res. 1995;14(2):93-104. doi:10.1016/0920-9964(94)00034-6

11. Carthy E, Ellender T. Histamine, Neuroinflammation and Neurodevelopment: A Review. Frontiers in Neuroscience. 2021;15. doi:10.3389/FNINS.2021.680214

12. Prell GD, Green JP, Elkashef AM, et al. The relationship between urine excretion and biogenic amines and their metabolites in cerebrospinal fluid of schizophrenic patients. Schizophrenia Research. 1996;19(2-3):171-176. doi:10.1016/0920-9964(96)88524-0

13. White JM, Rumbold GR. Behavioural effects of histamine and its antagonists: a review. Psychopharmacology (Berl). 1988;95(1):1-14. doi:10.1007/BF00212757

14. Santangelo A, Passani MB, Casarrubea M. Brain histamine and behavioral neuroscience. Oncotarget. 2017;8(10):16107-16108. doi:10.18632/ONCOTARGET.15365

15. Obara I, Telezhkin V, Alrashdi I, Chazot PL. Histamine, histamine receptors, and neuropathic pain relief. Br J Pharmacol. 2020;177(3):580-599. doi:10.1111/BPH.14696

16. Passani MB, Panula P, Lin JS. Histamine in the brain. Frontiers in Systems Neuroscience. 2014;8(APR). doi:10.3389/FNSYS.2014.00064

17. Loy BD, O’Connor PJ. The effect of histamine on changes in mental energy and fatigue after a single bout of exercise. Physiol Behav. 2016;153:7-18. doi:10.1016/J.PHYSBEH.2015.10.016

18. Morimoto T, Yamamoto Y, Yamatodani A. Brain histamine and feeding behavior. Behavioural brain research. 2001;124(2):145-150. doi:10.1016/S0166-4328(01)00225-X

19. Torrealba F, Riveros ME, Contreras M, Valdes JL. Histamine and motivation. Frontiers in Systems Neuroscience. 2012;6(JULY 2012). doi:10.3389/FNSYS.2012.00051

20. Ozdemir PG, Karadag AS, Selvi Y, et al. Assessment of the effects of antihistamine drugs on mood, sleep quality, sleepiness, and dream anxiety. Int J Psychiatry Clin Pract. 2014;18(3):161-168. doi:10.3109/13651501.2014.907919

21. Schaefer TS, Zito PM. Antiemetic histamine H1 receptor blockers. StatPearls. Published online November 15, 2021. Accessed April 8, 2022.

22. vande Griend JP, Anderson SL. Histamine-1 receptor antagonism for treatment of insomnia. J Am Pharm Assoc (2003). 2012;52(6). doi:10.1331/JAPHA.2012.12051

23. Zisapel N. Drugs for insomnia. Expert Opin Emerg Drugs. 2012;17(3):299-317. doi:10.1517/14728214.2012.690735

24. Patel RH, Mohiuddin SS. Biochemistry, histamine. StatPearls. Published online May 9, 2021. Accessed April 8, 2022.

25. Shim WS, Oh U. Histamine-induced itch and its relationship with pain. Molecular Pain. 2008;4:29. doi:10.1186/1744-8069-4-29

26. ROWLEY DA, BENDITT EP. 5-Hydroxytryptamine and histamine as mediators of the vascular injury produced by agents which damage mast cells in rats. J Exp Med. 1956;103(4):399-412. doi:10.1084/JEM.103.4.399

27. Studies of the mechanism of acute vascular reactions to injury. I. The relationship of mast cells and histamine to the production of edema by ovomucoid in rats. | Semantic Scholar. Accessed July 10, 2022.

28. Fedorowicz Z, van Zuuren EJ, Hu N. Histamine H2‐receptor antagonists for urticaria. The Cochrane Database of Systematic Reviews. 2012;2012(3). doi:10.1002/14651858.CD008596.PUB2

29. Hirasawa N, Ohuchi K. Roles of histamine in the exacerbated allergic dermatitis. Yakugaku Zasshi. 2011;131(2):179-184. doi:10.1248/YAKUSHI.131.179

30. Khalilzadeh E, Azarpey F, Hazrati R, Vafaei Saiah G. Evaluation of different classes of histamine H1 and H2 receptor antagonist effects on neuropathic nociceptive behavior following tibial nerve transection in rats. European Journal of Pharmacology. 2018;834:221-229. doi:10.1016/J.EJPHAR.2018.07.011

31. Zhong W, Shahbaz O, Teskey G, et al. Mechanisms of nausea and vomiting: Current knowledge and recent advances in intracellular emetic signaling systems. International Journal of Molecular Sciences. 2021;22(11). doi:10.3390/IJMS22115797

32. Chen MM, Xu LH, Chang L, Yin P, Jiang ZL. Reduction of Motion Sickness Through Targeting Histamine N-Methyltransferase in the Dorsal Vagal Complex of the Brain. Journal of Pharmacology and Experimental Therapeutics. 2018;364(3):367-376. doi:10.1124/JPET.117.244475

33. Bhargava KP, Dixit KS. Role of the chemoreceptor trigger zone in histamine-induced emesis. British Journal of Pharmacology. 1968;34(3):508-513. doi:10.1111/J.1476-5381.1968.TB08479.X

34. Ono HK, Hirose S, Narita K, et al. Histamine release from intestinal mast cells induced by staphylococcal enterotoxin A (SEA) evokes vomiting reflex in common marmoset. PLOS Pathogens. 2019;15(5):e1007803. doi:10.1371/JOURNAL.PPAT.1007803

35. Dyhrfjeld-Johnsen J, Attali P. Management of peripheral vertigo with antihistamines: New options on the horizon. Br J Clin Pharmacol. 2019;85(10):2255-2263. doi:10.1111/BCP.14046