Insufficient evidence exists to support the use of first-generation antihistamines (ie, both H1 and H2) as preventive migraine medications, with sedation and weight gain recognized as unacceptable side effects. A literature search on the subject was conducted, with the investigators examining all eligible studies on histamine, antihistamines, and histamine receptors relative to migraine and the central nervous system. Results of the analysis were published in The Journal of Headache and Pain

The researchers sought to review the existing literature on histamine and migraine, focusing on the molecule, its receptors, its utility in the induction of migraine, and the use of antihistamines for the treatment of migraine. They used the following terms in their literature search: histamine, migraine, migraine disorders, antihistamines, histamine antagonists, headache, induced headache, clinical trials, histamine H3 receptor, histamine H4 receptor, and pharmacology. Overall, 53 articles were used in this review, with the review process yielding 12 additional articles, for a total of 65 articles.

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Results of the analysis showed that early studies of H1 and H2 antihistamines lack scientific strength and are fraught with conflicting results. The majority of antihistaminic agents used in these trials also bind to other receptors, rendering it difficult to draw any conclusions on their antihistaminic effects. In patients who experience a migraine, histamine is an efficient inducer of migraine attacks by means of an H1 mechanism, which most likely works extracerebrally.

The findings from this review warrant further investigation of antihistamines in clinical drug trials. It has been shown that H3 receptors are found primarily in the central nervous system, whereas H4 receptors are found primarily in immune tissues. H3 antihistamines, which are likely to be involved in antinociception, have been linked to neurodegenerative, cognitive, and sleep disorders. Pitolisant — the only marketed H3 agent — is a brain penetrant H3 antagonist/inverse agonist that increases central histamine and causes the development of headache.

In studies of uncertain quality, the experimental H3 agonist Nα-methylhistamine has demonstrated promising results as a preventive agent for the treatment of migraine. The current limited knowledge about the H4 receptor renders it questionable as to whether that receptor is involved in migraine.

The investigators concluded that insufficient support has been demonstrated in favor of first-generation antihistamines (both H1 and H2) as preventive medications among patients who experience migraine. Studies on the impact of antihistamines in migraine are limited and of poor quality. The use of nonsedating H1 antihistamines needs to be appropriately tested. Central H3 receptors appear to play a role in migraine prevention that warrants additional research. Additional exploration of the histaminergic system — both peripheral and central — may help to reveal future goals for migraine therapy.


Worm J, Falkenberg K, Olesen J. Histamine and migraine revisited: mechanisms and possible drug targets J Headache Pain. 2019;20(1):30.