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It summarizes how antihistamines have been studied as potential migraine therapies and why earlier work lost momentum. PubMed/MEDLINE searches identified 53 full articles for synthesis. Findings evaluate H1/H2 evidence quality, highlight H3 and H4 receptor roles, and assess implications for novel drug targets.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/histamine-and-migraine-revisited-mechanisms-and-possible-drug-targets/142838/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/histamine-and-migraine-revisited-mechanisms-and-possible-drug-targets/142838.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-29","2026-08-25",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What was the main objective of this review?","Question",{"text":112,"@type":113},"To review existing literature on histamine and migraine, focusing on the histamine molecule, its receptors, its role in inducing migraine, and antihistamines for migraine treatment.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What do the findings say about first-generation antihistamines (H1 and H2)?",{"text":117,"@type":113},"Early studies of H1 and H2 antihistamines provide weak or conflicting evidence, and issues with off-target binding make antihistaminic effects difficult to conclude; there is insufficient support for their preventive use.",{"name":119,"@type":110,"acceptedAnswer":120},"Which histamine receptors are highlighted as potential targets for future migraine drugs?",{"text":121,"@type":113},"The review discusses H3 and H4 receptors: H3 appears linked to antinociception and is involved in related CNS and sleep/cognitive topics, while the role of H4 in migraine remains questionable due to limited knowledge.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},142838,1787689659,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":129,"read_time":41},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","Worm et al. The Journal of Headache and Pain (2019) 20:30  \n[https://doi.org/10.1186/s10194-019-0984-1](https://doi.org/10.1186/s10194-019-0984-1)  \nThe Journal of Headache and Pain  \nRESEARCH ARTICLE Open Access   \nHistamine and migraine revisited: mechanisms and possible drug targets  \n*  \nJacob Worm, Katrine Falkenberg and Jes Olesen   \nAbstract  \nObjective: To review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine.  \nBackground: Histamine has been known to cause a vascular type headache for almost a hundred years. Research has focused on antihistamines as a possible treatment and histamine as a migraine provoking agent but there has been little interest in this field for the last 25 years. In recent years two additional histamine (H3 and H4) receptors have been discovered and a series of non-sedating antihistamines have been developed. It is therefore timely to review the field again.  \nMethods: For this review the PubMed/MEDLINE database was searched for eligible studies. We searched carefully for all articles on histamine, antihistamines and histamine receptors in relation to migraine and the nervous system. The following search terms were used: histamine, migraine disorders, migraine, headache, antihistamines, histamine antagonists, clinical trials, induced headache, histamine H3 receptor, histamine H4 receptor and pharmacology. Four hundred thirty-six titles were read, 135 abstracts were read, 112 articles were read in full and 53 articles were used in this review. Review process resulted in 12 articles added to a total of 65 .  \nFindings: Early studies of H 1 and H2 antihistamines lack scientific strength and show conflicting results. Most of the antihistaminic drugs used in these trials bind also to other receptors which makes it difficult to conclude on the antihistaminic effect. Histamine is an efficient inducer of migraine attacks in migraine patients by an H 1 mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H3 and H4 receptors are found in primarily in CNS and immune tissues, respectively. H3 is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H3 agent, pitolisant, is a brain penetrant H3 antagonist/inverse agonist which increases central histamine and causes headache. The experimental H3 agonist Nα-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H4 receptor it is questionable whether or not the receptor is involved in migraine.  \nConclusion: There is insufficient support for first generation antihistamines (both H1 and H2) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H 1 antihistamines need tobe appropriately tested. Central H3 receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.  \nKeywords: Migraine, Histamine, Antihistamines, Histamine receptors, Drug targets  \n* Correspondence: [jes.olesen@regionh.dk](jes.olesen@regionh.dk)  \nDanish Headache Center and Department of Neurology N39, University of Copenhagen, Rigshospitalet Glostrup, DK-2600 Copenhagen, Denmark  \n© The Author(s) . 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4 .0 International License ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.  \nIntroduction  \nHistamine is a biogenic monoamine sy","cbCaisX7wDfzMdzn","https://ap.wps.com/l/cbCaisX7wDfzMdzn","pdf",1658974,12,"English","# Abstract\n# Objective and Background\n# Methods\n# Findings\n# Conclusion\n# Introduction","[{\"question\":\"What was the main objective of this review?\",\"answer\":\"To review existing literature on histamine and migraine, focusing on the histamine molecule, its receptors, its role in inducing migraine, and antihistamines for migraine treatment.\"},{\"question\":\"What do the findings say about first-generation antihistamines (H1 and H2)?\",\"answer\":\"Early studies of H1 and H2 antihistamines provide weak or conflicting evidence, and issues with off-target binding make antihistaminic effects difficult to conclude; there is insufficient support for their preventive use.\"},{\"question\":\"Which histamine receptors are highlighted as potential targets for future migraine drugs?\",\"answer\":\"The review discusses H3 and H4 receptors: H3 appears linked to antinociception and is involved in related CNS and sleep/cognitive topics, while the role of H4 in migraine remains questionable due to limited knowledge.\"}]","Histamine and migraine revisited - mechanisms and possible drug targets | PDF"]