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  • Review Article
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The 5-HT1F receptor as the target of ditans in migraine — from bench to bedside

Nature Reviews Neurology volume 19, pages 489–505 (2023)Cite this article

Subjects

Abstract

Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans — a group of selective serotonin 5-HT1F receptor agonists — has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency.

Key points

  • Various animal studies have shown that selective agonists for the serotonin 5-HT1F receptor can reduce signals from an activated trigeminovascular system, thereby highlighting the receptor as an attractive target for symptomatic treatment of migraine.

  • Long-term clinical studies involving two ditans — a group of 5-HT1F agonists — have provided class I evidence that lasmiditan, the first ditan, is both effective and safe in the symptomatic treatment of migraine.

  • The 5-HT1F receptor is expressed by cells within the brain parenchyma, as well as by the trigeminal neurons, but not in vascular smooth muscle, suggesting that ditans act through neuropeptide release leading to acute headache relief, rather than via potential vasoactive properties, such as vasodilatation.

  • Dizziness is the most common adverse event of lasmiditan; thus people should not drive for 8 h after taking lasmiditan.

  • Development of novel ditans that do not cross the blood–brain barrier is expected to result in better tolerability and improved clinical use.

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Fig. 1: The trigeminovascular system and cephalic pain neurotransmission.
Fig. 2: Timeline of ditan development.
Fig. 3: Chemical formulae of serotonin and ditans.
Fig. 4: Capsaicin induced c-fos immunoreactivity in the trigeminal nucleus caudalis.
Fig. 5: Phase III clinical trials of lasmiditan for acute treatment of migraine.
Fig. 6: Number needed to treat for symptomatic treatment of migraine with different drug classes.

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Acknowledgements

The authors thank I. V. Barla for contributions to identifying the chemical composition and structure of ditans.

Author information

Authors and Affiliations

  1. 1st Neurology Department, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Dimos D. Mitsikostas

  2. School of Pharmacy, University College Cork, Cork, Ireland

    Christian Waeber

  3. Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland

    Christian Waeber

  4. Neurology Department, Clinica Universidad de Navarra, Madrid, Spain

    Margarita Sanchez-del-Rio

  5. Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany

    Bianca Raffaelli

  6. Department of Neurology, Danish Headache Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Bianca Raffaelli, Håkan Ashina & Messoud Ashina

  7. Department of Brain and Spinal Cord Injury, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Håkan Ashina

  8. Department of Anaesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Håkan Ashina

  9. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands

    Antoinette Maassen van den Brink

  10. Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Anna Andreou

  11. Headache Centre, Guy’s and St Thomas’s NHS Foundation Trust, King’s Health Partners, London, UK

    Anna Andreou

  12. Neurology Department, Vall d’Hebron University Hospital, Barcelona, Spain

    Patricia Pozo-Rosich

  13. Headache Unit, Neurology Department, Vall d’Hebron University Hospital, Barcelona, Spain

    Patricia Pozo-Rosich

  14. Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    Patricia Pozo-Rosich

  15. Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Alan Rapoport

  16. Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Michael A. Moskowitz

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All authors researched data for the article, made substantial contributions to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Dimos D. Mitsikostas.

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Competing interests

D.D.M. has received honoraria, research and travel grants from Allergan/Abbvie, Amgen, Biogen, Cefaly, Genesis Pharma, Electrocore, Eli Lilly, Lundbeck, Merk-Serono, Mertz, Novartis, Roche, Sanofi, Specifar and Teva; has participated in clinical trials for Amgen, Cefaly, Electrocore, Eli Lilly, Genesis Pharma, Lundbeck, Mertz, Novartis, Specifar and Teva as principal investigator; is President of the board of the Hellenic Headache Society; and is Co-chairman of the management group of the Headache Panel at the European Academy of Neurology. M.S.d.R. has received honoraria and travel grants from Allergan/Abbvie, Eli Lilly, Novartis and Teva; and is Secretary of the Board of the European Headache Federation. B.R. has received honoraria from Allergan/Abbvie, Eli Lilly, Hormosan, Novartis and Teva; and has received research grants from the Charité Clinician Scientist Program, the German Migraine and Headache Society (Deutsche Migräne- und Kopfschmerzgesellschaft) and Novartis. H.A. reports personal fees from Teva, outside the submitted work. A.M.v.d.B. has received honoraria, research and/or travel grants from Allergan/Abbvie, Amgen/Novartis, Eli Lilly, Satsuma and Teva as principal investigator; is First Vice President of the European Headache Federation; and is a board member of the Dutch Headache Society. A.A. has received speaker and/or consultation fees from AbbVie, Eli Lilly and Neuresta Inc. P.P.-R. has received honoraria as a consultant and speaker for AbbVie, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis Pfizer and Teva; has received research grants from AbbVie, Novartis and Teva; has received funding for clinical trials from Alder, Amgen, Biohaven, Electrocore, Eli Lilly, Lundbeck, Novartis and Teva; and is the founder of www.midolordecabeza.org. A.R. has received honoraria as a consultant and speaker for AbbVie, Amgen, Biohaven, Cala Health, Impel, Lundbeck, Pfizer, Teva, Theranica and Xoc. M.A. has received personal fees from AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer and Teva; has participated in clinical trials as the principal investigator for AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis and Teva; has received research grants from Lundbeck Foundation, Novo Nordisk Foundation and Novartis; and serves as Associate Editor for Cephalalgia, Journal of Headache and Pain and Brain. C.W. and M.A.M. declare no competing interests.

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Mitsikostas, D.D., Waeber, C., Sanchez-del-Rio, M. et al. The 5-HT1F receptor as the target of ditans in migraine — from bench to bedside. Nat Rev Neurol 19, 489–505 (2023). https://doi.org/10.1038/s41582-023-00842-x

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