Chemistry:Dihydroergotamine

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Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines.[1][2][3] It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan. Nausea is a common side effect.[4]

It has similar actions to the triptans, acting as an agonist to the serotonin receptors and causing vasoconstriction of the intracranial blood vessels, but also interacts centrally with dopamine and adrenergic receptors. It can be used to treat acute intractable headache or withdrawal from analgesics.

Medical uses

Subcutaneous and intramuscular injections are generally more effective than the nasal spray and can be self-administered by patients.[4] Intravenous injection is considered very effective for severe migraine or status migrainosus. Dihydroergotamine is also used in the treatment of medication overuse headache.[5]

Dihydroergotamine is indicated for the acute treatment of migraine.[6][7]

Contraindications

Dihydroergotamine is contraindicated with potent CYP3A4 inhibitors, like macrolide antibiotics.[8]

Contraindications for dihydroergotamine include: pregnancy, kidney failure or liver failure, coronary, cerebral, and peripheral vascular disease, hypersensitivity reactions, sepsis, and uncontrolled hypertension.[8]

Side effects

Nausea is a common side effect of intravenous administration and less common in other modes.[9] Antiemetics can be given prior to DHE to counteract the nausea. Risks and contraindications are similar to the triptans. DHE and triptans should never be taken within 24 hours of each other due to the potential for coronary artery vasospasm.[10] DHE produces no dependence.[11]

Pharmacology

Pharmacodynamics

Dihydroergotamine's antimigraine activity is due to its action as an agonist at the serotonin 5-HT1B, 5-HT1D, and 5-HT1F receptors. It also interacts with other serotonin, adrenergic, and dopamine receptors.[12]

Dihydroergotamine is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.[13]

In spite of acting as an agonist of the serotonin 5-HT2A receptor, dihydroergotamine has been described as non-hallucinogenic.[14] This is also the case with certain other ergoline derivatives, such as bromocriptine and pergolide.[15]

Activities of dihydroergotamine at various sites[16][12][11][17]
Site Affinity (Ki/IC50 [nM]) Efficacy (Emax [%]) Action
5-HT1A 0.4–1.5 100% Agonist
5-HT1B 0.006–18 ? Agonist
5-HT1D 0.13–0.5 ? Agonist
5-HT1E 1,100 ? ?
5-HT1F 180 ? Agonist
5-HT2A 9.0 ? Agonist
5-HT2B 15–33 ? Agonist
5-HT2C 1.3 ? Agonist
5-HT3 >3,700–>10,000 ? ?
5-HT4 60 ? ?
5-HT5A ? ? ?
5-HT5B ? ? ?
5-HT6 5.4 ? ?
5-HT7 9.1–9.2 ? ?
α1A 6.6 ? ?
α1B 8.3 ? ?
α1D ? ? ?
α2A 1.9 ? ?
α2B 3.3 ? ?
α2C 1.4 ? ?
β1 3,100 ? ?
β2 2,700 ? ?
β3 271 ? ?
D1 2,779 ? ?
D2 1.2–5.0 ? Agonist
D3 6.4–16 ? ?
D4 8.7 ? ?
D5 ? ? ?
H1 ? ? ?
mACh ? ? ?
Notes: All receptors are human except 5-HT3 (rat/mouse), 5-HT4 (guinea pig), 5-HT5B (rat—no human counterpart), α1A-adrenergic (rat/human), and α2A-adrenergic (rat/human).[16]

Pharmacokinetics

Efficacy is variable in the nasal spray form with relative bioavailability of 32% compared to injection.[2]

History

Dihydroergotamine was synthesized by Albert Hofmann and Werner Stoll at Sandoz in 1943.[1] It was first described in the scientific literature that same year.[1][18][19][20][21] Dihydroergotamine was first approved for medical use under the brand name D.H.E. 45 in 1946.[1][2] Dihydroergotamine is derived from ergot, a fungus that grows on rye and other grains.[22][23]

Society and culture

In 2013, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended that medicines containing ergot derivatives no longer be used to treat several conditions involving problems with memory, sensation or blood circulation, or to prevent migraine headaches because the risks (increased risk of fibrosis and ergotism) were said to be greater than the benefits in these indications.[24][25][26]

Brand names

Brand names of dihydroergotamine include Diergo, Dihydergot, D.H.E. 45, Ergont, Ikaran, Migranal, Orstanorm, and Seglor, among others.[3]

References

  1. ↑ 1.0 1.1 1.2 1.3 "DHE - past, present, and future: a narrative review". Pain Manag: 1–15. March 2026. doi:10.1080/17581869.2026.2644524. PMID 41848189. 
  2. ↑ 2.0 2.1 2.2 "Dihydroergotamine (DHE) - Then and Now: A Narrative Review". Headache 60 (1): 40–57. January 2020. doi:10.1111/head.13700. PMID 31737909. 
  3. ↑ 3.0 3.1 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 340–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA340. 
  4. ↑ 4.0 4.1 "Parenteral dihydroergotamine for acute migraine headache: a systematic review of the literature". Annals of Emergency Medicine 45 (4): 393–401. April 2005. doi:10.1016/j.annemergmed.2004.07.430. PMID 15795718. 
  5. ↑ "DHE in the pharmacotherapy of migraine: potential for a larger role". Headache 46 (Suppl 4): S212–S220. November 2006. doi:10.1111/j.1526-4610.2006.00605.x. PMID 17078853. 
  6. ↑ "Atzumi- dihydroergotamine mesylate powder". 8 May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0982a44a-dc0c-75c0-e063-6394a90a6d6c. 
  7. ↑ "Brekiya- dihydroergotamine mesylate injection". 15 May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cdbf5619-767f-4165-aec2-17bdd92d9ca2. 
  8. ↑ 8.0 8.1 "Ergotamine and dihydroergotamine: a review". Current Pain and Headache Reports 7 (1): 55–62. February 2003. doi:10.1007/s11916-003-0011-7. PMID 12525272. 
  9. ↑ "Antiemetic Medications". StatPearls. Treasure Island (FL): StatPearls Publishing. 2024. https://www.ncbi.nlm.nih.gov/books/NBK532303/. Retrieved 18 August 2024. 
  10. ↑ "Dihydroergotamine (DHE) for Migraine Treatment | AMF" (in en-US). https://americanmigrainefoundation.org/resource-library/dhe-for-migraine/. 
  11. ↑ 11.0 11.1 "Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy". British Journal of Pharmacology 140 (2): 277–284. September 2003. doi:10.1038/sj.bjp.0705437. PMID 12970106. 
  12. ↑ 12.0 12.1 "Ergotamine and dihydroergotamine: history, pharmacology, and efficacy". Headache 43 (2): 144–166. February 2003. doi:10.1046/j.1526-4610.2003.03034.x. PMID 12558771. 
  13. ↑ "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". Journal of Pharmacological and Toxicological Methods 69 (2): 150–161. 2014. doi:10.1016/j.vascn.2013.12.004. PMID 24361689. 
  14. ↑ National Institute on Drug Abuse (1994). NIDA Research Monograph. DHEW publication. National Institute on Drug Abuse. p. 275. https://books.google.com/books?id=_D_5hbekFvIC&pg=PA275. Retrieved 26 October 2024. 
  15. ↑ "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology 49 (1): 119–127. January 2024. doi:10.1038/s41386-023-01567-7. PMID 36932180. 
  16. ↑ 16.0 16.1 "Ergotamine search results". PDSP Ki Database. University of North Carolina Chapel Hill. https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Ergotamine&doQuery=Submit+Query. 
  17. ↑ "Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy". Naunyn Schmiedebergs Arch Pharmacol 355 (6): 682–688. June 1997. doi:10.1007/pl00005000. PMID 9205951. 
  18. ↑ Müller-Schweitzer E. Über das Dihydroderivat der Mutterkornalkaloide. Klin Wochenschr. 1943;20:473–475.
  19. ↑ Horton, Bayard T.; Peters, G.A.; Blumenthal, L.S. (1945). "A new product in the treatment of migraine: a preliminary report". Mayo Clinic Proceedings 20 (14): 241–248. doi:10.1016/S0025-6196(26)04349-1. https://linkinghub.elsevier.com/retrieve/pii/S0025619626043491. Retrieved 24 March 2026. 
  20. ↑ "Dihydroergotamine in the treatment of migraine; preliminary clinical observations". Ohio State Med J 41: 1099. 1945. PMID 21003955. 
  21. ↑ "Parenteral use of dihydroergotamine in migraine". Ann Allergy 3: 440–442. 1945. PMID 21012441. 
  22. ↑ "Dihydroergotamine (DHE) for Migraine Relief: Are You a Good Candidate? What to Know" (in en-US). https://www.migraineagain.com/dihydroergotamine-dhe-for-migraine-relief/. 
  23. ↑ "Updated Evaluation of IV Dihydroergotamine (DHE) for Refractory Migraine: Patient Selection and Special Considerations". Journal of Pain Research 13: 859–864. 2020. doi:10.2147/JPR.S203650. PMID 32431533. 
  24. ↑ "Restrictions on use of medicines containing ergot derivatives" (PDF). 18 December 2013. https://www.ema.europa.eu/en/documents/referral/ergot-derivatives-article-31-referral-restrictions-use-medicines-containing-ergot-derivatives_en.pdf-0. 
  25. ↑ "New restrictions on use of medicines containing ergot derivatives". 28 June 2013. http://www.ema.europa.eu/ema//index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001832.jsp&mid=WC0b01ac058004d5c1. 
  26. ↑ "Ergot derivatives". 28 June 2013. https://www.ema.europa.eu/en/medicines/human/referrals/ergot-derivatives. 



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