DHE - past, present, and future: a narrative review.

Dihydroergotamine (DHE) was first approved in 1946 for the acute treatment of migraine. Its efficacy when administered as an intravenous (IV) injection explains its enduring use in the management of migraine today. More recently, attention has been focused on the development of formulations delivered by the inhalational route to either the nasal mucosa or lung with the objective of providing a product that enables easy, needle-free, "at-home" use that is rapidly effective. Three new DHE products for migraine (two administered by nasal delivery) have been Food and Drug Administration (FDA) approved in the past five years with two others using pulmonary delivery in clinical development attempting to optimize outcomes for subjects requiring "at-home" migraine treatment. This narrative review describes those DHE development programs, and others that have failed, with the objective of providing a broad perspective on various approaches, including those that may be more likely to achieve the goals of high efficacy rates, rapid relief, and convenience of use. In addition, DHE has been investigated for potential repurposing of other indications. These too are described. This review explores the past, present, and possible future roles of dihydroergotamine (DHE), an old drug, in the medical armamentarium. Its use for migraine headaches dates back to the nineteenth century.Ergotamine was later purified and sold as a drug in the 1920s but caused nausea and other side effects. To reduce these unwanted effects, the drug was altered to DHE, which was approved by the US Food and Drug Administration (FDA) in 1946. DHE has endured as an acute injectable treatment option for migraine ever since. In 1997, a nasal spray formulation was approved but produced variable results. Other programs have aimed to improve alternative delivery systems for DHE with the twin goals of convenience (e.g. self-administered, nasally delivered formulations) and preservation of the effectiveness that is observed following injection in a medical setting. Those efforts continue, with a new nasal spray receiving FDA approval in 2021 and, in 2025 both a new nasal powder and an autoinjector for DHE delivery obtaining FDA approval.Another recent advance is drug “repurposing” of DHE (i.e. finding different illnesses that can be treated with DHE). Alzheimer’s disease with depression; liver and lung cancer; coronavirus disease (specifically COVID); liver fibrosis and stroke are just some of the diseases where promising research data has suggested DHE may have a role. Whether DHE can be developed for any of these difficult diseases has yet to be seen. Lessons learned in this repurposing exercise may help scientists to investigate other drugs that may have uses that we have not appreciated.