Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to adverse effects. It is taken by mouth.
Methysergide is no longer recommended as a first line treatment protocol by international headache societies, hospitals, and neurologists in private practice, for migraines or cluster headaches as side effects were first reported with long-term use in the late 1960s, and ergot-based treatments fell out of favor for the treatment of migraines with the introduction of triptans in the 1980s.
Medical uses
Methysergide is used exclusively to treat episodic and chronic migraine and for episodic and chronic cluster headaches. Methysergide is one of the most effective medications for the prevention of migraine, but is not intended for the treatment of an acute attack, it is to be taken daily as a preventative medication.
Migraine and cluster headaches
Methysergide has been known as an effective treatment for migraine and cluster headache for over 50 years. A 2016 investigation by the European Medicines Agency due to long-held questions about safety concerns was performed. To assess the need for continuing availability of methysergide, the International Headache Society performed an electronic survey among their professional members.
The survey revealed that 71.3% of all respondents had ever prescribed methysergide and 79.8% would prescribe it if it were to become available. Respondents used it more in cluster headache than migraine, and reserved it for use in refractory patients.
The European Medicines Agency concluded "that the vast majority of headache experts in this survey regarded methysergide a unique treatment option for specific populations for which there are no alternatives, with an urgent need to continue its availability."
This position was supported by the International Headache Society.
Updated guidelines published by Britain's National Health Service Migraine Trust in 2014 recommended "Methysergide medicines are now only to be used for preventing severe intractable migraine and cluster headache when standard medicines have failed".
Other uses
Methysergide is also used in carcinoid syndrome to treat severe diarrhea. It may also be used in the treatment of serotonin syndrome.
Side effects
It has a known side effect, retroperitoneal fibrosis/retropulmonary fibrosis, which is severe, although uncommon. This side effect has been estimated to occur in 1/5000 patients. In addition, there is an increased risk of left-sided cardiac valve dysfunction.
Pharmacology
Pharmacodynamics
Methysergide interacts with the serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7 receptors and the α2A-, α2B-, and α2C-adrenergic receptors. It does not have significant affinity for human 5-HT3, dopamine, α1-adrenergic, β-adrenergic, acetylcholine, GABA, glutamate, cannabinoid, or histamine receptors, nor for the monoamine transporters. Methysergide is an agonist of 5-HT1 receptors, including a partial agonist at the 5-HT1A receptor, and is an antagonist at the 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. Methysergide is metabolized into methylergometrine in humans, which in contrast to methysergide is a partial agonist of the 5-HT2A and 5-HT2B receptors and also interacts with various other targets.
Methysergide antagonizes the effects of serotonin in blood vessels and gastrointestinal smooth muscle, but has few of the properties of other ergot alkaloids. It is thought that metabolism of methysergide into methylergonovine is responsible for the antimigraine effects of methysergide. Methylergonovine appears to be 10 times more potent than methysergide as an agonist of the 5-HT1B and 5-HT1D receptors and has higher intrinsic efficacy in activating these receptors. Methysergide produces psychedelic effects at high doses (3.5–7.5 mg). Metabolism of methysergide into methylergometrine is considered to be responsible for the psychedelic effects of methysergide. The psychedelic effects can specifically be attributed to activation of the 5-HT2A receptor. The medication can activate the 5-HT2B receptor due to metabolism into methylergometrine and for this reason has been associated with cardiac valvulopathy. It is thought that the serotonin receptor antagonism of methysergide is not able to overcome the serotonin receptor agonism of methylergonovine due to the much higher levels of methylergonovine during methysergide therapy.