Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the

ergoline Ergoline is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized in ergot. Some of these are implicated in the condition of ergotism, which can take a convulsive form or a gangrenous for ...

and lysergamide groups which is used in the

prophylaxis Preventive healthcare, or prophylaxis, is the application of healthcare measures to prevent diseases.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health a ...

and treatment of

migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...

and

cluster headache Cluster headache is a neurological disorder characterized by recurrent severe headaches on one side of the head, typically around the eye, eye(s). There is often accompanying eye watering, nasal congestion, or swelling around the eye on the aff ...

s. It has been withdrawn from the market in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

and

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

due to

safety Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...

concerns. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. The drug is a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

methylergometrine Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and as an antimigraine agent in the treatment of mi ...

(methylergonovine), which circulates at levels about 10times higher than those of methysergide during treatment with methysergide. Whereas methysergide is a mixed

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of some

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s (e.g., the 5-HT₁ receptors) and

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.5-HT₂ receptors), methylergonovine is a non-selective

of most of the serotonin receptors, including of both the serotonin 5-HT₁ and 5-HT₂ receptor subgroups. Methysergide and methylergometrine are

s and lysergamides and are related to the ergot alkaloids. Previously thought to be an exclusively

synthetic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-cont ...

, it has been reported to occur naturally in '' Argyreia nervosa'' (Hawaiian baby woodrose). Methysergide was first described in the literature by 1958. It is no longer recommended as a

first-line therapy A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications an ...

for migraines or cluster headaches. This is due to

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

, such as cardiac valvulopathy, which was first reported with long-term use in the late 1960s.

Ergot Ergot ( ) or ergot fungi refers to a group of fungi of the genus ''Claviceps''. The most prominent member of this group is '' Claviceps purpurea'' ("rye ergot fungus"). This fungus grows on rye and related plants, and produces alkaloids that c ...

-based medications like methysergide fell out of favor for treatment of migraine with the introduction of the

triptan Triptans are a family of tryptamine-based medication, drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual h ...

s in the 1980s.

Medical uses

Methysergide is used exclusively to treat episodic and chronic

and for episodic and chronic

s. 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 The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

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 The National Health Service (NHS) is the term for the publicly funded health care, publicly funded healthcare systems of the United Kingdom: the National Health Service (England), NHS Scotland, NHS Wales, and Health and Social Care (Northern ...

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 Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to neuroendocrine tumors (formerly known as carcinoid tumors). The syndrome is caused by neuroendocrine tumors most often found in the gut ...

to treat severe

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

. It may also be used in the treatment of

serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

Side effects

It has a known

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

retroperitoneal fibrosis Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue (fibrosis) in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and various other structures. It m ...

/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-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E, 5-HT_1F, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT_5A, 5-HT₆, and 5-HT₇ receptors and the α_2A-, α_2B-, and α_2C-adrenergic receptors. It does not have significant

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for human 5-HT₃,

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, α₁-adrenergic, β-adrenergic,

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

, or

histamine receptor The histamine receptors are a class of G protein–coupled receptors which bind histamine as their primary endogenous ligand. Histamine is a neurotransmitter involved in various physiological processes. There are four main types of histamine recep ...

s, nor for the

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

s. Methysergide is an

of 5-HT₁ receptors, including a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

at the 5-HT_1A receptor, and is an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Page 187 Methysergide is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

into

in humans, which in contrast to methysergide is a

of the 5-HT_2A and 5-HT_2B 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 its

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

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-HT_1B and 5-HT_1D 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 methylergonovine is considered to be responsible for the psychedelic effects of methysergide. The psychedelic effects can specifically be attributed to activation of the 5-HT_2A receptor. The medication can activate the 5-HT_2B receptor due to metabolism into methylergonovine 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. The antimigraine activity of methysergide might be specifically due to serotonin 5-HT_2B receptor antagonism.

Pharmacokinetics

The

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of methysergide is 13% due to high

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

into methylergonovine. Methysergide produces methylergonovine as a major

. Levels of methylergonovine are about 10-fold higher than those of methysergide during methysergide therapy. As such, methysergide may be considered a

of methylergonovine. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of methylergonovine is almost four times as long as that of methysergide.

Chemistry

Methysergide, also known as ''N''- 2''S'')-1-hydroxybutan-2-yl1,6-dimethyl-9,10-didehydroergoline-8α-carboxamide or ''N''-(1-(hydroxymethyl)propyl)-1-methyl-D-lysergamide, is a

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

of the

s and lysergamides and is structurally related to other members of these families, for instance

lysergic acid diethylamide Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a Semisynthesis, semisynthetic, Hallucinogen, hallucinogenic compound derived from ergot, known for its powerful psychological effects and ...

(LSD).

History

Harold Wolff's theory of

vasodilation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...

in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included. In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed. Methysergide was synthesized from lysergic acid by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause

after chronic intake. Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of

sumatriptan Sumatriptan, sold under the brand name Imitrex among others, is a medication used to treat migraine headaches and cluster headaches. It is taken Oral administration, orally, Nasal administration, intranasally, or by Subcutaneous injection, su ...

Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...

withdrew it from the U.S. market after taking over

Sandoz Sandoz Group AG is a Swiss company that focuses on generic pharmaceuticals and biosimilars. Prior to October 2023, it was part of a division of Novartis that was established in 2003, when Novartis united all of its generics businesses under the ...

, but currently lists it as a discontinued product.

Production and availability

US production of Methysergide, (Sansert), was discontinued on the manufacturer's own behalf in 2002. Sansert had previously been produced by

, which merged with

Ciba-Geigy Novartis AG is a Swiss multinational pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by revenue in 2024. Novartis manufactures the drugs ...

in 1996, and led to the creation of

. In 2003 Novartis united its global generics businesses under a single global brand, with the Sandoz name and product line reviewed and reestablished.

Society and culture

Controversy

Methysergide has been an effective treatment for migraine and cluster headache for over 50 years but has systematically been suppressed from the migraine and cluster headache marketplace for over 15 years due to unqualified risk benefit/ratio safety concerns. Many cite the potential side effects of

retroperitoneal The retroperitoneal space (retroperitoneum) is the anatomical space (sometimes a potential space) behind (''retro'') the peritoneum. It has no specific delineating anatomical structures. Organs are retroperitoneal if they have peritoneum on thei ...

/retropulmonary fibrosis as the prime reason methysergide is no longer frequently prescribed, but retroperitoneal fibrosis, and retropulmonary fibrosis, were documented as side effects as early as 1966, and 1967, respectively.

References

External links

Novartis Sansert site

Novartis Sansert product description

on methysergide.
neurologychannel.com
, general information on migraines.
History of methysergide in migraine.
{{Ergolines 5-HT1A agonists 5-HT1B agonists 5-HT1D agonists 5-HT1E agonists 5-HT1F agonists 5-HT2A agonists 5-HT2A antagonists 5-HT2B agonists 5-HT2B antagonists 5-HT2C agonists 5-HT2C antagonists 5-HT5A agonists 5-HT6 agonists 5-HT7 agonists 5-HT7 antagonists Antimigraine drugs Cardiotoxins Prodrugs Psychedelic lysergamides Respiratory toxins Serotonin receptor agonists Serotonin receptor antagonists