Chemistry:Methysergide

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Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication which is used in the prevention and treatment of migraine and cluster headaches.[1] It has been withdrawn from the market in the United States and Canada due to safety concerns.[2] The drug has also been found to produce psychedelic effects at high doses.[3][4] It is taken orally.[2]

The drug is a prodrug of methylergometrine (methylergonovine),[5] which circulates at levels about 10 times higher than those of methysergide.[6][7][5] Whereas methysergide is a mixed agonist of some serotonin receptors (e.g., the serotonin 5-HT1 receptors) and antagonist of other serotonin receptors (e.g., the serotonin 5-HT2 receptors), methylergonovine is a non-selective agonist of most of the serotonin receptors, including of both the serotonin 5-HT1 and 5-HT2 receptor subgroups.[8] Methysergide and methylergometrine are ergolines and lysergamides and are related to the ergot alkaloids.[9]

Methysergide was first described in the literature by 1958.[10][11] It is no longer recommended as a first-line therapy for migraines or cluster headaches. This is due to toxicity, such as cardiac valvulopathy, which was first reported with long-term use in the late 1960s.[12] Ergot-based medications like methysergide fell out of favor for treatment of migraine with the introduction of the triptans in the 1980s.

Medical uses

Migraine and cluster headaches

Methysergide is used exclusively to treat episodic and chronic migraine and for episodic and chronic cluster headaches.[13] Methysergide is one of the most effective[14] 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.

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 (EMA) 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.[15]

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".[16]

Other uses

Methysergide is also used in carcinoid syndrome to treat severe diarrhea.[13] It may also be used in the treatment of serotonin syndrome.[17]

Side effects

It has a known side effect, retroperitoneal and retropulmonary fibrosis,[18] which is severe, although uncommon. This side effect has been estimated to occur in 1 in 5,000 patients.[19] In addition, there is an increased risk of left-sided cardiac valve dysfunction.[14]

Interactions

Pre-treatment with methysergide has been reported to greatly potentiate and intensify the psychedelic effects of dimethyltryptamine (DMT) in humans.[20][21][22] Since methysergide was one of the most potent serotonin antagonists in vitro known at the time, this led to the erroneous conclusion that DMT acted as a serotonin antagonist to produce its hallucinogenic effects.[21][22] However, subsequent research has found that methysergide is a rapidly converted prodrug of methylergometrine, an efficacious serotonin receptor agonist,[6][23] and that both methysergide and methylergometrine produce psychedelic effects themselves at supratherapeutic doses.[3][4]

Pharmacology

Pharmacodynamics

Methysergide activities
Site Affinity
(Ki, nM) 		Efficacy
(Emax, %) 		Action
5-HT1A 14–25 89% Agonist
5-HT1B 2.5–162 ? Full agonist
5-HT1D 3.6–93 50% Partial agonist
5-HT1E 59–324 ? Full agonist
5-HT1F 34 ? Full agonist
5-HT2A 1.6–104 ? Full agonist
5-HT2B 0.1–150 0–20% Antagonist
5-HT2C 0.95–4.5 0 Antagonist
5-HT3 >10,000 – –
5-HT5A >10,000 – Antagonist
5-HT5B 41–1,000 ? ?
5-HT6 30–372 ? ?
5-HT7 30–83 ? Antagonist
α1A >10,000 – –
α1B >10,000 – –
α1D ? ? ?
α2A 170–>1,000 ? ?
α2B 106 ? ?
α2C 88 ? ?
β1 >10,000 – –
β2 >10,000 – –
D1 290 ? ?
D2 200–>10,000 ? ?
D3 >10,000 – –
D4 >10,000 – –
D5 >10,000 – –
H1 3,000–>10,000 ? ?
H2 >10,000 – –
M1 5,459 ? ?
M2 6,126 ? ?
M3 4,632 ? ?
M4 >10,000 – –
M5 >10,000 – –
Notes: All sites are human except 5-HT5B (mouse/rat—no human counterpart) and D3 (rat).[24] Negligible affinity (>10,000 nM) for various other receptors (GABA, glutamate, nicotinic acetylcholine, prostanoid) and for the monoamine transporters (SERT, NET, DAT).[24] Methysergide's major active metabolite, methylergonovine, also contributes to its activity, most notably 5-HT2A and 5-HT2B receptor partial agonism.[25][26][2][27] Refs: [24][28][29] Additional refs: [8][30][2][27][31][25]

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.[24] 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.[24] 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.[2][32][33][34][35][36][29] Methysergide is metabolized into methylergometrine in humans, which in contrast to methysergide is a partial agonist of the 5-HT2A and 5-HT2B receptors[25][36] and also interacts with various other targets.[37]

Methysergide antagonizes the effects of serotonin in blood vessels and gastrointestinal smooth muscle, but has few of the properties of other ergot alkaloids.[38] It is thought that metabolism of methysergide into its active metabolite methylergonovine is responsible for the antimigraine effects of methysergide.[6] 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.[5] The antimigraine activity of methysergide might be specifically due to serotonin 5-HT2B receptor antagonism.[39]

Metabolism of methysergide into methylergonovine, which is a potent serotonin 5-HT2A receptor agonist, is considered to be responsible for the psychedelic effects of methysergide at high doses.[37] The psychedelic effects can specifically be attributed to activation of the serotonin 5-HT2A receptor.[40] The drug can activate the serotonin 5-HT2B receptor due to metabolism into methylergonovine and for this reason has been associated with cardiac valvulopathy.[26][7][12] 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.[7]

Pharmacokinetics

Methysergide and methylergometrine levels after a single 2.7 mg oral dose of methysergide maleate in men.[41][37]

The oral bioavailability of methysergide is 13% due to high first-pass metabolism into methylergometrine.[6] Methysergide produces methylergonovine as a major active metabolite.[6][7][5] Levels of methylergonovine are about 10-fold higher than those of methysergide during methysergide therapy.[6][7][5] As such, methysergide may be considered a prodrug of methylergonovine.[5] The elimination half-life of methylergonovine is almost four times as long as that of methysergide.[5]

Chemistry

Methysergide, also known as N-[(2S)-1-hydroxybutan-2-yl]-1,6-dimethyl-9,10-didehydroergoline-8α-carboxamide or N-(1-(hydroxymethyl)propyl)-1-methyl-D-lysergamide, is a derivative of the ergolines and lysergamides and is structurally related to other members of these families, for instance lysergic acid diethylamide (LSD).

Analogues

A notable derivative of methysergide is D13H (possibly XC101-D13H).[42][43][44][45]

Natural occurrence

Previously thought to be an exclusively synthetic compound, methysergide has been reported to occur naturally in Argyreia nervosa (Hawaiian baby woodrose).[46][47]

History

Harold Wolff's theory of vasodilation 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 retroperitoneal fibrosis 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.[41]

Novartis withdrew it from the U.S. market after taking over Sandoz, but currently lists it as a discontinued product.[48] United States production of methysergide (Sansert) was discontinued on the manufacturer's own behalf in 2002. Sansert had previously been produced by Sandoz, which merged with Ciba-Geigy in 1996, and led to the creation of Novartis. 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

Recreational use

Methysergide produces psychedelic effects at high and supratherapeutic doses in the range of 3.5 to 7.5 mg.[3][49] Slight psychedelic effects have also been observed with methysergide at therapeutic doses in some individuals.[4]

Controversy

Methysergide has been an effective treatment for migraine and cluster headache for over 50 years but is said to have been systematically been suppressed from the migraine and cluster headache marketplace for over 15 years due to unqualified risk benefit/ratio safety concerns.[50][who?] Many[who?] cite the potential side effects of retroperitoneal and retropulmonary fibrosis as the prime reason methysergide is no longer frequently prescribed, but these complications were documented as early as the mid-1960s.[51][52]

Canada

Methysergide is not a controlled substance in Canada as of 2025.[53]

United States

Methysergide is not an explicitly controlled substance in the United States.[54]

See also

  • Substituted lysergamide
  • XC101-D13H (XC-101)

References

  1. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 677–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA677. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs". Expert Opinion on Pharmacotherapy 14 (12): 1599–1610. August 2013. doi:10.1517/14656566.2013.806487. PMID 23815106. 
  3. ↑ 3.0 3.1 3.2 "Entheogenic (hallucinogenic) effects of methylergonovine". Journal of Psychedelic Drugs 12 (2): 165–166. 1980. doi:10.1080/02791072.1980.10471568. PMID 7420432. "A related compound, 1-methyl-d-lysergic acid-(+)-2-butanolamide, a serotonin antagonist marketed as a treatment for migraine by Sandoz under the trade name Sansert® (also known as Deseril®, Methysergide® or UML-491®) has also been shown to be entheogenic at doses of 3.5–7.5 mg (Abramson & Rollo 1967). Evidently Sansert® has roughly the same entheogenic potency as ergonovine, which we estimate to be about 1/200th the potency of LSD. From our limited experience, we estimate that methylergonovine is about 1/40th the potency of LSD.". 
  4. ↑ 4.0 4.1 4.2 Fanchamps, A. (1978). "Some Compounds With Hallucinogenic Activity". Ergot Alkaloids and Related Compounds. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 567–614. doi:10.1007/978-3-642-66775-6_8. ISBN 978-3-642-66777-0. http://link.springer.com/10.1007/978-3-642-66775-6_8. Retrieved 30 June 2025. "[...] methysergide (UML491, No. 34a), which is the 1-methyl analogue of the purely uterotonic methylergometrine (d-lysergic acid L-2-butanolamide, No. 73a), may produce in some migraine patients mental changes reminiscent of a slight LSD reaction, such as unworldly feelings, dreamy state (GRAHAM, 1964), or even hallucinations (HALE and REED, 1962). According to ABRAMSON (1959), this action amounts to 1% of the effect of LSD." 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Receptor - Based Drug Design. CRC Press. 10 April 1998. pp. 181–182. ISBN 978-1-4200-0113-6. https://books.google.com/books?id=YYk04RMvSSUC&pg=PA181. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Multipotent and Poly-therapeutic Fungal Alkaloids of Claviceps purpurea". Medicinal Plants and Fungi: Recent Advances in Research and Development. Medicinal and Aromatic Plants of the World. 4. 2017. pp. 229–252. doi:10.1007/978-981-10-5978-0_8. ISBN 978-981-10-5977-3. "Metabolites of methysergide also exhibit pharmacological activity. Methylergometrine (one of methysergide’s metabolites) is responsible for methysergide’s therapeutic effects regarding migraine treatment (Müller-Schweinitzer and Tapparelli 1986). [...] The systemic availability of methysergide after oral administration is only 13%, due to a high degree of first-pass metabolism by N-1 demethylation to methylergometrine. After oral administration, the plasma concentrations of the metabolite are considerably higher than those of the parent drug, and the area under the plasma concentration curve (AUC) for methylergometrine is more than ten times greater than for methysergide." 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation 102 (23): 2836–2841. December 2000. doi:10.1161/01.cir.102.23.2836. PMID 11104741. 
  8. ↑ 8.0 8.1 "Novel Receptor Activity Mapping of Methysergide and its Metabolite, Methylergometrine, Provides a Mechanistic Rationale for both the Clinically Observed Efficacy and Risk of Fibrosis in Patients with Migraine (2663)". Neurology 94 (15 Supplement). April 2020. doi:10.1212/WNL.94.15_supplement.2663. https://www.xocpharma.com/file.cfm/7/docs/AHS_2019_Poster_1_XocPharma_Final.pdf. 
  9. ↑ "Ergot Alkaloids". Industrial Applications. Berlin, Heidelberg: Springer Berlin Heidelberg. 2002. pp. 157–181. doi:10.1007/978-3-662-10378-4_8. ISBN 978-3-642-07481-3. 
  10. ↑ "Comparison of lysergic acid derivatives and antihistamines as inhibitors of the edema provoked in the rat's paw by serotonin". Int Arch Allergy Appl Immunol 12 (1–2): 89–97. 1958. doi:10.1159/000228445. PMID 13549054. 
  11. ↑ "Prophylactic and therapeutic properties of 1-methyl-lysergic acid butanolamide in migraine". Int Arch Allergy Appl Immunol 15 (4–5): 300–307. 1959. doi:10.1159/000229055. PMID 14446408. 
  12. ↑ 12.0 12.1 "Cardiac murmurs and endocardial fibrosis associated with methysergide therapy". Am Heart J 88 (5): 640–655. November 1974. doi:10.1016/0002-8703(74)90251-8. PMID 4420941. 
  13. ↑ 13.0 13.1 "tranquilene page". Tranquility Labs. http://tranquilene.com/methysergide.html. 
  14. ↑ 14.0 14.1 "Successful repair of aortic and mitral incompetence induced by methylsergide maleate: confirmation by intraoperative transesophageal echocardiography". Echocardiography 20 (3): 283–287. April 2003. doi:10.1046/j.1540-8175.2003.03027.x. PMID 12848667. 
  15. ↑ "The role of methysergide in migraine and cluster headache treatment worldwide - A survey in members of the International Headache Society". Cephalalgia 37 (11): 1106–1108. October 2017. doi:10.1177/0333102416660551. PMID 27449673. 
  16. ↑ "Methysergide" (in en-GB). The Migraine Trust. https://www.migrainetrust.org/living-with-migraine/treatments/methysergide/. 
  17. ↑ "The serotonin syndrome. Implicated drugs, pathophysiology and management". Drug Safety 13 (2): 94–104. August 1995. doi:10.2165/00002018-199513020-00004. PMID 7576268. 
  18. ↑ "Retroperitoneal Fibrosis Imaging: Overview, Radiography, Computed Tomography". EMedicine (MedScape). 30 March 2017. https://emedicine.medscape.com/article/380772-overview. 
  19. ↑ "Methysergide". Cephalalgia 18 (7): 421–435. September 1998. doi:10.1046/j.1468-2982.1998.1807421.x. PMID 9793694. 
  20. ↑ "Drug-drug interactions involving classic psychedelics: A systematic review". J Psychopharmacol 38 (1): 3–18. January 2024. doi:10.1177/02698811231211219. PMID 37982394. 
  21. ↑ 21.0 21.1 Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. http://www.erowid.org/library/books_online/tihkal/tihkal.shtml.  "A study conducted on 40 normals, this in Hungary some 30 years ago, found that the administration of 40 mg quantities to be symptom free. With several of the experimental subjects in this study, the DMT was preceded by the administration of 1-methyl-d-lysergic acid butanolamide (UML-491), a potent serotonin antagonist. This was given either orally (1-2 mg 30 to 40 minutes before) or intramuscularly (0.5 mg 10 minutes before). This served to greatly intensify the effects of the DMT, with intense and agitated hallucinations, highly intensified colors, and a more extreme loss of time and space perception. It was assumed that UML-491 was inactive, but recent trials indicate that there can be central effects produced. It is discussed in the entry for LSD."
  22. ↑ 22.0 22.1 "The effect of antiserotonin on the experimental psychosis induced by dimethyltryptamine". Experientia 18: 137–138. March 1962. doi:10.1007/BF02153861. PMID 14496041. 
  23. ↑ "Methylergometrine, an active metabolite of methysergide". Cephalalgia: An International Journal of Headache 6 (1): 35–41. March 1986. doi:10.1046/j.1468-2982.1986.0601035.x. PMID 3698092. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 "PDSP Database - UNC". https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Methysergide&doQuery=Submit+Query. 
  25. ↑ 25.0 25.1 25.2 "Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine". Molecular Pharmacology 57 (1): 75–81. January 2000. doi:10.1016/S0026-895X(24)26444-0. PMID 10617681. 
  26. ↑ 26.0 26.1 "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. 
  27. ↑ 27.0 27.1 "Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment". Headache 52 (4): 707–714. April 2012. doi:10.1111/j.1526-4610.2012.02124.x. PMID 22444161. 
  28. ↑ "BDBM50031942". BindingDB. https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50031942. 
  29. ↑ 29.0 29.1 "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. 
  30. ↑ "61st Annual Scientific Meeting American Headache Society July 11‐14 2019 Pennsylvania Convention Center Philadelphia, PA: P180 Serotonin Receptor Activity Profiles (5-HT2B and 5-HT2A) for Nine Commercialized Ergot Alkaloids Correspond to Known Risks of Fibrosis and Hallucinations". Headache: The Journal of Head and Face Pain 59 (S1): 1–208. 2019. doi:10.1111/head.13549. ISSN 0017-8748. https://www.xocpharma.com/file.cfm/7/docs/AHS_2019_Poster_3_XocPharma_Final.pdf. Retrieved 2026-01-25. 
  31. ↑ "Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy". Naunyn-Schmiedeberg's Archives of Pharmacology 355 (6): 682–688. June 1997. doi:10.1007/pl00005000. PMID 9205951. 
  32. ↑ Pharmacology. Edinburgh: Churchill Livingstone. 2003. ISBN 978-0-443-07145-4.  Page 187
  33. ↑ "A comparison of cardiovascular and smooth muscle effects of 5-hydroxytryptamine and 5-carboxamidotryptamine, a selective agonist of 5-HT1 receptors". Archives Internationales de Pharmacodynamie et de Therapie 277 (2): 235–252. October 1985. PMID 2933009. 
  34. ↑ "Methysergide". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/9681. 
  35. ↑ "In vivo evidence of partial agonist activity exerted by purported 5-hydroxytryptamine antagonists". European Journal of Pharmacology 58 (4): 505–509. October 1979. doi:10.1016/0014-2999(79)90326-1. PMID 510385. 
  36. ↑ 36.0 36.1 "Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors". Naunyn-Schmiedeberg's Archives of Pharmacology 370 (2): 114–123. August 2004. doi:10.1007/s00210-004-0951-4. PMID 15322733. 
  37. ↑ 37.0 37.1 37.2 "Pharmacokinetics of methysergide and its metabolite methylergometrine in man". European Journal of Clinical Pharmacology 30 (1): 75–77. 1 January 1986. doi:10.1007/BF00614199. PMID 3709634. 
  38. ↑ "methysergide" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/methysergide#section=Top. 
  39. ↑ "Putative role of 5-HT2B receptors in migraine pathophysiology". Cephalalgia 37 (4): 365–371. April 2017. doi:10.1177/0333102416646760. PMID 27127104. https://nbn-resolving.org/urn:nbn:de:bvb:29-opus4-112198. 
  40. ↑ "Serotonin and serotonin receptors in hallucinogen action". Handbook of the Behavioral Neurobiology of Serotonin. Handbook of Behavioral Neuroscience. 31. 2020. pp. 843–863. doi:10.1016/B978-0-444-64125-0.00043-8. ISBN 978-0-444-64125-0. 
  41. ↑ 41.0 41.1 "History of methysergide in migraine". Cephalalgia 28 (11): 1126–1135. November 2008. doi:10.1111/j.1468-2982.2008.01648.x. PMID 18644039. 
  42. ↑ "Polycyclic compounds and uses thereof". 10 April 2019. https://patents.google.com/patent/US10815235B2/en. 
  43. ↑ "61st Annual Scientific Meeting American Headache Society ® July 11 ‐14 2019 Pennsylvania Convention Center Philadelphia, PA: P182 Development of a Novel, Clinical-stage Drug for the Prevention of Migraine Based on Receptor Activity Mapping and Achievement of a Target Receptor Profile". Headache: The Journal of Head and Face Pain 59 (S1): 1–208. 2019. doi:10.1111/head.13549. ISSN 0017-8748. https://www.xocpharma.com/file.cfm/7/docs/AHS_2019_Poster_2_XocPharma_Final.pdf. Retrieved 2026-01-25. 
  44. ↑ "62nd Annual Scientific Meeting American Headache Society: Interim Results of a Phase 1 Single Ascending Dose Study of XC101-D13H, a Novel Compound for the Prevention of Migraine". Headache: The Journal of Head and Face Pain 60 (S1): 1–156. 2020. doi:10.1111/head.13854. ISSN 0017-8748. https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.13854. Retrieved 24 January 2026. 
  45. ↑ "Development of a Novel, Clinical-stage Drug for the Prevention of Migraine Based on Receptor Activity Mapping and Achievement of a Target Receptor Profile (4409)". Neurology 96 (15_supplement). 13 April 2021. doi:10.1212/WNL.96.15_supplement.4409. ISSN 0028-3878. 
  46. ↑ Risk assessment of Argyreia nervosa (Report). 2020. doi:10.21945/rivm-2019-0210. https://www.rivm.nl/bibliotheek/rapporten/2019-0210.pdf. 
  47. ↑ "Studies on the alkaloid composition of the Hawaiian Baby Woodrose Argyreia nervosa, a common legal high". Forensic Sci Int 249: 281–293. April 2015. doi:10.1016/j.forsciint.2015.02.011. PMID 25747328. 
  48. ↑ "Sansert / methysergide maleate FDA New drug application 012516 international drug patent coverage, generic alternatives and suppliers" (in en). DrugPatentWatch. https://www.drugpatentwatch.com/p/NDA/012516. 
  49. ↑ "Lysergic acid diethylamide (LSD-25). 38. Comparison with action of methysergide and psilocybin on test subjects". J Asthma Res 3 (1): 81–96. September 1965. doi:10.3109/02770906509106904. PMID 5318626. 
  50. ↑ "CHMP referral assessment report". http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ergot_derivatives-containing_products/WC500161303.pdf. 
  51. ↑ 1966 "Methysergide and Retroperitoneal Fibrosis.". British Medical Journal 1 (5495): 1110. April 1966. doi:10.1136/bmj.1.5495.1110-a. 
  52. ↑ "Fibrotic disorders associated with methysergide therapy for headache". The New England Journal of Medicine 274 (7): 359–368. February 1966. doi:10.1056/NEJM196602172740701. PMID 5903120. 
  53. ↑ "Controlled Drugs and Substances Act". 5 December 2025. https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html. 
  54. ↑ Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026), United States: U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division, January 2026, https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf 



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