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Ergine

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Ergine
Clinical data
Other namesLSA; d-Lysergic acid amide; d-Lysergamide; Ergine; LA-111
Pregnancy
category
Routes of
administration		Oral, intramuscular injection
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic
ExcretionRenal
Identifiers
  • (8β)-9,10-didehydro-6-methyl-
    ergoline-8-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.006.841 Edit this at Wikidata
Chemical and physical data
FormulaC16H17N3O
Molar mass267.332 g·mol−1
3D model (JSmol)
Melting point135 °C (275 °F) Decomposes[4]
  • O=C(N)[C@@H]1C=C2C3=CC=CC4=C3C(C[C@@]2([H])N(C1)C)=CN4
  • InChI=1S/C16H17N3O/c1-19-8-10(16(17)20)5-12-11-3-2-4-13-15(11)9(7-18-13)6-14(12)19/h2-5,7,10,14,18H,6,8H2,1H3,(H2,17,20)/t10-,14-/m1/s1 checkY
  • Key:GENAHGKEFJLNJB-QMTHXVAHSA-N checkY
  (verify)

Ergine, also known as d-lysergic acid amide (LSA) and d-lysergamide, is an ergoline alkaloid that occurs in various species of vines of the Convolvulaceae and some species of fungi. The psychedelic properties in the seeds of ololiuhqui, Hawaiian baby woodrose and morning glories have been linked to ergine and/or isoergine, its epimer, as it is an alkaloid present in the seeds.[5][6][7]

Occurrence in nature

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Ergine has been found in high concentrations of 20 μg/g dry weight in the sleepygrass infected with an Acremonium endophytic fungus together with other ergot alkaloids.[8]

Ergine is one of the alkaloids contained in the ergot fungus and related fungi, such as Periglandula, which are connected with Ipomoea tricolor, Ipomoea corymbosa, Argyreia nervosa, (i.e., “morning glory”, ololiuhqui and Hawaiian baby woodrose) and an estimated over 440 other vines.[9]

Ergine is not a biosynthetic endpoint in itself but rather a hydrolysis product of LAH and some additional ergot alkaloids.[10][11][12]

History

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Ololiuhqui was used by South American healers in shamanic healing ceremonies.[13] Similarly, ingestion of morning glory seeds by Mazatec tribes to "commune with their gods" was reported by Richard Schultes in 1941 and is still practiced today.[14][13]

Additional reports of the use of ergine were made by Don Thomes MacDougall. He reported that the seeds of Ipomoea violacea were used as sacraments by certain Zapotecs, sometimes in conjunction with the seeds of Rivea corymbosa, another species which has a similar chemical composition, with lysergol instead of ergometrine.[7]

Ergine was assayed for human activity by Albert Hofmann in self-trials in 1947, well before it was known to be a natural compound. Intramuscular administration of a 500 microgram dose led to a tired, dreamy state, with an inability to maintain clear thoughts. After a short period of sleep the effects were gone, and normal baseline was recovered within five hours.[6]

In 1956, the Central Intelligence Agency conducted research on the psychedelic properties of the ergine in the seeds of Rivea corymbosa, as Subproject 22 of MKULTRA.[15]

In 1959, Hofmann was the first to isolate chemically pure ergine from the seeds of Turbina corymbosa, determining that it, and other alkaloids, were acting as the main active components in the seeds.[7] Twenty years prior to its isolation, ergine was first chemically defined by English chemists S. Smith and G. M. Timmis as the cleavage product of ergot alkaloids. Additionally, Guarin and Youngkin reportedly isolated the crude alkaloid in 1964 from morning glory seeds.[16]

Ingestion

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Like other psychedelics, ergine is not considered to be addictive. Additionally, there are no known deaths directly associated with pharmacological effects of ergine consumption. All associated deaths are due to indirect causes, such as self-harm, impaired judgement, and adverse drug interactions. One known case involved a suicide that was reported in 1964 after ingestion of morning glory seeds.[17] Another instance is a death due to falling off of a building after ingestion of Hawaiian baby woodrose seeds and alcohol.[18]

Physiological effects

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While its physiological effects vary from person to person, the following symptoms have been attributed to the consumption of ergine or ergine containing seeds:[7][13][19]

One study found that 2 of 4 human subjects experienced cardiovascular dysregulation and the study had to be halted, concluding that the ingestion of seeds containing ergine was less safe then commonly believed. Importantly this may have been a product of other substances within the seeds. The same study also observed that reactions were highly differing in type and intensity between different subjects.[20] Another study in mice found that the drug had aphrodisiac properties, inducing increased sexual behavior.[21]

A study gave mice 3000 mg/kg with no lethal effects.[citation needed]

Psychedelic component

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Ergine is thought to be a serotonergic psychedelic and its psychedelic effects are thought to be due to it being a partial agonist of the 5-HT2A receptor. Though, the reason as to why this may be hallucinogenic remains elusive.

The idea that ergine is the main psychedelic component in ergine containing seeds (morning glory, Hawaiian baby woodrose) is well debated, as the effects of isolated synthetic ergine are reported to be only mildly psychedelic.[23][19] Thus, the overall psychedelic experience after consumption of such seeds has been proposed to be due to a mixture of ergoline alkaloids.

Pharmacology

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Pharmacodynamics

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Affinities of LSA and LSD for various receptors[24]
Receptor Affinity (Ki [nM])
LSA LSD
5-HT1A 10 2.5
5-HT2 28 0.87
D1 832 87
D2L 891 155
D2S 145 25
D3 437 65
D4.4 141 30
α1 912 60
α2 62 1.0
Notes: 5-HT1A and D1 are for pig receptors.[24]

Ergine interacts with serotonin, dopamine, and adrenergic receptors similarly to but with lower affinity than lysergic acid diethylamide (LSD).[24][25] The psychedelic effects of ergine can be attributed to activation of serotonin 5-HT2A receptors.[26]

Chemistry

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Biosynthesis

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Biosynthesis of the ergoline scaffold
Biosynthesis of the ergoline scaffold

The biosynthetic pathway to ergine starts like most other ergoline alkaloid- with the formation of the ergoline scaffold. This synthesis starts with the prenylation of L-tryptophan in an SN1 fashion with dimethylallyl diphosphate (DMAPP) as the prenyl donor and catalyzed by prenyltransferase 4-dimethylallyltryptophan synthase (DMATS), to form 4-L-dimethylallyltryptophan (4-L-DMAT). The DMAPP is derived from mevalonic acid. A three strep mechanism is proposed to form 4-L-DMAT: the formation of an allylic carbocation, a nucleophilic attack of the indole nucleus to the cation, followed by deprotonation to restore aromaticity and to generate 4-L-DMAT.[27] 4-Dimethylallyltyptophan N-methyltransferase (EasF) catalyzes the N-methylation of 4-L-DMAT at the amino of the tryptophan backbone, using S-Adenosyl methionine (SAM) as the methyl source, to form 4-dimethylallyl-L-abrine (4-DMA-L-abrine).[27] The conversion of 4-DMA-L-abrine to chanoclavine-I is thought to occur through a decarboxylation and two oxidation steps, catalyzed by the FAD dependent oxidoreductase, EasE, and the catalase, EasC. The chanoclavine intermediate is then oxidized to chanoclavine-l-aldehyde, catalyzed by the short-chain dehydrogenase/reductase (SDR), EasD.[27][28]

Formation of argoclavine
Formation of argoclavine

From here, the biosynthesis diverges and the products formed are plant and fungus-specific. The biosynthesis of ergine in Claviceps purpurea will be exemplified, in which agroclavine is produced following the formation of chanoclavine-l-aldehyde, catalyzed by EasA through a keto-enol tautomerization to facilitate rotation about the C-C bond, followed by tautomerization back to the aldehyde and condensation with the proximal secondary amine to form an iminium species, which is subsequently reduced to the tertiary amine and yielding argoclavine.[27][28] Cytochrome P450 monooxygenases (CYP450) are then thought to catalyze the formation of elymoclavine from argoclavine via a 2 electron oxidation. This is further converted to paspalic acid via a 4 electron oxidation, catalyzed by cloA, a CYP450 monooxygenase. Paspalic acid then undergoes isomerization of the C-C double bond in conjugation with the acid to form D-lysergic acid.[27] While the specifics of the formation of ergine from D-lysergic acid are not known, it is proposed to occur through a nonribosomal peptide synthase (NRPS) with two enzymes primarily involve: D-lysergyl peptide synthase (LPS) 1 and 2.[27][28]

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The legality of consuming, cultivating, and possessing ergine varies depending on the country.

There are no laws against possession of ergine-containing seeds in the United States. However, possession of the pure compound without a prescription or a DEA license would be prosecuted, as ergine, under the name "lysergic acid amide", is listed under Schedule III of the Controlled Substances Act.[29] Similarly, ergine is considered a Class A substance in the United Kingdom, categorized as a precursor to LSD.

In most Australian states, the consumption of ergine containing materials is prohibited under state legislation.

In Canada, ergine is not illegal to possess as it is not listed under Canada's Controlled Drugs and Substances Act, though it is likely illegal to sell for human consumption.[30]

In New Zealand, ergine is a controlled drug, however the plants and seeds of the morning glory species are legal to possess, cultivate, buy, and distribute.

See also

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References

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  1. ^ Erowid Morning Glory Basics, Erowid.org, retrieved 2012-02-03
  2. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  3. ^ "Arrêté du 20 mai 2021 modifiant l'arrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants". www.legifrance.gouv.fr (in French). 20 May 2021.
  4. ^ Smith S, Timmis GM (1932). "98. The alkaloids of ergot. Part III. Ergine, a new base obtained by the degradation of ergotoxine and ergotinine". Journal of the Chemical Society (Resumed): 763. doi:10.1039/jr9320000763.
  5. ^ Perrine DM (2000). "Mixing the Kykeon" (PDF). ELEUSIS: Journal of Psychoactive Plants and Compounds. New Series 4: 9. Archived from the original (PDF) on 2019-07-20. Retrieved 2008-05-05.
  6. ^ a b Alexander Shulgin, "#26. LSD-25", TiHKAL, Erowid.org, retrieved 2012-02-03
  7. ^ a b c d Hofmann A (2009). LSD My Problem Child: Reflections on Sacred Drugs, Mysticism, and Science (4th ed.). MAPS.org. ISBN 978-0979862229.
  8. ^ Petroski RJ, Powell RG, Clay K (1992). "Alkaloids of Stipa robusta (sleepygrass) infected with an Acremonium endophyte". Natural Toxins. 1 (2): 84–88. doi:10.1002/nt.2620010205. PMID 1344912. Archived from the original on 2012-12-16.
  9. ^ Leistner E, Steiner U (2018). "The Genus Periglandula and Its Symbiotum with Morning Glory Plants (Convolvulaceae)". In Anke R, Schüffler A (eds.). Physiology and Genetics. Cham: Springer International Publishing. pp. 131–147. doi:10.1007/978-3-319-71740-1_5. ISBN 978-3-319-71739-5. Retrieved 2024-11-18.
  10. ^ Flieger M, Sedmera P, Vokoun J, R̆ic̄icovā A, R̆ehác̆ek Z (1982-02-19). "Separation of four isomers of lysergic acid α-hydroxyethylamide by liquid chromatography and their spectroscopic identification". Journal of Chromatography A. 236 (2): 441–452. doi:10.1016/S0021-9673(00)84895-5. ISSN 0021-9673.
  11. ^ Ramstad E (1968). "Chemistry of alkaloid formation in ergot". Lloydia. 31: 327–341.
  12. ^ Kleinerová E, Kybal J (September 1973). "Ergot alkaloids. IV. Contribution to the biosynthesis of lysergic acid amides". Folia Microbiologica. 18 (5): 390–392. doi:10.1007/BF02875934. PMID 4757982.
  13. ^ a b c Sewell RA (2008). "Unauthorized research on cluster headache" (PDF). The Entheogen Review. 16 (4): 117–125.
  14. ^ Schultes RE (1941). A Contribution to Our Knowledge of Rivea Corymbosa: The Narcotic Ololinqui of the Aztecs (1st ed.). Botanical Museum of Harvard University.
  15. ^ "PROJECT MKULTRA, SUBPROJECT 22 (W/ATTACHMENTS)". Central Intelligence Agency.
  16. ^ Der Marderosian AH, Guarino AM, De Feo JJ, Youngken Jr HW (1964). "A Uterine Stimulant Effect of Extracts of Morning Glory Seeds". Pschedelic Review: 317–323.
  17. ^ Cohen S (April 1964). "Suicide Following Morning Glory Seed Ingestion". The American Journal of Psychiatry. 120 (1): 1024–1025. doi:10.1176/ajp.120.10.1024. PMID 14138842.
  18. ^ Klinke HB, Müller IB, Steffenrud S, Dahl-Sørensen R (April 2010). "Two cases of lysergamide intoxication by ingestion of seeds from Hawaiian Baby Woodrose". Forensic Science International. 197 (1–3): e1–e5. doi:10.1016/j.forsciint.2009.11.017. PMID 20018470.
  19. ^ a b Ingram AL (December 1964). "Morning Glory Seed Reaction". JAMA. 190 (13) (13 ed.): 1133–1134. doi:10.1001/jama.1964.03070260045019. PMID 14212309.
  20. ^ a b Kremer C, Paulke A, Wunder C, Toennes SW (January 2012). "Variable adverse effects in subjects after ingestion of equal doses of Argyreia nervosa seeds". Forensic Science International. 214 (1–3): e6–8. doi:10.1016/j.forsciint.2011.06.025. PMID 21803515.
  21. ^ a b Subramoniam A, Madhavachandran V, Ravi K, Anuja VS (December 2007). "Aphrodisiac property of the elephant creeper Argyreia nervosa". Journal of Endocrinology and Reproduction. 11 (2): 82–85.
  22. ^ a b c d e Marneros A, Gutmann P, Uhlmann F (October 2006). "Self-amputation of penis and tongue after use of Angel's Trumpet". European Archives of Psychiatry and Clinical Neuroscience. 256 (7): 458–9. doi:10.1007/s00406-006-0666-2. PMID 16783491. S2CID 9261722.
  23. ^ Chao JM, Der Marderosian AH (April 1973). "Ergoline alkaloidal constituents of Hawaiian baby wood rose, Argyreia nervosa (Burm. f.) Bojer". Journal of Pharmaceutical Sciences. 62 (4): 588–591. doi:10.1002/jps.2600620409. PMID 4698977.
  24. ^ a b c Paulke A, Kremer C, Wunder C, Achenbach J, Djahanschiri B, Elias A, et al. (July 2013). "Argyreia nervosa (Burm. f.): receptor profiling of lysergic acid amide and other potential psychedelic LSD-like compounds by computational and binding assay approaches". Journal of Ethnopharmacology. 148 (2): 492–497. doi:10.1016/j.jep.2013.04.044. PMID 23665164.
  25. ^ Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, et al. (January 2017). "Crystal Structure of an LSD-Bound Human Serotonin Receptor". Cell. 168 (3): 377–389.e12. doi:10.1016/j.cell.2016.12.033. PMC 5289311. PMID 28129538. See “LSD Diethylamide Stereoselectivity and Function”, figure 3, and “Discussion” (pages 382, 381, and 385). “Two noteworthy observations stand out. First, the key amide side chain of LSD—the group that distinguishes it from the far less hallucino- genic lysergamide (LSA)—adopts a constrained conformation in the binding site that cannot exchange readily with alternative conformational states.” (Discussion)
  26. ^ Halberstadt AL, Nichols DE (2020). "Serotonin and serotonin receptors in hallucinogen action". Handbook of the Behavioral Neurobiology of Serotonin. Handbook of Behavioral Neuroscience. Vol. 31. pp. 843–863. doi:10.1016/B978-0-444-64125-0.00043-8. ISBN 9780444641250. ISSN 1569-7339.
  27. ^ a b c d e f Gerhards N, Neubauer L, Tudzynski P, Li SM (December 2014). "Biosynthetic pathways of ergot alkaloids". Toxins. 6 (12): 3281–3295. doi:10.3390/toxins6123281. PMC 4280535. PMID 25513893.
  28. ^ a b c Willingale J, Atwell SM, Mantle PG (1983-07-01). "Unusual Ergot Alkaloid Biosynthesis in Sclerotia of a Claviceps purpurea Mutant". Microbiology. 129 (7): 2109–2115. doi:10.1099/00221287-129-7-2109. ISSN 1350-0872.
  29. ^ "Initial schedules of controlled substances (Schedule III), Section 812". www.deadiversion.usdoj.gov. Archived from the original on 2021-11-04. Retrieved 2020-01-17.
  30. ^ "Erowid LSA Vault : Legal Status". erowid.org. Retrieved 2020-05-05.

Further reading

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