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Ergine

Clinical data
Other names	LSA; d-Lysergic acid amide; d-Lysergamide; Ergine; LA-111
Pregnancy category	X
Routes of administration	Oral, intramuscular injection
ATC code	none
Legal status
Legal status	BR: Class F2 (Prohibited psychotropics) DE: NpSG (Industrial and scientific use only) UK: Class A US: Schedule III Illegal in France
Pharmacokinetic data
Metabolism	Hepatic
Excretion	Renal
Identifiers
IUPAC name (8β)-9,10-didehydro-6-methyl- ergoline-8-carboxamide
CAS Number	478-94-4
PubChem CID	442072
ChemSpider	390611
UNII	073830XH10
ChEBI	CHEBI:4819
ChEMBL	ChEMBL227213
CompTox Dashboard (EPA)	DTXSID20893673
ECHA InfoCard	100.006.841
Chemical and physical data
Formula	C16H17N3O
Molar mass	267.332 g·mol
3D model (JSmol)	Interactive image
Melting point	135 °C (275 °F) Decomposes
SMILES O=C(N)1C=C2C3=CC=CC4=C3C(C2()N(C1)C)=CN4
InChI 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 Key:GENAHGKEFJLNJB-QMTHXVAHSA-N
(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.

Occurrence in nature

Ergine is not a biosynthetic endpoint itself, but rather a hydrolysis product of lysergic acid hydroxyethylamide (LAH), lysergic acid hydroxymethylethylamide (ergonovine), and ergopeptines or their ergopeptam precursors

Lysergic acid hydroxyethylamide is very vulnerable to this hydrolysis, and many analyses of ergoline-containing fungi show little to no LAH and substantial amounts of ergine.

Ergine, LAH, and ergonovine are natural ergoamides. An ergine analog, 8-hydroxyergine, has also been found in natural products in two studies. Methylergonovine and methylmethylergonovine (methysergide) have also been found in a natural product, only in one study, and these are documented as semisynthetic chemicals, so the findings need to be repeated. The aforementioned chemicals are the only natural ergoamides.

LAH & ergine are predominant in Claviceps paspali, but are only found in trace amounts in the more well-known Claviceps purpurea (both are ergot-spreading fungi). The major products of C. purpurea are ergopeptines, but C. paspali does not generate ergopeptines. Ergonovine is the only ergoamide in C. purpurea in substantial amounts.

LAH & ergine are also found in the related fungi, Periglandula, which are permanently connected with Ipomoea tricolor, Ipomoea corymbosa, Argyreia nervosa (“morning glory”, coaxihuitl, Hawaiian baby woodrose), and an estimated over 440 other Convolvulaceae (ergolines have been identified in 42 of these plants and not all of them contain ergine). Ipomoea tricolor contains 1/6 the amount of ergonovine of ergine.

Other fungi that have been found to contain LAH & ergine. All of these fungi are related to Claviceps fungi.

Unidentified Acremonium species that infects sleepy grass (C. purpurea also infects sleepy grass).

Unidentified Acremonium species that infects drunken horse grass

Acremonium coenophialum (infects Festuca arundinacea)

Epichloë gansuensis var. inebriens (infects drunken horse grass)

Metarhizium brunneum

Metarhizium acridum

Metarhizium anisopliae

Metarhizium flavoviride

Metarhizium robertsii

Aspergillus leporis,

Aspergillus homomorphus

Aspergillus hancockii

Other fungi that possibly contain ergine (i.e. they have been found to contain ergonovine and/or ergopeptines):

Claviceps hirtella

Neotyphodium lolii

Unidentified Epichlöe and Neotyphodium (asexual forms of Epichlöe) species

Aspergillus fumigata, Aspergillus flavus

Botritis fabae

Curvularia lunata

Geotrichum candidum

Balansia cyperi, Balansia claviceps, Balansia epichloë

Epichloë amarillans

Epichloë cabralii (H)

Epichloë canadensis (H)

Epichloë coenophiala (H)

Epichloë festucae

Epichloë festucae var. lolii

Epichloë festucae var. lolii x E. typhina (H)

Epichloë inebriens

Epichloë glyceriae

Epichloë mollis

Epichloë typhina

Epichloë typhina ssp. poae

Epichloë typhina ssp. clarkii

Epichloë sp. AroTG-2(H)

Epichloë sp. FaTG-2(H)

Epichloë sp. FaTG-4(H)

Hypomyces aurantius

Sepedonium sp.

Cunnigbamella blakesleana

Mucor biemalis

Rhizopus nigricans

History

Ololiuhqui was used by South American healers in shamanic healing ceremonies. 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.

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.

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.

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.

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. 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.

Ingestion

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. Another instance is a death due to falling off of a building after ingestion of Hawaiian baby woodrose seeds and alcohol.

Physiological effects

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

• Sedation
• Visual and auditory hallucinations
• Euphoria
• Loss of motor control
• Nausea
• Vasoconstriction
• Delusion
• Anxiety
• Paranoia
• Irregular heartbeat
• Sexual arousal
• Tachycardia
• Mydriasis
• Hypertonia
• Respiratory disturbances
• Cramps

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. Another study in mice found that the drug had aphrodisiac properties, inducing increased sexual behavior.

A study gave mice 3000 mg/kg with no lethal effects.

Psychedelic component

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-HT_2A 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. Thus, the overall psychedelic experience after consumption of such seeds has been proposed to be due to a mixture of ergoline alkaloids.

Pharmacology

Pharmacodynamics

Ergine interacts with serotonin, dopamine, and adrenergic receptors similarly to but with lower affinity than lysergic acid diethylamide (LSD). The psychedelic effects of ergine can be attributed to activation of serotonin 5-HT_2A receptors.

Chemistry

Biosynthesis

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. 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). 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.

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. 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. 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.

Legal status

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. 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.

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

• Argyreia nervosa
• List of entheogenic/hallucinogenic species
• List of psychoactive plants
• Tlitliltzin (Ipomoea violacea)

References

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    Table 4.4 Unambiguously ergoline-positive Argyreia species (p. 236)
    Table 4.5 Unambiguously ergoline-positive Stictocardia and Turbina species (p. 238)
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Further reading

• Powell W (2002). The Anarchist Cookbook. Ozark Press. p. 44. ISBN 978-0-8488-1130-3.
• Sydney S, Timmis GM (1932). "98. The Alkaloids of Ergot. Part III. Ergine, a New Base obtained by the Degradation of Ergotoxine and Ergotinine". J. Chem. Soc. 1932: 763–766. doi:10.1039/JR9320000763.
• Juszczak GR, Swiergiel AH (2013-01-01). "Recreational use of D-lysergamide from the seeds of Argyreia nervosa, Ipomoea tricolor, Ipomoea violacea, and Ipomoea purpurea in Poland". Journal of Psychoactive Drugs. 45 (1): 79–93. doi:10.1080/02791072.2013.763570. PMID 23662334. S2CID 22086799.
• Burillo-Putze G, López Briz E, Climent Díaz B, Munné Mas P, Nogue Xarau S, Pinillos MA, et al. (2013-09-01). "[Emergent drugs (III): hallucinogenic plants and mushrooms]". Anales del Sistema Sanitario de Navarra. 36 (3): 505–518. doi:10.4321/s1137-66272013000300015. PMID 24406363.

External links

• Hofmann, A. Teonanácatl and Ololiuqui, two ancient magic drugs of Mexico Bulletin on Narcotics 1971 1 3
• TiHKAL (A & A Shulgin) #26
• LSA Vault – Erowid