Ergine

Ergine is most commonly used as a drug in the form of morning glory seeds, including those of Ipomoea tricolor (tlitliltzin), Ipomoea corymbosa (ololiuhqui), and Argyreia nervosa (Hawaiian baby woodrose).^[13] They may be consumed whole and intact, crushed or ground up, or drunk as an extract following soaking of the seeds in water.^[38][9][10] A hallucinogenic dose (~0.5–1 mg) is 150 to 200 seeds (3–6 g) of Ipomoea tricolor (0.02% ergine by dry weight) or 5 to 10 seeds (0.5–1 g) of Argyreia nervosa (0.14% ergine by dry weight).^{[38][9][10][24][19]} The onset is 0.3 to 3 hours and the duration is 4 to 10 hours.^[38][9][10]

Ergine may be used as a drug in pure or purified form as well, either isolated or synthesized.^[15][18][39] Albert Hofmann and colleagues found that a 0.5 to 2 mg dose by intramuscular or subcutaneous injection produced relatively weak but significant hallucinogenic effects as well as marked sedation.^{[15][16][30][24][18][39][40]} Another study described the effects of pure ergine by injection but the doses were not clearly provided (although appeared to be around 0.1–1 mg).^{[24][31][41][42]} Based on the preceding studies, Alexander Shulgin describes pure ergine as having a dosage of 0.5 to 1 mg and being 10-fold less potent than LSD, but as being "not hallucinogenic".^[27] Hofmann also stated that ergine was 10- to 40-fold less potent than LSD and that it had qualitatively different effects.^[30][40] Robert Oberlender has stated that ergine is about 30-fold less potent than LSD in humans.^[43] Heim and colleagues assessed ergine at higher of 3 to 6 mg orally and observed toxic-like effects, whereas isoergine at 2 to 5 mg orally produced notable hallucinogenic effects, including some euphoria, synaesthesia, and altered time perception.^[19][44][26]

Sleepy grass (Achnatherum robustum) and Claviceps paspali (ergot) have similar ergoline constituents as morning glory seeds and have also been used to produce psychoactive effects, albeit rarely.^[45][46]

A 2016 study showed that penniclavine was the predominant alkaloid in Ipomoea tricolor seeds.^[51] Ergoclavines are known to cause convulsive ergotism,^[52] the milder form of ergotism. Gangrenous ergotism is caused by ergopeptines: the complex peptide moiety forces persistence at the receptor sites.^[53] Ergopeptines are rare in Convolvulaceae, being found in 10 species,^[53][54] not including the three that are commonly ingested, although Paulke 2014 says analytical evidence suggests that A. nervosa contains ergopeptines.^[55] Many people desire purified seed extracts, but the efficacy of this is questionable, as even pure ergine and ergonovine have shown toxic effects.

The side effects of ergine have been described as follows: "The expression and behavior of the test subjects changed just 45 minutes after taking the substance: the test subjects appeared to be suffering, their facial expressions were deteriorating as if they had suffered a serious illness, and their movements were noticeably slower. [...] In the self-reports of both test subjects, complaints about vegetative symptoms predominated: unpleasant, flu-like feeling of illness, nausea, sudden onset of nausea, with vomiting that could be stopped with 2 cm³ of Cyclicinum hydrochloricum. In addition, sensations of heat, sweating, dizziness, a feeling of heaviness and general tiredness were observed."^[26]

And the side effects of ergonovine have been described as follows: "Walking in this dreamy state was difficult due to leg cramps and slight incoordination. There was always a great desire to lie supine. [...] One of us (J.B.) felt the cramping in the legs as painful and debilitating. [...] We all had a slight hangover the following morning. [...] The mild entheogenic effects of ergonovine are similar to those of LSD. However, in dramatic contrast to LSD, the somatic effects of ergonovine greatly overshadow its psychic effects, so much so that we had no wish to ingest more than 10.0 mg, [...]".^[56]

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.^[57] Another instance is a death due to falling off of a building after ingestion of Hawaiian baby woodrose seeds and alcohol.^[58] A study gave mice 3000 mg/kg with no lethal effects.^{[citation needed]}

Cases of overdose of ergine and morning glory seeds and associated toxicity have been reported.^[19]

The interactions of ergine and of morning glory seeds have been discussed.^[19]

Ergine, also known as lysergic acid amide (LSA) or as lysergamide, is a ergoline and lysergamide. It is the simplest lysergamide and is the parent structure of this family of compounds. Hence, all lysergamides are derivatives of ergine. Lysergic acid diethylamide (LSD) is the analogue of ergine with two ethyl groups substituted on its amide moiety.

The extraction of ergine from morning glory seeds has been described.^[72][73]

Ergine is not a biosynthetic endpoint itself, but rather a hydrolysis product of lysergic acid hydroxyethylamide (LSH), lysergic acid propanolamide (ergonovine), and ergopeptines or their ergopeptam precursors.^{[74][75][76][77][78]}

LSH is very vulnerable to this hydrolysis,^[24][47] and many analyses of ergoline-containing products show little to no LSH and substantial amounts of ergine.

An ergine analog, 8-hydroxyergine, has also been found in natural products in two studies.^[79][80] Methylergonovine and methysergide (1-methylmethylergonovine) have also been found in a natural product in one study;^[55] these are documented as semisynthetic compounds, so the findings need to be repeated for certainty. The aforementioned chemicals are the only natural lysergamides.

LSH and ergine are predominant in Claviceps paspali,^[81][82][83] but are only found in trace amounts in the more well-known Claviceps purpurea.^[84][85] Both are ergot-spreading fungi. The major products of C. purpurea are ergopeptines, but C. paspali does not generate ergopeptines.^[78] Ergonovine is the only lysergamide in C. purpurea in a substantial amount.^[85]

LSH and 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^[86] (ergolines have been identified in 42 of these plants and not all of them contain ergine).^[53] Ergonovine is present in Ipomoea tricolor in one-tenth to one-third of the amount of ergine.^[51] This variable may account for the varying reports about the psychedelic effect of these seeds.^[25]

Other fungi that have been found to contain LSH and/or ergine:

• Unidentified Acremonium species that infects sleepy grass (C. purpurea also infects sleepy grass^[87]).^[80]
• Unidentified Acremonium species that infects drunken horse grass^[88]
• Acremonium coenophialum (infects Festuca arundinacea)^[89]
• Epichloë gansuensis var. inebriens (infects drunken horse grass)^[90]
• Metarhizium brunneum^[91]
• Metarhizium acridum^[91]
• Metarhizium anisopliae^[91]
• Metarhizium flavoviride^[91]
• Metarhizium robertsii^[91]
• Aspergillus leporis^[92]
• Aspergillus homomorphus^[92]
• Aspergillus hancockii^[92]

All of these fungi are related to Claviceps fungi. Aspergillus is considered to be a more distant relative of Claviceps.

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

• Claviceps hirtella^[93]
• Neotyphodium lolii^[94]
• Unidentified Epichlöe and Neotyphodium (asexual forms of Epichlöe) species^[95]
• Aspergillus fumigata^[96]
• Aspergillus flavus^[96]
• Botritis fabae^[96]
• Curvularia lunata^[96]
• Geotrichum candidum^[96]
• Balansia cyperi^[96]
• Balansia claviceps^[96]
• Balansia epichloë^[96]
• Epichloë amarillans^[97]
• Epichloë cabralii (H)^[98]
• Epichloë canadensis (H)^[99][100]
• Epichloë coenophiala (H)^{[99][101][102][103]}
• Epichloë festucae^[97]
• Epichloë festucae var. lolii^[94][104]
• Epichloë festucae var. lolii x E. typhina (H)^[99][105]
• Epichloë inebriens^[97]
• Epichloë glyceriae^[97]
• Epichloë mollis^[99]
• Epichloë typhina^[96]
• Epichloë typhina ssp. poae^[97][98]
• Epichloë typhina ssp. clarkii^[106]
• Epichloë sp. AroTG-2(H)^[107]
• Epichloë sp. FaTG-2(H)^{[99][101][103][108][105]}
• Epichloë sp. FaTG-4(H)^[99][103]
• Hypomyces aurantius^[96]
• Sepedonium sp.^[96]
• Cunnigbamella blakesleana^[96]
• Mucor biemalis^[96]
• Rhizopus nigricans^[96]

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.^[109] 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).^[109] 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.^[109][110]

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.^[109][110] 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.^[109] 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.^[109][110]

Ergine was first obtained by Sidney Smith and Geoffrey Willward Timmis in 1932.^[12]

Albert Hofmann was first to identify ergine as a natural constituent of Turbina corymbosa seeds.^[22]

Albert Hofmann describes ergine as "the main constituent of ololiuhqui".^[111] Ololiuhqui was used by South American healers in shamanic healing ceremonies.^[48] 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.^[112][48]

According to the ethnobotanist R. Gordon Wasson, Thomas MacDougall and Francisco Ortega ("Chico"), a Zapotec guide and trader, should be credited for the discovery of the ceremonial use of Ipomoea tricolor seeds in Zapotec towns and villages in the uplands of southern Oaxaca. The seeds of both Ipomoea tricolor and Rivea corymbosa, another species which has a similar chemical profile, are used in some Zapotec towns.^[113]

The Central Intelligence Agency conducted research on the psychedelic properties of Rivea corymbosa seeds for MKULTRA.^[114]

My chemical investigations of Ololiuhqui seeds led to the unexpected discovery that the entheogenic principles of Ololiuhqui are alkaloids, especially lysergic acid amide, which exhibits a very close relationship to lysergic acid diethylamide (=ʟsᴅ). It follows therefrom that ʟsᴅ, which hitherto had been considered to be a synthetic product of the laboratory, actually belongs to the group of sacred Mexican drugs.

— Albert Hofmann, Burg i.L., Switzerland, November 1992^[115]

• Isoergine (isolyergic acid amide; iso-LSA; isolysergamide)
• Aztec use of entheogens § Ololiuqui and Tlitliltzin
• Morning glory § Chemistry and ethnobotany
• List of entheogens
• List of psychoactive plants