Ergine, also known as d-lysergic acid amide (LSA) and d-lysergamide, is an ergoline

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...

that occurs in various species of vines of the Convolvulaceae and some species of

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...

. The psychedelic properties in the seeds of

ololiuhqui ''Ipomoea corymbosa'' is a species of morning glory, native throughout Latin America from Mexico as far south as Peru and widely naturalised elsewhere. Its common names include Christmasvine, Christmaspops, and snakeplant. Description and names ...

, Hawaiian baby woodrose and morning glories have been linked to ergine and/or isoergine, its

epimer In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is ...

, as it is an alkaloid present in the seeds.

Occurrence in nature

Ergine has been found in high concentrations of 20 μg/g dry weight in the sleepygrass infected with an '' Acremonium''

endophytic An endophyte is an endosymbiont, often a bacterium or fungus, that lives within a plant for at least part of its life cycle without causing apparent disease. Endophytes are ubiquitous and have been found in all species of plants studied to date; h ...

fungus A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...

together with other ergot alkaloids. Ergine is a component of the alkaloids contained in the

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 ...

fungus, which grows on the heads of infected rye grasses. It is also found in the seeds of several varieties of morning glories in concentrations of approximately 10 μg per seed, as well as Hawaiian baby woodrose seeds, at a concentration of around 0.13% of dry weight.

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

sacrament A sacrament is a Christian rite that is recognized as being particularly important and significant. There are various views on the existence and meaning of such rites. Many Christians consider the sacraments to be a visible symbol of the rea ...

s by certain Zapotecs, sometimes in conjunction with the seeds of '' Rivea corymbosa'', another species which has a similar chemical composition, with

lysergol Lysergol is an alkaloid of the ergoline family that occurs as a minor constituent in some species of fungi (most within ''Claviceps''), and in the morning glory family of plants (Convolvulaceae), including the hallucinogenic seeds of ''Rivea co ...

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 Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles ha ...

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 The Central Intelligence Agency (CIA ), known informally as the Agency and historically as the Company, is a civilian foreign intelligence service of the federal government of the United States, officially tasked with gathering, processing, ...

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 ''Ipomoea corymbosa'' is a species of morning glory, native throughout Latin America from Mexico as far south as Peru and widely naturalised elsewhere. Its common names include Christmasvine, Christmaspops, and snakeplant. Description and names ...

, 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

death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

s directly associated with pharmacological effects of ergine consumption. All associated deaths are due to indirect causes, such as

self-harm Self-harm is intentional behavior that is considered harmful to oneself. This is most commonly regarded as direct injury of one's own skin tissues usually without a suicidal intention. Other terms such as cutting, self-injury and self-mutilati ...

, impaired judgement, and adverse drug interactions. One known case involved a

suicide Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and ...

that was reported in 1964 after

ingestion Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in a substance through the mouth into the gastrointestinal tract, such as through eating or drinking. In single-celled organisms in ...

of morning glory

seeds A seed is an embryonic plant enclosed in a protective outer covering, along with a food reserve. The formation of the seed is a part of the process of reproduction in seed plants, the spermatophytes, including the gymnosperm and angiosperm ...

. Another instance is a death due to falling off of a

building A building, or edifice, is an enclosed structure with a roof and walls standing more or less permanently in one place, such as a house or factory (although there's also portable buildings). Buildings come in a variety of sizes, shapes, and func ...

after ingestion of Hawaiian baby woodrose

seed A seed is an embryonic plant enclosed in a protective outer covering, along with a food reserve. The formation of the seed is a part of the process of reproduction in seed plants, the spermatophytes, including the gymnosperm and angiosper ...

s and

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

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 Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

* Visual and auditory hallucinations *

Euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and d ...

* Loss of motor control *

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

Vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...

Delusion A delusion is a false fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or som ...

Anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

Paranoia Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy c ...

Irregular heartbeat Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

Kremer, C., Paulke, A., Wunder, C., & Toennes, S. W. (2012). Variable adverse effects in subjects after ingestion of equal doses of Argyreia nervosa seeds. Forensic science international, 214(1-3), e6-e8. * Sexual arousalSubramoniam, A., Madhavachandran, V., Ravi, K., & Anuja, V. S. (2007). Aphrodisiac property of the elephant creeper Argyreia nervosa. J Endocrinol Reprod, 11(2), 82-85. *

Tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

Marneros A, Gutmann P, Uhlmann F. Self-amputation of penis and tongue after use of Angel's Trumpet. Eur Arch Psychiatry Clin Neurosci. 2006 Oct;256(7):458-9. doi: 10.1007/s00406-006-0666-2. Epub 2006 Jun 16. PMID 16783491. *

Mydriasis Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drugs. Normally, a ...

* 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 drug is more dangerous than commonly believed. 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 In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

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 Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

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. Dopamine constitutes about 80% o ...

, and

adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...

s 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 Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar ...

of L-tryptophan in an SN1 fashion with

dimethylallyl diphosphate Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosyn ...

(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 Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonat ...

. A three strep mechanism is proposed to form 4-L-DMAT: the formation of an allylic

carbocation A carbocation is an ion with a positively charged carbon atom. Among the simplest examples are the methenium , methanium and vinyl cations. Occasionally, carbocations that bear more than one positively charged carbon atom are also encount ...

, 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 ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...

(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 Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...

, EasC. The chanoclavine intermediate is then oxidized to chanoclavine-l-aldehyde, catalyzed by the short-chain dehydrogenase/reductase (SDR), EasD. Ergine_biosynthesis_part_2

From here, the biosynthesis diverges and the products formed are plant and fungus-specific. The biosynthesis of ergine in C''laviceps purpurea'' will be exemplified, in which agroclavine is produced following the formation of chanoclavine-l-aldehyde, catalyzed by EasA through a keto-enol

tautomerization Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...

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. Ergine_biosynthesis_part_3

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 USA. However, possession of the pure compound without a prescription or DEA license would be prosecuted, as ergine, under the name "lysergic acid amide", is listed under Schedule III of the

Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal U.S. drug policy under which the manufacture, importation, possession, use, and distribution of certain substances is regulated. It was passed by the 91st United States ...

. 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 The ''Controlled Drugs and Substances Act'' (french: Loi réglementant certaines drogues et autres substances) (the ''Act'') is Canada's federal drug control statute. Passed in 1996 under Prime Minister Jean Chrétien's government, it repeal ...

, 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.

Notes

* * * *

References

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
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