Lysergic acid hydroxyethylamide

Chemical compound From Wikipedia, the free encyclopedia

Lysergic acid hydroxyethylamide (LSH or LAH), also known as lysergic acid N-(α-hydroxyethyl)amide or as lysergic acid methyl carbinolamide, is a lysergamide alkaloid related to the psychedelic drug lysergic acid diethylamide (LSD). It is found in ergot species such as Claviceps paspali^[2]^[3]^[4] and Claviceps purpurea^[5]^[6] and in the seeds of morning glory species which contain symbiotic fungi such as Periglandula ipomoeae and Periglandula clandestina.^[7]

Other namesLAH; LSH; Lysergic acid N-(α-hydroxyethyl)amide; Lysergic acid α-hydroxyethylamide; Lysergic acid methyl carbinolamide; N-(1-Hydroxyethyl)lysergamide; N(HOE)-LA; 9,10-Didehydro-N-(1-hydroxyethyl)-6-methylergoline-8-carboxamide

ATC code

None

Legal status

Illegal in France^[1]

CAS Number

3343-15-5^Y

Quick facts Clinical data, Other names ...

LSH
Clinical data


Other names	LAH; LSH; Lysergic acid N-(α-hydroxyethyl)amide; Lysergic acid α-hydroxyethylamide; Lysergic acid methyl carbinolamide; N-(1-Hydroxyethyl)lysergamide; N(HOE)-LA; 9,10-Didehydro-N-(1-hydroxyethyl)-6-methylergoline-8-carboxamide
ATC code	None
Legal status
Legal status	Illegal in France^[1]
Identifiers
IUPAC name (6aR,9R)-N-(1-hydroxyethyl)-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
CAS Number	3343-15-5^Y
PubChem CID	134553
ChemSpider	27470958^Y
CompTox Dashboard (EPA)	DTXSID10955057
ECHA InfoCard	100.020.079
Chemical and physical data
Formula	C₁₈H₂₁N₃O₂
Molar mass	311.385 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CC(NC(=O)[C@H]1CN([C@@H]2CC3=CNC4=CC=CC(=C34)C2=C1)C)O
InChI InChI=1S/C18H21N3O2/c1-10(22)20-18(23)12-6-14-13-4-3-5-15-17(13)11(8-19-15)7-16(14)21(2)9-12/h3-6,8,10,12,16,19,22H,7,9H2,1-2H3,(H,20,23)/t10?,12-,16-/m1/s1^Y Key:WYTJZJPVCDWOOI-WPJLSRQMSA-N^Y
(verify)

Use and effects

According to Albert Hofmann, Alexander Shulgin, and other researchers, LSH might be a psychedelic drug and might contribute to or be substantially responsible for the hallucinogenic effects of morning glory seeds.^[8]^[9]^[10]^[11] Relatedly, per Shulgin in his 1997 book TiHKAL (Tryptamines I Have Known and Loved), both ergine (lysergic acid amide; LSA) and isoergine (iso-LSA) are "probably correctly dismissed" as not contributing to the effects of morning glory seeds.^[12] However, LSH has not been studied in humans and this hypothesis has not been tested or confirmed.^[8]^[11] LSH is said to be extremely chemically unstable, rapidly degrading into ergine, and this has made its investigation difficult.^[8]^[9]^[10]^[11]

Interactions

Pharmacology

Pharmacodynamics

The pharmacology of LSH has been very limitedly studied.^[10]^[8]^[11] It has about 30 to 50% of the potency as ergonovine (ergometrine) as an oxytocic in the isolated guinea pig and rabbit uterus, produces sympathomimetic effects like piloerection, mydriasis, and hyperthermia that are very similar to those of ergine (LSA) in mice and rabbits, and has weak ergotamine-like sympatholytic or antiadrenergic effects but with approximately 200-fold lower potency in comparison.^[10]^[11] These effects are potentially indicative of LSH having LSD-like activity.^[10]^[8]^[11] However, LSH is not known to have been tested in humans.^[8]^[11] LSH may simply function as a prodrug of ergine.^[8]^[10]

Chemistry

The structure of LSH is similar to that of LSD, with the N,N-diethylamide group replaced by an N-(1-hydroxyethyl)amide in D-lysergic acid α-hydroxyethylamide. LSH is also very similar in structure to ergonovine (ergometrine), which is also known as lysergic acid hydroxyisopropylamide.^[13]

Natural occurrence

Claviceps paspali and Claviceps purpurea are ergot alkaloid-producing fungi that occur as endophytes or pathogens of grasses. Clavicipitaceous fungi of the genus Periglandula are mutualistically associated with, and vertically inherited among, an estimated 450 species of Convolvulaceae.^[14] Some of them produce LSH, with 42 generating ergolines per Eckart Eich's review.^[15] The most well-known plant hosts are Ipomoea tricolor ("morning glory"), Turbina corymbosa (coaxihuitl), and Argyreia nervosa (Hawaiian baby woodrose).

The more well-known analogue, ergine (lysergic acid amide; LSA), is more prominent in analytical results because LSH easily decomposes to ergine.^[10]^[16] Ergine is only present because of the decomposition of LSH (and ergonovine and ergopeptines or their ergopeptam precursors) and is not otherwise generated.^[17]^[18]^[19]^[20]^[21] A 2016 analysis found that fresher Ipomoea tricolor seeds contained more LSH than the other two batches analyzed.^[22]

History

LSH was first described in the scientific literature in 1960.^[23] It was isolated from Claviceps paspali.^[23]

Society and culture

Legal status

Canada

LSH is not a controlled substance in Canada.^[24]

France

LSH is illegal in France.^[1]

United States

LSH is not an explicitly controlled substance in the United States.^[25] However, it could be considered a controlled substance under the Federal Analogue Act if intended for human consumption.

References

[1]
"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.
[2]
Arcamone F, Bonino C, Chain EB, Ferretti A, Pennella P, Tonolo A, Vero L (July 1960). "Production of lysergic acid derivatives by a strain of Claviceps paspali Stevens and Hall in submerged culture". Nature. 187 (4733): 238–239. Bibcode:1960Natur.187..238A. doi:10.1038/187238a0. PMID 13794048.
[3]
Castagnoli N, Corbett K, Chain EB, Thomas R (April 1970). "Biosynthesis of N-(alpha-hydroxyethyl) lysergamide, a metabolite of Claviceps paspali Stevens and Hall". The Biochemical Journal. 117 (3) (published 1970-04-01): 451–455. doi:10.1042/bj1170451. PMC 1178946. PMID 5419742.
[4]
Basmadjian G, Floss HG, Gröger D, Erge D (1969). "Biosynthesis of ergot alkaloids. Lysergylalanine as precursor of amide-type alkaloids". J. Chem. Soc. D (8): 418–419. doi:10.1039/C29690000418. ISSN 0577-6171.
[5]
Schultes R (1973). "4. Plants of Hallucinogenic Use / The Fungi". The Botany and Chemistry of Hallucinogens. Springfield, IL: Charles Thomas. p. 37. ISBN 9780398064167.
"Whereas ergine, lysergic acid hydroxyethylamide, and lysergyl L-valine methylester occur in ergot of rye only in trace amounts, ergonovine (synonyms ergometrine, ergobasin), which is the specific oxytocic factor of a ergot, is often found in remarkable quantities. In contrast, ergine and hydroxyethylamide of lysergic acid are the main constituents of certain ergot growing on wild grasses, e.g. Paspalum distichum." 4. Plants of Hallucinogenic Use / The Fungi, p. 37
[6]
Wasson RG, Hofmann A, Ruck CA, Webster P (November 25, 2008) [1978]. Forte R (ed.). The Road to Eleusis: Unveiling the Secret of the Mysteries (30th Anniversary ed.). Berkeley, Calif.: North Atlantic Books. ISBN 978-1-55643-752-6. "We analyzed ergot of wheat and ergot of barley in our laboratory and they were found to contain basically the same alkaloids as ergot of rye, viz. alkaloids of the ergotamine and ergotoxine group, ergonovine, and sometimes also traces of lysergic acid amide. As I said before, ergonovine and lysergic acid amide, both psychoactive, are soluble in water whereas the other alkaloids are not." Albert Hofmann, 2. A Challenging Question and my Answer, p. 42
[7]
Florea S, Panaccione DG, Schardl CL (May 2017). "Ergot Alkaloids of the Family Clavicipitaceae". Phytopathology. 107 (5): 504–518. Bibcode:2017PhPat.107..504F. doi:10.1094/PHYTO-12-16-0435-RVW. PMC 5480214. PMID 28168931.
[8]
Hofmann A (1968). "Psychotomimetic Agents". In Burger A (ed.). Drugs Affecting the Central Nervous System. Vol. 2. New York: M. Dekker. pp. 169–235. OCLC 245452885. OL 13539506M. d-Lysergic acid N-(1-hydroxyethyl)amide (16b), and d-isolysergic acid N-(1-hydroxyethyl)amide (17b) are hydrolyzed very easily to the corresponding amides and acetaldehyde (186). This could also occur in the organism. d-Lysergic acid N-(1-hydroxyethyl)amide induces contractions in the isolated uterus of the guinea pig and in the rabbit uterus in situ, showing about 30—50 % of the activity of ergometrine. In mice and rabbits it produced the syndrome of central sympathetic stimulation, such as piloerection, mydriasis, and hyperthermia, which suggests that it could have an LSD-like activity, but this hypothesis has not yet been verified by experiments on humans (193).
[9]
Shulgin AT (1972). "Hallucinogens, CNS Stimulants, And Cannabis". In Mulé, SJ, Brill H (eds.). Chemical and Biological Aspects of Drug Dependence. CRC Press. pp. 163–176. doi:10.1201/9780429260629-16. ISBN 978-0-87819-011-9. The major alkaloids present were found to be ergine (d-Lysergic acid amide, Figure 2; R1, R2, R3 = H) and the enantiomorph isoergine (d-Isolysergic acid amide, identical with ergine, but with the opposite epimeric configuration on the carbon atom that carries the amide carbonyl group). These two compounds have been shown to have some activity in man, but it is possible that their presence in the natural seed as the extremely labile acetaldehyde condensates (the hydroxyethylamides) may explain the activity of the seed compared to the lack of activity of the ergot isolates.8 [...] 8. Hofmann, A., Teonanacatl and Ololiuqui, two ancient magic drugs of Mexico, Bull. Narc., 23, 3, 1971.
[10]
Shulgin AT (1976). "Psychotomimetic Agents". In Gordon M (ed.). Psychopharmacological Agents: Use, Misuse and Abuse. Medicinal Chemistry: A Series of Monographs. Vol. 4. Academic Press. pp. 59–146. doi:10.1016/b978-0-12-290559-9.50011-9. ISBN 978-0-12-290559-9. These compounds, although well documented as components in the Convolvulaceae, are possibly lost in several of the analyses of alkaloid composition. They are extremely unstable, and are very readily degraded into acetaldehyde and the corresponding amide, ergine or isoergine." (p. 72) [...] "Lysergic acid hydroxyethylamide appears, in uterus response studies of the guinea pig and rabbit (Glasser, 1961), to be about half as potent as its homolog ergometrine, and in mice and rabbits it shows a sympathomimetic response very similar to that described for ergine. This is indicative of potential LSD-like activity.
[11]
Glässer A (January 1961). "Some Pharmacological Actions of ᴅ-Lysergic Acid Methyl Carbinolamide". Nature. 189 (4761): 313–314. Bibcode:1961Natur.189..313G. doi:10.1038/189313a0. PMID 13705953. S2CID 4260358. [...] the new naturally occurring alkaloid ᴅ-lysergic acid methyl carbinolamide has powerful ergometrine-like oxytocic action and weak ergotamine-like adrenergic blocking actions. It must be included, on the basis of pharmacological evidence, in the ergometrine group of ergot alkaloids. Ergometrine, however, is less toxic and more active than the new alkaloid. Results suggest that it could have a lysergic acid diethylamide-like activity, but this hypothesis must be checked by experiments on humans.
[12]
Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. https://www.erowid.org/library/books_online/tihkal/tihkal26.shtml "LA-111, Ergine, d-Lysergamide. This is an active compound and has been established as a major component in morning glory seeds. It was assayed for human activity, by Albert Hofmann in self-trials back in 1947, well before this was known to be a natural compound. An i.m. administration of a 500 microgram dose led to a tired, dreamy state with an inability to maintain clear thoughts. [...] The epimer, inverted at C-8, is isoergine or d-isolysergamide, and is also a component of morning glory seeds. Hofmann tried a 2 milligram dose of this amide, and as with ergine, he experienced nothing but tiredness, apathy, and a feeling of emptiness. Both compounds are probably correctly dismissed as not being a contributor to the action of these seeds. It is important to note that ergine, as well as lysergic acid itself, is listed as a Schedule III drug in the Controlled Substances Act, as a depressant. This is, in all probability, a stratagem to control them as logical precursors to LSD. [...] Although there are many other chemical treasures in the ergot fungal world, I would like to wrap this commentary up with a return to the topic of morning glory seeds. Four additional alkaloids of the ergot world must be acknowledged as being potentially participating factors in the MGS story. [...] These structures in effect define absolute obscurity, and most probably do not contribute to the morning glory intoxication state. But the others, some present is sizable amounts, may someday help explain why the pharmacology of these seeds is so different than that of the major isolates, the ergines."
[13]
Jarvik LF, Kato T, Saunders B, Moralishvili E (1968). "LSD and Human Chromosomes". In Efron DH (ed.). Psychopharmacology. A Review of Progress 1957-1967. LSD 2054 Proc. 6th Annual Meeting, Amer. Coll. Neuropsychopharmacol., San Juan/Puerto Rico, Dec. 12-15, 1967. Washington, D. C.: United States Public Health Service. pp. 1247–1252. [...] lysergic acid hydroxyisopropylamide—ergonovine maleate, U.S.P. (Ergotrate Maleate, Lilly) [...]
[14]
Leistner E, Steiner U (February 3, 2018). "The Genus Periglandula and Its Symbiotum with Morning Glory Plants (Convolvulaceae)". In Anke T, 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 2024-11-21.
[15]
Eich E (January 12, 2008). "4.2 Ergolines". Solanaceae and convolvulaceae - secondary metabolites: biosynthesis, chemotaxonomy, biological and economic significance: a handbook. Berlin, Heidelberg: Springer-Verlag. doi:10.1007/978-3-540-74541-9. ISBN 978-3-540-74540-2. OCLC 195613136
Table 4.1 Unambiguously ergoline-positive Ipomoea species (pages 225-227)
Table 4.4 Unambiguously ergoline-positive Argyreia species (p. 236)
Table 4.5 Unambiguously ergoline-positive Stictocardia and Turbina species (p. 238){{cite book}}: CS1 maint: postscript (link)
[16]
Schultes RE, Hofmann A (1973). The Botany and Chemistry of Hallucinogens. Springfield, IL: Charles Thomas. p. 246. ISBN 9780398064167. "Later, it was found that ergine and isoergine were present in the seeds to some extent in the form of lysergic acid N-(1-hydroxyethyl) amide and isolysergic acid N-(1-hydroxyethyl) amide, respectively, and that, during the isolation procedure, they easily hydrolize to ergine and isoergine, respectively, and acetaldehyde." 4. Plants of Hallucinogenic Use / Convolvulaceae, p. 246
[17]
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.
[18]
Ramstad E (1968). "Chemistry of alkaloid formation in ergot". Lloydia. 31: 327–341.
[19]
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.
[20]
Panaccione DG, Tapper BA, Lane GA, Davies E, Fraser K (October 2003). "Biochemical outcome of blocking the ergot alkaloid pathway of a grass endophyte". Journal of Agricultural and Food Chemistry. 51 (22): 6429–6437. Bibcode:2003JAFC...51.6429P. doi:10.1021/jf0346859. PMID 14558758.
[21]
Panaccione DG (2010). "Ergot alkaloids". In Hofrichter M (ed.). The Mycota, Industrial Applications. Vol. 10 (2nd ed.). Berlin-Heidelberg, Germany: Springer-Verlag. pp. 195–214.
[22]
Nowak J, Woźniakiewicz M, Klepacki P, Sowa A, Kościelniak P (May 2016). "Identification and determination of ergot alkaloids in Morning Glory cultivars". Analytical and Bioanalytical Chemistry. 408 (12) (published February 14, 2016): 3093–3102. doi:10.1007/s00216-016-9322-5. PMC 4830885. PMID 26873205. "As has been demonstrated in this study, LSH is a labile compound, and therefore the variances in its concentration may be due to different age and storage conditions of the seeds rather than difference in plant metabolism. Indeed, seeds IT-HB2, which express highest concentration of LSH, were bought directly from the producer, whereas seeds IP-HB1 were purchased in retail stores." (Analysis of different Ipomoea seeds)
See Table 3 under "Analysis of different Ipomoea seeds".
Concentration values for "LSH", "Lyzergol/isobars", penniclavine, and chanoclavine can be obtained by dividing the concentration values of ergine or ergometrine by their relative abundance values and multiplying that number by the relative abundance value of the specified chemical.
[23]
Arcamone F, Bonino C, Chain EB, Ferretti A, Pennella P, Tonolo A, Vero L (July 1960). "Production of lysergic acid derivatives by a strain of Claviceps paspali Stevens and Hall in submerged culture". Nature. 187 (4733): 238–239. Bibcode:1960Natur.187..238A. doi:10.1038/187238a0. PMID 13794048. [...] Neither the two isomers of lysergic acid amide [(LSA)] nor those of lysergic acid methyl carbinolamide [(LSH)] have previously been reported to occur in Nature.
[24]
"Controlled Drugs and Substances Act". Department of Justice Canada. 5 December 2025. Retrieved 20 January 2026.
[25]
Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026) (PDF), United States: U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division, January 2026

Lysergic acid hydroxyethylamide

Use and effects

Interactions

Pharmacology

Pharmacodynamics

Chemistry

Natural occurrence

History

Society and culture

Legal status

Canada

France

United States

See also

References

External links

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"Ergot Alkaloids of the Family Clavicipitaceae"

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