L-Iso-LSD

Pharmaceutical compound From Wikipedia, the free encyclopedia

l-Iso-LSD, also known as (–)-iso-LSD or (5S,8R)-iso-LSD, as well as l-isolysergic acid diethylamide, is a lysergamide and one of four possible stereoisomers of the lysergic acid diethylamide (LSD) molecule (with the psychedelic drug actually being the enantiopure d-isomer).^[1]^[2]

Other names(–)-Iso-LSD; (5S,8R)-Iso-LSD; levo-Iso-LSD; l-Isolysergic acid diethylamide; N,N-Diethyl-6-methyl-9,10-didehydro-5α-ergoline-8β-carboxamide

ATC code

None

PubChem CID

56841613

ChemSpider

32809688

Quick facts Clinical data, Other names ...

l-Iso-LSD
Clinical data


Other names	(–)-Iso-LSD; (5S,8R)-Iso-LSD; levo-Iso-LSD; l-Isolysergic acid diethylamide; N,N-Diethyl-6-methyl-9,10-didehydro-5α-ergoline-8β-carboxamide
ATC code	None
Identifiers
IUPAC name (6aS,9R)-N,N-Diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide
PubChem CID	56841613
ChemSpider	32809688
Chemical and physical data
Formula	C₂₀H₂₅N₃O
Molar mass	323.440 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CCN(CC)C(=O)[C@H]1CN([C@H]2CC3=CNC4=CC=CC(=C34)C2=C1)C
InChI InChI=1S/C20H25N3O/c1-4-23(5-2)20(24)14-9-16-15-7-6-8-17-19(15)13(11-21-17)10-18(16)22(3)12-14/h6-9,11,14,18,21H,4-5,10,12H2,1-3H3/t14-,18+/m1/s1 Key:VAYOSLLFUXYJDT-KDOFPFPSSA-N

The LSD molecule has two chiral centers at carbons 5 and 8 of the ergoline ring system and hence there are four possible enantiomeric stereoisomers of LSD.^[2]^[3] l-Iso-LSD, also known as (–)-iso-LSD or (5S,8R)-iso-LSD, is one of four possible stereoisomers.^[2]^[3] The other isomers are LSD (d-LSD, (+)-LSD, or (5R,8R)-LSD), iso-LSD (d-iso-LSD, (+)-iso-LSD, or (5R-8S)-LSD), and l-LSD ((–)-LSD or (5S,8S)-LSD).^[2]^[3] None of them are known to have significant psychoactivity in humans besides LSD.^[2]^[3]^[4]

l-Iso-LSD showed only 0.1% of the antiserotonergic activity of LSD in the isolated rat uterus.^[5] Hence, it was about 1,000-fold less potent than LSD in this assay and was regarded as essentially inactive.^[5]

l-Iso-LSD showed no psychedelic effects in humans at a dose of up to 500 μg orally or up to 20 times the minimum effective dose of LSD (~25 μg).^[6]^[7]^[8]^[4]^[1] According to Albert Hofmann, the only effect of l-iso-LSD at a dose of 500 μg was mild nausea.^[4]

l-Iso-LSD was first described in the scientific literature by at least the 1950s.^[5]^[7]^[4]

References

[1]
Alexander T. Shulgin; Ann Shulgin (1997). "#26. LSD-25 Acid; Lysergide; D-Lysergic Acid Diethylamide; Meth-LAD; D-Lysergamide, N,N-Diethyl; N,N-Diethyl-D-Lysergamide; 9,10-Didehydro-N,N-Diethyl-6-Methylergoline-8b-Carboxamide". TiHKAL: The Continuation (1st ed.). Berkeley, CA: Transform Press. pp. 490–499. ISBN 978-0-9630096-9-2. OCLC 38503252. Let me mention in passing, that there are three stereoisomers possible for d-LSD. There are d-iso-LSD, l-LSD, and l-iso-LSD. The inversion of the stereochemistry of the attached diethylcarboxyamido group of d-LSD gives the diastereoisomer (d-iso-LSD) which is a frequent synthetic impurity of d-LSD itself. The corresponding optical antipodes l-LSD and l-iso-LSD are also known and have been tasted. All three are completely inactive: d-iso-LSD shows no psychological changes at an oral dose of 4 milligrams; l-LSD none at up to 10 milligrams orally; and l-iso-LSD none at 500 micrograms orally. These dramatic decreases in potency show both the stereoselectivity of the native LSD molecule in producing its central effects, and the LSD-free purity of these isomers.
[2]
Panik K, Presti D (29 January 2021). "LSD". In Grob CS, Grigsby J (eds.). Handbook of Medical Hallucinogens. Guilford Publications. pp. 159–180. ISBN 978-1-4625-4545-2. The LSD molecule (see Figure 8.1) possesses two chiral centers at carbons 5 and 8; thus, there are four enantiomeric stereoisomers. Of these, only one—(5R,8R)-LSD—is known to have significant physiological activity. This isomer is dextrorotatory; thus, the physiologically active isomer is sometimes referred to as (+)-LSD or d-LSD. Hereafter, we will simply designate it as LSD. Inverting (reflecting) the chiral configuration at the 8-position gives (5R,8S)-d-iso-LSD. Inverting the configuration at the 5-position gives (5S,8R)-l-iso-LSD. And inverting the chiral configuration at both the 5v-position and the 8-position gives (5S,8S)-l-LSD (Nichols, 2018a). None of these enantiomers has shown any significant psychoactivity in humans (Shulgin & Shulgin, 1997). [...] FIGURE 8.1. (5R,8R)-Lysergic acid diethylamide, or d-LSD.
[3]
Mangner TJ (1978). Potential Psychotomimetic Antagonists. N,n -diethyl-1-methyl-3-aryl-1, 2, 5, 6-tetrahydropyridine-5-carboxamides (Ph.D. thesis). University of Michigan. doi:10.7302/11268. Archived from the original on 30 March 2025. As depicted in structure 1 and in Table 1, there exists in the molecule of LSD two asymmetric carbons— those at C-5 and C-8. Consequently, there are four possible stereoisomers for the lysergate ring system of which only one, that found in d-LSD, is active. The absolute configuration about each of the two asymmetric centers in LSD has been a i established as 5-R; 8-R.61 The C-8 epimer of LSD, d-isoLSD, (34), with the 5-R; 8-S absolute configuration, as well as the two diastereomeric diethyllysergamides l-LSD (5-S; 8-S) (35) and l-iso-LSD (5-S; 8-R) (36), are reported to be without psychotomimetic effects in man.52,54,57,59 These inactive stereoisomers, since both C-5 and C-8 occur in the D ring, can also be considered structural variants in the upper part of the LSD molecule which, like virtually all D-ring modifications, do not retain the potent activity characteristic of LSD itself. [...] 52. A. Cerletti in "Neuropsychopharmacology," P. B. Bradley, P. Deniker and C. Rodouco—Thomas, Eds., Elsevier, New York, 1959, p. 117. [...] 54. H. Isbell, E. J. Miner and C. R. Logan, Psychopharm., 1, 20 (1959). [...] 57. A. Hofmann, Acta Physiol. Pharmacol. Neer., 8, 240 (1959). [...] 59. H. B. Murphree, J. Pharmacol. Exp. Ther., 122, 55A (1958).
[4]
Hofmann A (1958). "The LSD-Psychosis: III. Lysergic Acid Diethylamide and Related Compounds. Relationship Between Spatial Arrangement and Mental Effects". In Rinkel M (ed.). Chemical Concepts of Psychosis: Proceedings of the Symposium on Chemical Concepts of Psychosis held at the Second International Congress of Psychiatry in Zurich, Switzerland, September 1 to 7, 1957. New York: McDowell, Obolensky. pp. 85–90. doi:10.1037/11190-006. Archived from the original on 4 June 2025. A trial on myself and on one coworker, under medical supervision, of the stereoisomers of LSD led to the following findings: l-LSD, in doses up to 500 micrograms, produced no LSD-like symptoms. Above 500 micrograms, very slight drowsiness was noted.2 d-iso-LSD, in doses up to 250 micrograms, was completely without effect. l-iso-LSD, in doses up to 500 micrograms, also proved to have no mental effects. After the ingestion of 500 micrograms, only mild nausea was noted. As both persons participating in the study (the author and his assistant) had previously had a very marked response to 20 micrograms of LSD, it would appear that the three stereoisomers of LSD are at least fifteen to thirty times less active than d-lysergic acid diethylamide. More extensive studies in human beings, using increasing doses would be necessary to determine whether there are qualitative and quantitative differences between the three relatively inactive isomers by comparison with d-lysergic acid diethylamide. However, these preliminary studies clearly show that the mental effects of LSD are highly stereospecific.
[5]
Cerletti A (1956). "Lysergic Acid Diethylamide (LSD) and Related Compounds". In Abramson HA (ed.). Neuropharmacology: Transactions of the 2nd Conference, May 25-27, 1955, Princeton, N.J. New York: Josiah Macy. pp. 9–84. Besides that, there are two other isomers as a consequence of the asymmetry at C8, namely lysergic and isolyergic acid. Therefore, LSD and iso-LSD are different only concerning the spatial arrangement at C8. The difference between lysergic acid and isolysergic acid was once attributed to a shifting of the double bond already mentioned, but, as shown by Stoll and his coworker (5) this is not true. We had the opportunity to test, pharmacologically, the diethylamide derivatives of all four isomers of lysergic acid and now I can state that l-LSD as well as d-iso- and l-iso-LSD are very different from d-LSD or LSD-25, in that they are practically inactive.
[6]
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. Removal of the double bond in ring D, either by hydrogenation (to form 9,10-dihydro-LSD) or by hydration (to form lumi-LSD) appears to destroy all psychic activity (Cerletti, 1959). As to optical isomers, both d-iso-LSD (II) and l-LSD (III) are also inactive (Cerletti, 1959), the latter even at 400 times the effective dosage of LSD (Murphree et al., 1960). The fourth isomer, l-iso-LSD (IV), produces no effects in man at 20 times the active dose of LSD (Hofmann, 1959).
[7]
Hofmann A (June 1959). "Psychotomimetic drugs; chemical and pharmacological aspects" (PDF). Acta Physiologica et Pharmacologica Neerlandica. 8: 240–258. PMID 13852489. Variations in the spatial arrangement of the atoms in the LSD molecule led to 3 stereoisomers (d-iso-LSD, l-LSD, l-iso-LSD) as shown in fig. 1. These proved to be practically inactive when compared with the ordinary LSD (d-LSD). The author and his assistant have tested these 3 stereoisomers under medical supervision. They were found to be without any psychotomimetic activity in doses up to 500 γ [(μg)]. This means that these stereoisomers are at least 20 times less active than the d-lysergic form. More extensive studies in human beings, using increasing doses, would be necessary to determine whether there are qualitative and quantitative differences between the three relatively inactive isomers. However, these preliminary studies clearly show that the mental effects of LSD are highly stereospecific. [...] Fig. 1. Stereoisomers of LSD. [...]
[8]
Shulgin AT (1971), "Chemistry and Sources", in Epstein SS, Lederberg J (eds.), Drugs of Abuse: Their Genetic and Other Chronic Nonpsychiatric Hazards, Cambridge, Massachusetts: MIT Press, pp. 3–26, ISBN 9780262050098, OCLC 208409, OL 22156530M, The optical enantiomorphs and the isomeric diastereoisomers of LSD (Vis.. l-LSD, d-iso-LSD and l-iso-LSD) have been also assayed in human subjects and have been found inactive [Hofmann 1958; Murphree et al. 1960]. [...]

L-Iso-LSD

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References

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