Iso-LSD

Iso-LSD
Clinical data
Other names	IsoLSD; I-LSD; d-Iso-LSD; (+)-Iso-LSD; (5R-8S)-LSD; Isolysergic acid diethylamide; N,N-Diethylisolysergamide; iso-Lysergic acid diethylamide; N,N-Diethyl-6-methyl-9,10-didehydroergoline-8α-carboxamide; d-Isolysergic acid diethylamide
Routes of; administration	Oral
Drug class	Serotonin receptor modulator
ATC code	None;
Pharmacokinetic data
Elimination half-life	12 hours
Identifiers
	IUPAC name (6aR,9S)-N,N-diethyl-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide;
CAS Number	2126-78-5;
PubChem CID	638252;
IUPHAR/BPS	154;
UNII	R1XBQ6NTFR;
CompTox Dashboard (EPA)	DTXSID30858950 ;
ECHA InfoCard	100.387.572
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+/m0/s1; Key:VAYOSLLFUXYJDT-KBXCAEBGSA-N;

Iso-LSD, also known as d-iso-LSD, (+)-iso-LSD, or (5R-8S)-LSD, as well as N,N-diethylisolysergamide, is a serotonin receptor modulator of the lysergamide family related to lysergic acid diethylamide (LSD).^[2]^[3]^[4]^[5] It is the 8-position epimer of LSD, with iso-LSD being 8α (8S) and LSD being 8β (8R).^[6]^[7]^[2]^[3]^[4]^[5] Iso-LSD is also the N,N-diethyl derivative of isoergine (isolysergic acid amide; iso-LSA), a constituent found in morning glory seeds.^[2]^[8]^[9]^[5] Iso-LSD is one of four possible stereoisomers of LSD.^[10]

^ Cite error: The named reference Libanio_Osorio_Marta_2019 was invoked but never defined (see the help page).
^ ^a ^b ^c Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524. It is only ergolines with the 5R,8R stereochemistry, as illustrated earlier in Fig. 1 that have biological activity. That isomer is dextrorotatory, so LSD is referred to as (+)-LSD or d-LSD. Receptor binding studies by Bennett and Snyder in 1976 first demonstrated that LSD had nanomolar affinity for [3 H]LSD-labeled binding sites in rat cortex (Bennett and Snyder 1976). By contrast, its 5S,8S enantiomer, (−)-LSD, had 2500-fold lower affinity. The 8-position epimerizes readily, particularly at acidic pH, to provide the 5R,8S epimer (+)-isolysergic acid diethylamide 22, which has about 30-fold lower receptor affinity and is inactive as a psychedelic.
^ ^a ^b Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi:10.1002/wmts.42. ISSN 2190-460X. FIGURE 11 | N, N-diethyllysergamide (LSD) and inactive epimeric iso-LSD. [...] Both carbons 5 and 8 are chiral, and it is only ergolines with the 5R,8R-configuration, as illustrated in Figure 1, which have biological activity. That isomer is dextrorotatory, so LSD is referred to as (+)-LSD or d-LSD. Early receptor binding studies by Bennett and Snyder25 demonstrated that (+)-LSD had nanomolar affinity for [3H]LSD-labeled sites in rat cortex, whereas its enantiomer, 5S,8S-(−)-LSD, had 2500-fold lower affinity. The 8-position readily epimerizes to provide (+)-isolysergic acid diethylamide, which has about 30-fold lower affinity and is inactive as an hallucinogen. This transformation is facile and occurs under slightly acidic pH (Figure 11).
^ ^a ^b Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994). "Lysergamides revisited". NIDA Research Monograph. 146: 52–73. PMID 8742794. The stereochemistry is critical for the lysergic acid molecule. The R stereochemistries at both the C(5) and C(8) positions are essential. Inversion of either stereocenter abolishes hallucinogenic activity (Brimblecombe and Pinder 1975). C(5) inversion gives l-lysergic acid derivatives, as compared with the natural d-lysergic acid. Epimerization at the C(8) position gives the isolysergic acid or iso-LSD derivatives.
^ ^a ^b ^c Shulgin AT (1980). "Hallucinogens". In Burger A, Wolf ME (eds.). Burger's Medicinal Chemistry. Vol. 3 (4 ed.). New York: Wiley. pp. 1109–1137. ISBN 978-0-471-01572-7. OCLC 219960627. The lysergic acid four-ring nucleus possesses two asymmetric centers requiring four isomeric forms. All have been prepared and the hallucinogenic action is uniquely ascribable to the stereoisomer 60.33a. The 8-substituent, lying between two unsaturated systems, is easily epimerized with base. Thus a common synthetic contaminant in syntheses involving the lysergic acid ring system is the pharmacologically inert iso form as shown in 60.33b.
^ Rutschmann J, Stadler PA (1978). "Chemical Background". Ergot Alkaloids and Related Compounds. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 29–85. doi:10.1007/978-3-642-66775-6_2. ISBN 978-3-642-66777-0. Retrieved 4 June 2025. Traditionally, in many important instances, the α-isomer (15) is distinguished from the β-form (14) (e.g., d-Iysergic acid, ergotamine) by the prefix iso- (e.g., d-isolysergic acid) or by the ending -inine (e.g., ergotaminine).
^ 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).
^ Cite error: The named reference Bennett_1975 was invoked but never defined (see the help page).
^ Cite error: The named reference Bennett_1976 was invoked but never defined (see the help page).
^ Cite error: The named reference GrobGrigsby2021 was invoked but never defined (see the help page).

[Libanio_Osorio_Marta_2019-1] Cite error: The named reference Libanio_Osorio_Marta_2019 was invoked but never defined (see the help page).

[Nichols_2018-2] Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524. It is only ergolines with the 5R,8R stereochemistry, as illustrated earlier in Fig. 1 that have biological activity. That isomer is dextrorotatory, so LSD is referred to as (+)-LSD or d-LSD. Receptor binding studies by Bennett and Snyder in 1976 first demonstrated that LSD had nanomolar affinity for [3 H]LSD-labeled binding sites in rat cortex (Bennett and Snyder 1976). By contrast, its 5S,8S enantiomer, (−)-LSD, had 2500-fold lower affinity. The 8-position epimerizes readily, particularly at acidic pH, to provide the 5R,8S epimer (+)-isolysergic acid diethylamide 22, which has about 30-fold lower receptor affinity and is inactive as a psychedelic.

[Nichols_2012-3] Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi:10.1002/wmts.42. ISSN 2190-460X. FIGURE 11 | N, N-diethyllysergamide (LSD) and inactive epimeric iso-LSD. [...] Both carbons 5 and 8 are chiral, and it is only ergolines with the 5R,8R-configuration, as illustrated in Figure 1, which have biological activity. That isomer is dextrorotatory, so LSD is referred to as (+)-LSD or d-LSD. Early receptor binding studies by Bennett and Snyder25 demonstrated that (+)-LSD had nanomolar affinity for [3H]LSD-labeled sites in rat cortex, whereas its enantiomer, 5S,8S-(−)-LSD, had 2500-fold lower affinity. The 8-position readily epimerizes to provide (+)-isolysergic acid diethylamide, which has about 30-fold lower affinity and is inactive as an hallucinogen. This transformation is facile and occurs under slightly acidic pH (Figure 11).

[Pfaff_1994-4] Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994). "Lysergamides revisited". NIDA Research Monograph. 146: 52–73. PMID 8742794. The stereochemistry is critical for the lysergic acid molecule. The R stereochemistries at both the C(5) and C(8) positions are essential. Inversion of either stereocenter abolishes hallucinogenic activity (Brimblecombe and Pinder 1975). C(5) inversion gives l-lysergic acid derivatives, as compared with the natural d-lysergic acid. Epimerization at the C(8) position gives the isolysergic acid or iso-LSD derivatives.

[Alexander_1980-5] Shulgin AT (1980). "Hallucinogens". In Burger A, Wolf ME (eds.). Burger's Medicinal Chemistry. Vol. 3 (4 ed.). New York: Wiley. pp. 1109–1137. ISBN 978-0-471-01572-7. OCLC 219960627. The lysergic acid four-ring nucleus possesses two asymmetric centers requiring four isomeric forms. All have been prepared and the hallucinogenic action is uniquely ascribable to the stereoisomer 60.33a. The 8-substituent, lying between two unsaturated systems, is easily epimerized with base. Thus a common synthetic contaminant in syntheses involving the lysergic acid ring system is the pharmacologically inert iso form as shown in 60.33b.

[Rutschmann_1978-6] Rutschmann J, Stadler PA (1978). "Chemical Background". Ergot Alkaloids and Related Compounds. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 29–85. doi:10.1007/978-3-642-66775-6_2. ISBN 978-3-642-66777-0. Retrieved 4 June 2025. Traditionally, in many important instances, the α-isomer (15) is distinguished from the β-form (14) (e.g., d-Iysergic acid, ergotamine) by the prefix iso- (e.g., d-isolysergic acid) or by the ending -inine (e.g., ergotaminine).

[Mangner_1978-7] 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).

[Bennett_1975-8] Cite error: The named reference Bennett_1975 was invoked but never defined (see the help page).

[Bennett_1976-9] Cite error: The named reference Bennett_1976 was invoked but never defined (see the help page).

[GrobGrigsby2021-10] Cite error: The named reference GrobGrigsby2021 was invoked but never defined (see the help page).

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