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Iso-LSD

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Iso-LSD
Clinical data
Other namesIsoLSD; 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 classSerotonin receptor modulator
ATC code
  • None
Pharmacokinetic data
Elimination half-life12 hours[1]
Identifiers
  • (6aR,9S)-N,N-diethyl-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.387.572 Edit this at Wikidata
Chemical and physical data
FormulaC20H25N3O
Molar mass323.440 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)[C@@H]1CN([C@@H]2CC3=CNC4=CC=CC(=C34)C2=C1)C
  • 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]

Use and effects

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According to Albert Hofmann and colleagues, iso-LSD is inactive as a psychedelic in humans at doses of up to 500 μg, which is up to 25 times the minimum given doses of LSD (i.e., 20–50 μg).[11][12][13][2][14][15] In other sources, iso-LSD was also stated as being inactive at doses of up to 50 μg/kg (3.5 mg for a 70-kg person), whereas LSD is active at a dose of 1 μg/kg (70 μg for a 70-kg person).[16][17] Hence, iso-LSD is inactive in humans at doses of up to 50 times those of a common psychedelic dose of LSD and at doses of up to 175 times the minimum dose of LSD.[16][17][17] Alexander Shulgin has additionally reported that iso-LSD was inactive at a dose of 4 mg orally.[18] The related drug isoergine is known to be active in terms of psychoactive and hallucinogenic effects at doses of 2 to 5 mg orally.[11][19][16][20][21][22][23][24]

Pharmacology

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Pharmacodynamics

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Iso-LSD shows significant affinity for serotonin receptors.[2][8][9] It had an affinity (IC50Tooltip half-maximal inhibitory concentration) of about 200 nM for serotonin receptors in rat brain membranes.[2][8][9] For comparison, LSD had an affinity of about 8 to 10 nM in the studies, while isoergine had an affinity of 100 to 200 nM and ergine (LSA) had an affinity of about 200 nM.[8][9][25] Hence, iso-LSD showed about 10- to 30-fold lower affinity for serotonin receptors than LSD but had similar affinity for the receptors as ergine and isoergine.[2][8][9][25] Despite these findings however, iso-LSD showed only 0.12% of the antiserotonergic activity of LSD (~1,000-fold lower in comparison) in the isolated rat uterus.[26][22][27][28][17][29]

In studies by David E. Nichols and colleagues, iso-LSD fully substituted for LSD in rodent drug discrimination tests.[30] Full substitution occurred at a dose of 0.32 mg/kg and its ED50Tooltip median effective dose was 0.14 mg/kg, whereas the LSD training dose was 0.08 mg/kg.[30] Iso-LSD was about 7-fold less potent than LSD in terms of ED50 in this assay.[30] In other studies, the drug had about 3.7% of the toxic potency of LSD in rabbits (presumably in terms of LD50Tooltip median lethal dose) and, unlike LSD, was not pyretogenic.[27][22]

Pharmacokinetics

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Iso-LSD is said to have identical metabolism to LSD.[31] It has a longer elimination half-life than LSD.[1] Their half-lives were 12 hours and 4.2 hours, respectively.[1]

Chemistry

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Chemical structures of LSD and its three stereoisomers, including iso-LSD ((+)-iso-LSD).

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.[10][7] Iso-LSD, also known as d-iso-LSD, (+)-iso-LSD, or (5R-8S)-LSD, is one of four possible stereoisomers.[10][7] The other isomers are LSD (d-LSD, (+)-LSD, or (5R,8R)-LSD), l-iso-LSD ((–)-iso-LSD or (5S,8R)-iso-LSD), and l-LSD ((–)-LSD or (5S,8S)-LSD).[10][7] None of them are known to have significant psychoactivity in humans besides LSD.[10][7][15]

LSD is easily epimerized into iso-LSD with base.[5][32][33] Consequently, iso-LSD is a common synthetic contaminant in chemical synthesis of LSD.[5] Iso-LSD can be easily epimerized back into LSD.[33] LSD can degrade into iso-LSD depending on temperature, solvent and pH, among other factors.[34][18] In clinical studies, up to 30% of LSD administered in capsules has been found to isomerize into iso-LSD.[34]

Iso-LSD is said to be a metabolite of LSD in animals and humans.[35][31][36] However, according to other sources, iso-LSD not a metabolite of LSD but is instead only a contaminant.[1][37]

History

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Iso-LSD was first described in the scientific literature, by Albert Hofmann and colleagues, in the 1940s.[35][13][12] The psychedelic effects of LSD were discovered by Hofmann in 1943 when he was using column chromatography to separate LSD from iso-LSD that had resulted as an impurity during the synthesis of LSD.[35]

References

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  1. ^ a b c d Libânio Osório Marta RF (August 2019). "Metabolism of lysergic acid diethylamide (LSD): an update". Drug Metabolism Reviews. 51 (3): 378–387. doi:10.1080/03602532.2019.1638931. PMID 31266388. Literature data reveal the presence of iso-LSD in the urine and other body fluids from LSD users at higher concentrations than LSD (Cai and Henion 1996). However, iso-LSD is not an LSD metabolite but as a major contaminant in many illicit preparations, which is used as an additional marker for LSD consumption (Wagmann et al. 2019). It is an inactive diastereoisomer formed during the synthesis from lysergic acid (Reuschel, Eades, et al. 1999). Iso-LSD showed an elimination half-life greater than LSD, median 12 and 4.2 h, respectively (Steuer et al. 2017).
  2. ^ a b c d e f g 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.
  3. ^ 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).
  4. ^ 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.
  5. ^ a b c d e 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.
  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).
  7. ^ a b c d e 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).
  8. ^ a b c d e Bennett JP, Snyder SH (September 1975). "Stereospecific binding of D-lysergic acid diethylamide (LSD) to brain membranes: relationship to serotonin receptors". Brain Research. 94 (3): 523–544. doi:10.1016/0006-8993(75)90234-6. PMID 239784. TABLE IV DISPLACEMENT OF D-[3H]LSD) BY ANALOGUES AND DRUGS [...] (1) Lysergic acid derivatives [...] D-LSD: ED50 (nM): 9.5. [...] D-iso-LSD: ED50 (nM): 200. D-isolysergic acid amide: ED50 (nM): 200. D-lysergic acid amide: ED50 (nM): 200. [...] D-lysergic acid: ED50 (nM): 10,000. L-LSD: ED50 (nM): 20,000.
  9. ^ a b c d e Bennett JP, Snyder SH (May 1976). "Serotonin and lysergic acid diethylamide binding in rat brain membranes: relationship to postsynaptic serotonin receptors". Molecular Pharmacology. 12 (3): 373–389. doi:10.1016/S0026-895X(25)10753-0. PMID 6896. Substrate specificity of [3H]5-HT and [3H]LSD binding. In confirmation of earlier studies (3–6), d-LSD inhibits d-[3H]LSD binding with an value of about 6–10 nM, while the psychotropically inactive isomer l-LSD has about 1000 times less affinity for the LSD binding sites (Table 1). d-LSD has about the same d-Isolysergic acid amide and methysergide have similar affinities for both [3H]5-HT and d-[3H]LSD binding sites, about 1/10 that of d-LSD itself. [...] TABLE 1 Displacement of specifically bound [3H]serotonin and d-[3H]LSD from rat cerebral cortex membranes [...] LSD analogues [...] d-LSD: IC50: [3H]5-HT: 10 [nM]. d-[3H]LSD: 8 [nM]. [...] d-Isolysergic acid amide. IC50: [3H]5-HT: 100 [nM]. d-[3H]LSD: 200 [nM]. [...] l-LSD. IC50: [3H]5-HT: 100,000 [nM]. d-[3H]LSD: 20,000 [nM].
  10. ^ a b c d e 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.
  11. ^ a b 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).
  12. ^ a b 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 inhuman 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. [...]
  13. ^ a b 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.
  14. ^ 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]. [...]
  15. ^ a b 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.
  16. ^ a b c Brimblecombe RW, Pinder RM (1975). "Indolealkylamines and Related Compounds". Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 98–144. ISBN 978-0-85608-011-1. OCLC 2176880. OL 4850660M. Oral doses of 2 mg. of isolysergic acid amide are reported to produce a feeling of mental emptiness and total detachment from the outside world. Heim and his colleagues suggest that the overall effects of ololiuqui are due to these two compounds, the d-lysergic acid amide giving intoxication with strong autonomic side-effects and the d-isolysergic acid amide producing some euphoria, synaesthesia, and altered time experience. [...] Table 4.3.—COMPARATIVE HALLUCINOGENIC POTENCIES IN MAN OF DERIVATIVES OF D-LYSERGIC ACID* [...]
  17. ^ a b c d Isbell H, Miner EJ, Logan CR (1959). "Relationships of psychotomimetic to anti-serotonin potencies of congeners of lysergic acid diethylamide (LSD-25)". Psychopharmacologia. 1: 20–28. doi:10.1007/BF00408108. PMID 14405872. No psychotomimetic effects were observed with L-LSD (maximum dose 70 mcg/kg), I-LSD (50 mcg/kg), and MBL-61 (175 mcg/kg), so that further comparisons of these drugs with LSD were not undertaken. [...] Table I. Comparison of psychotomimetic amd antiserotonin potencies [...] Code: I-LSD. Compound: d-Iso-lysergic acid diethylamide. Dose approximately* equivalent to 1.0 mcg/kg of LSD-25: >50. Relative psychotomimetic activity (LSD-25 = 100): 0. Relative** anti-serotonin activity (LSD-25 = 100): 0. Remarks: No psychotomimetic effect in doses used.
  18. ^ a b Shulgin AT, Shulgin A (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. LSD is an unusually fragile molecule and some comments are in order as to its stability and storage. As a salt, in water, cold, and free from air and light exposure, it is stable indefinitely. There are two sensitive aspects of its structure. The position of the carboxamide attachment, the 8-position, is affected by basic, or high pH, conditions. Through a process called epimerization, this position can scramble, producing isolysergic acid diethylamide, or iso-LSD. This product is biologically inactive, and represents a loss of a proportionate amount of active product. [...] 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.
  19. ^ Shulgin A. "#26. LSD-25". TiHKAL. Erowid.org. Retrieved 2012-02-03. 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. After a short period of sleep, the effects were gone and normal baseline was recovered within five hours. Other observers have confirmed this clouding of consciousness leading to sleep. 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.
  20. ^ Hofmann A (1963). "The Active Principles of the Seeds of Rivea Corymbosa and Ipomoea Violacea". Botanical Museum Leaflets, Harvard University. 20 (6). Harvard University Herbaria: 194–212. doi:10.5962/p.168542. ISSN 0006-8098. JSTOR 41762231. Archived from the original on 28 March 2025.
  21. ^ Hofmann A (1970). "The Discovery of LSD and Subsequent Investigations on Naturally Occurring Hallucinogens". In Ayd FJ, Blackwell B (eds.). Discoveries in Biological Psychiatry. J.B. Lippincott Company. pp. 96–106. ISBN 978-0-397-59044-5. Archived from the original on 30 March 2025. After taking 2.0 mg of isolysergic amide orally, I experienced tiredness, apathy, a feeling of mental emptiness and of the unreality and complete meaninglessness of the outside world.[11] [...]
  22. ^ a b c Fanchamps A (1978). "Some Compounds With Hallucinogenic Activity". In Berde B, Schild HO (eds.). Ergot Alkaloids and Related Compounds. Handbook of Experimental Pharmacology (HEP). Vol. 49. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 567–614. doi:10.1007/978-3-642-66775-6_8. ISBN 978-3-642-66777-0. Archived from the original on 30 March 2025. 1. LSD Isomers The levorotatory isomer I-LSD (No. 61 2) is completely devoid of psychotomimetic activity (GERONIMUS et ai., 1956; HOFMANN, 1958; MURPHREE et ai., 1958; ISBELL et ai., 1959a) and modifies neither the cortical nor subcortical EEG in man (MONROE et ai., 1957). Also devoid of psychotomimetic activity are the two derivatives of isolysergic acid, d-iso-LSD (No. 93c) (HOFMANN, 1958; ISBELL et ai., 1959a) and I-iso-LSD (No. 62) (HOFMANN, 1958). Compared to LSD, these three inactive isomers are extremely weak serotonin antagonists (CERLETTI and DOEPFNER, 1958 a) and are not pyretogenic in the rabbit (Sandoz Research Laboratories, 1958, 1959) (Table 2). On the other hand, I-LSD and d-iso-LSD do not differ from LSD regarding cholinesterase inhibition (ZSIGMOND et ai., 1960); rat brain alkaline phosphatase and malic dehydrogenase are activated to the same extent by LSD and 1-LSD; the only difference was found with respect to lactic dehydrogenase, which is not affected by LSD but slightly inhibited by I-LSD (CLARK et ai., 1956) [...] The second main component was d-isolysergic acid amide, or Iso-LA819 (No. 18a). After its identification in ololiuqui, trials were performed in man with oral doses up to 5 mg; they revealed central effects which were not LSD-like (ISBELL, 1962) but chiefly consisted in relaxation, synesthesias, and altered time experience (HEIMANN, 1965; HElM et al., 1968). [...] Table 2. Psychotomimetic activity and some pharmacodynamic effects of structural analogues of LSD [...]
  23. ^ Chen W, De Wit-Bos L (2020). Risk assessment of Argyreia nervosa (PDF) (Report). doi:10.21945/rivm-2019-0210. A. nervosa contains ergot alkaloids, with D-lysergic acid amide (LSA) or ergine and its epimer iso-LSA or isoergine as main active components (see Chapter 3). [...] Human volunteer studies [...] Heim, Heimann & Lukács (1968) conducted experiments with increasing doses of LSA (0.04 or 0.09 mg/kg bw [3–6 mg total]), iso-LSA (0.03, 0.06 or 0.07 mg/kg bw [2–5 mg total]), or total alkaloids from the drug Ololiuqui (Rivea corymbosa; 0.02, 0.06, 0.08 or 0.10 mg/kg bw) in healthy volunteers. [...] Ingestion of LSA led to nausea, vomiting, an illness-like state with general fatigue, sweating and dizziness, vision problems, slower movements and speech (a state of lethargy and apathy), beginning approximately 45 minutes after ingestion and becoming more pronounced over the next hours. [...] Based on these results, the authors suggest that the vegetative symptoms are probably caused by LSA while iso-LSA leads to impairment of the thinking ability and effects on a persons' conscious (Heim, Heimann & Lukács, 1968). [...] Heim, E., Heimann, H., & Lukács, G., Die psychische Wirkung der mexikanischen Droge „Ololiuqui" am Menschen. Psychopharmacologia, 1968. 13(1): p. 35-48. doi:10.1007/BF00401617
  24. ^ Heim E, Heimann H, Lukács G (1968). "Die psychische Wirkung der mexikanischen Droge "Ololiuqui" am Menschen" [Psychotomimetic effects of the mexican drug “Ololiuqui”]. Psychopharmacologia (in German). 13 (1): 35–48. doi:10.1007/BF00401617. ISSN 0033-3158. PMID 5675457.
  25. ^ a b Gupta SP, Singh P, Bindal MC (1 December 1983). "QSAR studies on hallucinogens". Chemical Reviews. 83 (6): 633–649. doi:10.1021/cr00058a003. ISSN 0009-2665.
  26. ^ Cerletti A, Doepfner W (January 1958). "Comparative study on the serotonin antagonism of amide derivatives of lysergic acid and of ergot alkaloids". The Journal of Pharmacology and Experimental Therapeutics. 122 (1): 124–136. doi:10.1016/S0022-3565(25)11933-2. PMID 13502837. According to the molecular structure of lysergic acid, four isomers of LSD are possible. All four have been synthetized and tested. As shown in figure 2, the diethylamide of l-lysergic acid as well as the analogous derivatives of d- and l-isolysergic acid are practically ineffective, being about one thousand times weaker than LSD-25. [...] FIG. 2. Relative antiserotonin potency of LSD-isomers and C9, C10-saturated LSD derivatives. [...] [...] d-iso-LSD = 0,12
  27. ^ a b Hoffer A (1965). "D-Lysergic acid diethylamide (LSD): A review of its present status". Clinical Pharmacology and Therapeutics. 6 (2): 183–255. doi:10.1002/cpt196562183. PMID 14288188. Table I. Comparative activity of some lysergic acid alkaloids [...]
  28. ^ Caldwell J, Sever PS (October 1974). "The biochemical pharmacology of abused drugs. I. Amphetamines, cocaine, and LSD". Clinical Pharmacology and Therapeutics. 16 (4): 625–638. doi:10.1002/cpt1974164625. PMID 4607666.
  29. ^ Cerletti A, Konzett H (1956). "Spezifische Hemmung von 5-Oxytryptamin-Effekten durch Lysergsäurediäthylamid und ähnliche Körper" [Specific inhibition of serotonin effects by lysergic acid diethylamide and similar compounds]. Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie (in German). 228 (1–2). doi:10.1007/BF00259761. ISSN 0028-1298. Retrieved 5 June 2025.
  30. ^ a b c Marona-Lewicka D, Nichols DE (October 2007). "Further evidence that the delayed temporal dopaminergic effects of LSD are mediated by a mechanism different than the first temporal phase of action". Pharmacology, Biochemistry, and Behavior. 87 (4): 453–461. doi:10.1016/j.pbb.2007.06.001. PMID 17618679. The 8-epimer of LSD, isoLSD, fully mimicked LSD-30 (Table 2), although with a potency about seven times lower than LSD itself (LSD ED50 0.044 μmol/kg vs 0.296 μmol/kg for isoLSD). [...] Table 2 Compounds that produced full or partial substitution in LSD-30-trained rats (for details and definitions see the Method section)
  31. ^ a b Dolder P (2017). The Pharmacology of d-Lysergic Acid Diethylamide (LSD) (PDF) (Thesis). University of Basel. p. 112. doi:10.5451/UNIBAS-006786123. Retrieved 3 June 2025.
  32. ^ Herian M (2022). "Pharmacological Action of LSD: LSD Effect on the Neurotransmission and Animal Behavior". Handbook of Substance Misuse and Addictions. Cham: Springer International Publishing. pp. 2457–2475. doi:10.1007/978-3-030-92392-1_131. ISBN 978-3-030-92391-4. Retrieved 4 June 2025. Too high pH value of the solution results in the transformation to an inactive form of iso-LSD, light can also convert LSD to inactive lumi-LSD.
  33. ^ a b Gumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)". British Journal of Pharmacology. doi:10.1111/bph.17361. PMID 39354889. Ergolines are relatively flat and rigid tetracyclic molecules. For psychedelic activity, the 5R,8R–(+)-stereoisomer, shown in Figure 1, is the only one with activity. The stereochemistry of the diethylamide function at the 8-positon is labile and under acidic conditions can epimerize to the alpha-position (iso-LSD), with loss of biological activity. Treatment under basic conditions can epimerize iso-LSD back to normal LSD with the diethylamide moiety residing in the planar beta orientation.
  34. ^ a b Liechti ME, Holze F (2022). "Dosing Psychedelics and MDMA". Disruptive Psychopharmacology. Curr Top Behav Neurosci. Vol. 56. pp. 3–21. doi:10.1007/7854_2021_270. ISBN 978-3-031-12183-8. PMID 34734392. Furthermore, such substances as LSD and psilocybin may decompose over time, and the content of pharmaceutically active substance may thus be lower than initially thought (Holze et al. 2019). For example, LSD is inactivated to iso-LSD, depending on temperature, solvent, and pH, and may be unstable in certain formulations. Other stress factors, such as light, oxygen, and chlorine in tap water, may lead to decomposition of the LSD molecule. In fact, amounts of iso-LSD were detected in plasma from research subjects in one of our studies that used LSD in capsules (Mueller et al. 2017a, b; Dolder et al. 2016), indicating that approximately 30% of the LSD that was administered likely isomerized to inactive iso-LSD within the LSD capsules that were used (Steuer et al. 2017). {{cite book}}: |journal= ignored (help)
  35. ^ a b c Nichols DE (October 2018). "Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)". ACS Chemical Neuroscience. 9 (10): 2331–2343. doi:10.1021/acschemneuro.8b00043. PMID 29461039. The extraordinary nature of this mental disturbance led Hofmann to suspect that some exogenous compound might be responsible. He had been using column chromatography to separate the lysergic acid diethylamide from the epimeric isolysergic acid diethylamide that resulted from the synthesis and had prepared the crystalline water-soluble tartrate salt of lysergic acid diethylamide. [...] Iso-LSD, 2-oxo-3-OH-LSD, nor-LSD, LAE, LEO, 13/14-hydroxy-LSD, and 2-oxo-LSD could be detected only sporadically, and concentrations were too low for quantification.
  36. ^ Omidian H, Omidian A (March 2025). "Clinical Research on Lysergic Acid Diethylamide (LSD) in Psychiatry and Neuroscience". Pharmaceuticals. 18 (4). Basel, Switzerland: 499. doi:10.3390/ph18040499. PMC 12030196. PMID 40283936.
  37. ^ Joyce I (2017). "A Comparative Literature Survey of Psilocybin and LSD-25 Metabolism". ScholarWorks. The iso-LSD* compound in the left graph is not psychoactive and is generally synthesized during the drug manufacturing process.46,48 Because of this fact, it is debateable as to whether LSD-25 is actually metabolized to iso-LSD in vivo. 46,48 However, in terms of forensic analysis and drug testing, toxicologists generally agree that the presence of iso-LSD is a good indicator of LSD-25 drug use.46
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