-LSD.svg) | |
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| Other names | (–)-LSD; (5S,8S)-LSD;levo-LSD;l-Lysergic acid diethylamide;l-Lysergide;N,N-Diethyl-6-methyl-9,10-didehydro-5α-ergoline-8α-carboxamide |
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| Chemical and physical data | |
| Formula | C20H25N3O |
| Molar mass | 323.440 g·mol−1 |
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l-LSD, also known as(–)-LSD or(5S,8S)-LSD, as well asl-lysergic acid diethylamide orl-lysergide, is alysergamide and one of four possiblestereoisomers of thelysergic acid diethylamide (LSD) molecule (with thepsychedelic drug actually being theenantiopured-isomer).[1][2]
The LSD molecule has twochiral centers at carbons 5 and 8 of theergolinering system and hence there are four possibleenantiomeric stereoisomers of LSD.[2][3]l-LSD, also known as (–)-LSD or (5S,8S)-LSD, is one of four possible stereoisomers.[2][3] The other isomers areLSD (d-LSD, (+)-LSD, or (5R,8R)-LSD),iso-LSD (d-iso-LSD, (+)-iso-LSD, or (5R-8S)-LSD), andl-iso-LSD ((–)-iso-LSD or (5S,8R)-iso-LSD).[2][3] None of them are known to have significantpsychoactivity in humans besides LSD.[2][3][4]
l-LSD showed only 0.06% of theantiserotonergic activity of LSD in the isolated ratuterus.[5] Hence, it was more than 1,000-fold less potent than LSD in thisassay and was regarded as essentially inactive.[5] In subsequentreceptorbinding studies,l-LSD showed 2,000- to 10,000-fold lower affinity forserotonin receptors than LSD.[6][7]
l-LSD showed no psychedelic effects in humans at a dose of up to 10 mgorally or up to 400 times the minimum effective dose of LSD (~25 μg).[8][9][10][11][4][1] However,Albert Hofmann reported that althoughl-LSD produced no LSD-like effects, it caused "very slight drowsiness" at doses above 500 μg.[4]
l-LSD was first described in thescientific literature by at least the 1950s.[5][10][4]
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.
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.
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).
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.
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.
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.
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].
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).
Comparison was made in normal human volunteers of the effects of l-lysergic acid diethylamide, dl-α-methyl tryptamine, 5-hydroxytryptamine, dl-DOPA, d-DOPA and l-DOPA with d-lysergic acid diethylamide. The subjects were highly trained to recognize the effects of d-LSD and other hallucinogens. All compounds were given orally. Blood pressure, pulse rate, pupil diameter, body temperature, hand steadiness were measured at hourly intervals, and the subjects kept running diaries of subjective effects. l-LSD was previously reported by this department to have no effect in doses up to 2 mg. In this study, dosage was increased progressively to 10 mg with no effect. It was concluded that [...] the levo- isomer is less active than the dextro- by a factor greater than 400:1. [...]
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. [...]
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]. [...]
