 | |
| Clinical data | |
|---|---|
| Other names | 12-Hydroxylysergic acid diethylamide; 12-OH-LSD; 12-HO-LSD; "5-OH-LSD"; "5-HO-LSD"; "5-Hydroxy-LSD"; 9,10-Didehydro-N,N-diethyl-6-methyl-12-hydroxyergoline-8β-carboxamide |
| Drug class | Serotonin receptor modulator |
| ATC code |
|
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| ChemSpider | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C20H25N3O2 |
| Molar mass | 339.439 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
12-Hydroxy-LSD is adrug of theergoline andlysergamide families and aderivative oflysergic acid diethylamide (LSD).[1][2][3][4][5] In terms ofchemical structure, 12-hydroxy-LSD is to LSD asbufotenin (5-HO-DMT) is todimethyltryptamine (DMT), with 12-hydroxy-LSD notably containing bufotenin within itsconformationally constrained structure.[6][5] 12-Hydroxy-LSD producespsychedelic-like effects in animals,[7][5] whereas reports on its activities in humans are very limited and have been conflicting.[1][4][2][8][3]
12-Hydroxy-LSD is known to bepharmacologically active inanimal studies.[1] The drug's effects in rabbits includeantiserotonergic activity (25% of that of LSD) andhyperthermia (dose ratio relative toLD50Tooltip median lethal dose of 1:44 for 12-hydroxy-LSD and 1:725 for LSD).[1] In addition, like LSD, it is highlypotent in terms oflethality, with amedian lethal dose (LD50) of 0.3 mg/kgi.v.Tooltip intravenous administration in rabbits (relative to 0.1 mg/kg for LSD).[1][2] 12-Hydroxy-LSD also produces LSD-likeelectroencephalogram (EEG) changes in rabbits.[9]
According to Robert C. Pfaff andDavid E. Nichols and colleagues, 12-hydroxy-LSD substitutes for LSD in rodentdrug discrimination tests.[7][5] Hence, it appears to show psychedelic-like effects in animals.[7][5] However, 12-hydroxy-LSD was described as having unremarkable properties in this assay and only having about 20 to 50% of thepotency of LSD.[7][5] Its reduced potency compared to LSD could be due to its increasedpolarity and associatedpharmacokinetic differences.[5] It was reported in the 1960s that 12-hydroxy-LSD does not producehallucinogenic effects in humans.[1][4][2][8] On the other hand however, Michael Valentine Smith claimed in his 1981 bookPsychedelic Chemistry that 12-hydroxy-LSD has "about the same activity as LSD".[3]
Presumably 12-hydroxy-LSD acts as anagonist ofserotonin anddopamine receptors, as with LSD and other related lysergamides, but itspharmacology has not been studied with modern techniques.[1][2]
Thechemical synthesis of 12-hydroxy-LSD is described as being very difficult.[7]
Ananalogue of 12-hydroxy-LSD is12-methoxy-LSD, which would be structurally akin to5-MeO-DMT.[1][2][3] As with 12-hydroxy-LSD, it has been reported that 12-methoxy-LSD is inactive as apsychedelic in humans.[1]
12-Hydroxy-LSD was first described in thescientific literature by 1962.[10][11][12][1] Subsequently, it was further described in the 1970s and 1980s.[2][8][9][3][4]David E. Nichols and colleagues reported that 12-hydroxy-LSD producespsychedelic-like effects in animals in 1994.[7] It was initially thought that 12-hydroxy-LSD might be ametabolite of LSD,[10][13] but this proved not to be the case.[12][14][15]
Fig. 2. Listed are several pharmacodynamic properties of various lysergic acid derivatives: Ps = psychotomimetic activity in man; P.I. = pyretogenic index (ratio of the i.v. LD50 and the dose producing an increase in rectal temperature of 1°C in rabbits); Tox. = i.v. LD50 in rabbits; 5-HT = antiserotonin activity in isolated rat uterus expressed in percentages of that for LSD-25. It is evident that the psychotomimetic action does not correlate with 5-HT antagonism nor with the toxicity of the compound. A close correlation is observed with the pyretogenic index (i.e. the specific pyretogenic action in rabbits. [...]
2,3-dihydro-LSD can be converted directly to 12-hydroxy-LSD, which has about the same activity as LSD and this process is also given below.
The assessment of a particular LSD derivative as a candidate for a future [Controlled Substance Analog (CsA)] involves the consideration of several points. The most important are those attempts made by other researchers to modify the structure of LSD while retaining hallucinogenic activity. To date, all attempts to modify the tetracyclic ring system have resulted in a loss of hallucinogenic activity. For instance, of the four possible C-8 stereoisomers only the dextro isomer of LSD is hallucinogenic (Rothlin 1957a). Modification of the amide alkyl substituents also reduces hallucinogenic activity substantially (Usdin and Efron 1972). Additionally, substitution with either a hydroxyl or a methoxy at the C-12 of LSD results in a compound with no hallucinogenic activity (Usdin and Efron 1972), whereas a comparably substituted methoxyindolealkylamine appears to always be hallucinogenic (Gessner and Page 1962). The only structural modification which results in the maintenance of hallucinogenic activity on par with LSD is the substitution of either a methyl or an acetyl to the indole nitrogen (Rothlin 1957b).
8. Substitutions at Position 12: This position corresponds to the 5-position of indole, thereby making 12-OH-LSD that much more structurally similar to serotonin, whose receptors so potently interact with LSD. In drug discrimination tests, 12-OH-LSD completely substituted for LSD, but was only about half as potent.200 However, this derivative would also be more polar than LSD and pharmacokinetic factors could play a role in its decreased activity. Further work investigating in more detail the resulting effects of oxygen substitution at this key position could prove valuable in understanding hallucinogenic activity. [...] 200. Oberlender, R. and Nichols, D. E., unpublished.
Ring substitution at the C(12) or C(13) positions is fairly difficult. Because entire doctoral theses have been written about the total synthesis of lysergic acid, it is apparent that the synthesis of derivatives modified at the 12-, 13-, or 14-position would be quite a formidable task. Nevertheless, the 12-hydroxy compound was prepared years ago. The authors obtained a sample of this and performed drug discrimination (DD) studies in LSD-trained rats. It had unremarkable properties, with only about 20 percent of the potency of LSD (Pffaf et al., unpublished observations).
Table 1. Human psychotomimetic potencies of LSD analogs. [...] Compound: 28 [(12-hydroxy-LSD)]. R1: C2H5. R2: C2H5. R3: H. R4: H. R5: OH. Rel Act (Ref): – (60). [...] Compound: 29 [(12-methoxy-LSD)]. R1: C2H5. R2: C2H5. R3: H. R4: H. R5: OCH3. Rel Act (Ref): – (60). [...] –, inactive. [...] The final two entries in Table 1, 12-hydroxy-LSD (28) and 12-methoxy-LSD (29), were reported to be inactive by Taeschler,60 although no details were given.
EEG studies. Synthetic and biosynthetic metabolites of LSD were injected intravenously into conscious restrained male chinchilla rabbits. With LSD itself, de-ethyl-LSD, 12-hydroxy-LSD, 12-methoxy-LSD, 13-hydroxy-LSD, 13-methoxy-LSD and 13-hydroxy-LSD glucuronide, a persistent alerting EEG trace was seen as indicated by an increase in frequency and decrease in amplitude of the waveform. No changes were observed after administration of lysergic acid, di-LSD-disulphide [10], nor-LSD, 14-hydroxy-LSD-glucuronide, 14-methoxy-LSD, lumi-LSD or the metabolic 2-oxo-LSD.
Until now only a few hydroxylated metabolites of LSD have been reported. Axelrod et al. (1956, 1957) showed that 2-oxy-LSD was formed by guinea-pig liver microsomes supplemented with oxygen and NADPH, by comparing the metabolite with synthetic 2-oxy-LSD (Freter, Axelrod and Witkop 1957). Slaytor and Wright (1962) presumed that 12-hydroxy-LSD and 12-hydroxy-iso-LSD were obtained from rat bile, by analogy with the formation of 12-hydroxy-ergometrine in the metabolism of ergometrine; Szara (1963) reported that a hydroxyl group of a metabolite formed by rat liver microsomal system was probably at the 13-position from the fact that the absorption peak of the diazotized sulphanilic acid product of the metabolite was identical with that of 6-hydroxyindole, and recently Siddik et al. (1975) suggested that the phenolic metabolites obtained from rat urine and faeces were 13- and 14-hydroxy-LSD, since the metabolites were different from authentic 12-hydroxy-LSD (Stadler et al. 1964) in chromatographic characteristics. In our experiment using the rat liver microsomal system, however, it was verified by n.m.r. spectroscopy that the metabolite M, was 13-hydroxy-LSD.
[...] 12-hydroxy-LSD (105c), a metabolite of LSD, [...] Fig. 27. Ergot derivatives substituted in the benzene ring [...] (105c): 12-Hydroxy-LSD. R = H, X = CON(C2H5)2, Y = H, Z = OH [...] F. Subject Index: [...] Names: 12-Hydroxy-d-lysergic acid diethylamide, 12-Hydroxy-LSD. Fig.: 27. Nr.: 105c.
A recent report by Siddik et al. (3) stated that lysergic acid diethylamide (LSD) is not hydroxylated in the 12 position as previously suggested (4), but showed that, although the mass spectrum of one of the hydroxy LSD metabolites was identical to 12-hydroxy LSD, the metabolite had different chromatographic characteristics. The two hydroxylated phenolic metabolites have been tentatively assigned the structures of 13-hydroxy and 14-hydroxy LSD.
The presence of 12-OH-LSD and derivatives suggested by Slaytor and Wright (1962) were not detected. The metabolites 13-OH-L5D and 13-OH-LSD glucuronide were reported to have central activity in rabbits, evidenced by an alerting EEG trace following an intravenous injection (Siddik et al., 1979a); however, quantitative studies with these compounds are lacking.
