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12-Hydroxy-LSD
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| 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 |
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| Chemical and physical data | |
| Formula | C20H25N3O2 |
| Molar mass | 339.439 g·mol−1 |
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12-Hydroxy-LSD is a drug of the ergoline and lysergamide families and a derivative of lysergic acid diethylamide (LSD).[1][2][3][4][5] In terms of chemical structure, 12-hydroxy-LSD is to LSD as bufotenin (5-HO-DMT) is to dimethyltryptamine (DMT), with 12-hydroxy-LSD notably containing bufotenin within its conformationally constrained structure.[6][5] 12-Hydroxy-LSD produces psychedelic-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]
Interactions
[edit]Pharmacology
[edit]12-Hydroxy-LSD is known to be pharmacologically active in animal studies.[1] The drug's effects in rabbits include antiserotonergic activity (25% of that of LSD) and hyperthermia (dose ratio relative to LD50 of 1:44 for 12-hydroxy-LSD and 1:725 for LSD).[1] In addition, like LSD, it is highly potent in terms of lethality, with a median lethal dose (LD50) of 0.3 mg/kg i.v. in rabbits (relative to 0.1 mg/kg for LSD).[1][2] 12-Hydroxy-LSD also produces LSD-like electroencephalogram (EEG) changes in rabbits.[9]
According to Robert C. Pfaff and David E. Nichols and colleagues, 12-hydroxy-LSD substitutes for LSD in rodent drug 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 the potency of LSD.[7][5] Its reduced potency compared to LSD could be due to its increased polarity and associated pharmacokinetic differences.[5] It was reported in the 1960s that 12-hydroxy-LSD does not produce hallucinogenic effects in humans.[1][4][2][8] On the other hand however, Michael Valentine Smith claimed in his 1981 book Psychedelic Chemistry that 12-hydroxy-LSD has "about the same activity as LSD".[3]
Presumably 12-hydroxy-LSD acts as an agonist of serotonin and dopamine receptors, as with LSD and other related lysergamides, but its pharmacology has not been studied with modern techniques.[1][2]
Chemistry
[edit]Synthesis
[edit]The chemical synthesis of 12-hydroxy-LSD is described as being very difficult.[7]
Analogues
[edit]An analogue of 12-hydroxy-LSD is 12-methoxy-LSD, which would be structurally akin to 5-MeO-DMT.[1][2][3] As with 12-hydroxy-LSD, it has been reported that 12-methoxy-LSD is inactive as a psychedelic in humans.[1]
History
[edit]12-Hydroxy-LSD was first described in the scientific 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 produces psychedelic-like effects in animals in 1994.[7] It was initially thought that 12-hydroxy-LSD might be a metabolite of LSD,[10][13] but this proved not to be the case.[12][14][15]
See also
[edit]References
[edit]- ^ a b c d e f g h i j M. Taeschler (1967). "Pharmacology of Psychotomimetic Agents". In Brill H, Cole JO, Deniker P, Hippius H, Bradley PB (eds.). Neuro-psycho-pharmacology: Proceedings of the Fifth International Congress of the Collegium Internationale Neuropsychopharmacologicum. Washington, D.C., 28-31 March 1966. International Congress Series. Vol. 129. Amsterdam: Excerpta Medica. pp. 393–397. ISSN 0531-5131. OCLC 458719.
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. [...]
- ^ a b c d e f g Usdin E, Efron DH (1972). Psychotropic Drugs and Related Compounds. National Institute of Mental Health. pp. 96, 100. ASIN B002X3CDIY.
- ^ a b c d e Smith MV (1981). "[Chapter 7:] LSD". Psychedelic Chemistry. Loompanics Unlimited. pp. 103–137 (136). ISBN 978-0-915179-10-7. Retrieved 18 March 2025.
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.
- ^ a b c d Cooper DA (1989). "Future Synthetic Drugs of Abuse". Proceedings of the International Symposium on the Forensic Aspects of Controlled Substances: March 28-April 1, 1988, Forensic Science Research and Training Center, FBI Academy, Quantico, Virginia. Laboratory Division, Federal Bureau of Investigation, U.S. Department of Justice. pp. 79–103 (81). ISBN 978-0-932115-09-6. Retrieved 18 March 2025.
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).
- ^ a b c d e f g Nichols DE, Oberlender R, McKenna DJ (1991). "Stereochemical Aspects of Hallucinogenesis". In Watson RR (ed.). Biochemistry and Physiology of Substance Abuse. Vol. 3. Boca Raton, Fla.: CRC Press. pp. 1–39. ISBN 978-0-8493-4463-3. OCLC 26748320.
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.
- ^ "Ergoline-8-beta-carboxamide, 9,10-didehydro-N,N-diethyl-12-hydroxy-6-methyl-". PubChem. Retrieved 20 March 2025.
- ^ a b c d e f Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994). "Lysergamides revisited". NIDA Research Monograph. 146: 52–73. PMID 8742794.
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).
- ^ a b c 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.
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.
- ^ a b Siddik ZH, Barnes RD, Dring LG, Smith RL, Williams RT (October 1979). "The fate of lysergic acid DI[14C]ethylamide ([14C]LSD) in the rat, guinea pig and rhesus monkey and of [14C]iso-LSD in rat". Biochemical Pharmacology. 28 (20): 3093–3101. doi:10.1016/0006-2952(79)90618-x. PMID 117811.
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.
- ^ a b Slaytor MB, Wright SE (May 1962). "The metabolites of ergometrine and lysergic acid diethylamide in rat bile". Journal of Medicinal and Pharmaceutical Chemistry. 5 (3): 483–491. doi:10.1021/jm01238a008. PMID 14056385.
- ^ Stadler PA, Frey AJ, Troxler F, Hofmann A (1964). "Selektive Reduktions- und Oxydationsreaktionen an lysergsäure- Derivaten. 2.3-Dihydro- und 12-Hydroxy-lysergsäureamide. 59. Mitteilung über Mutterkornalkaloide" [Selective reduction and oxidation reactions of lysergic acid derivatives. 2,3-Dihydro- and 12-Hydroxy-lysergic acid amides. 59th Report on ergot alkaloids] (PDF). Helvetica Chimica Acta. 47 (3): 756–769. doi:10.1002/hlca.19640470309. ISSN 0018-019X.
- ^ a b Inoue T, Niwaguchi T, Murata T (May 1980). "Enzymic formation of dehydrogenated and hydroxylated metabolites from lysergic acid diethylamide by rat liver microsomes". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 10 (5): 343–348. doi:10.3109/00498258009033766. PMID 7415216.
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.
- ^ Rutschmann J, Stadler PA (1978). "Chemical Background". In Berde B, Schild HO (eds.). Ergot Alkaloids and Related Compounds. Handbook of Experimental Pharmacology (HEP). Vol. 49. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 29–85. doi:10.1007/978-3-642-66775-6_2. ISBN 978-3-642-66777-0.
[...] 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.
- ^ Parli CJ, Schmidt B, Shaar CJ (May 1978). "Metabolism of lergotrile to 13-hydroxy lergotrile, a potent inhibitor of prolactin release in vitro". Biochemical Pharmacology. 27 (9): 1405–1408. doi:10.1016/0006-2952(78)90131-4. PMID 29651.
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.
- ^ Barbara L. Jones Ebersole. Interaction of D-LSD with Binding Sites in Brain: A Study In Vivo and In Vitro. ProQuest (Thesis). ProQuest 303382332. Retrieved 20 March 2025.
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.