12-Hydroxy-LSD

vanc 6 12-Hydroxy-LSD.svg skin-invert-image 175px 12-Hydroxy-LSD 3D.png bg-transparent 225px Serotonin receptor modulator None 60573-89-9 3042820 2305940 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 (6aR,9R)-N,N-diethyl-1-hydroxy-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide 20 25 3 2 CCN(CC)C(=O)[C@H]1CN([C@@H]2CC3=CNC4=C3C(=C(C=C4)O)C2=C1)C 1S/C20H25N3O2/c1-4-23(5-2)20(25)13-8-14-16(22(3)11-13)9-12-10-21-15-6-7-17(24)19(14)18(12)15/h6-8,10,13,16,21,24H,4-5,9,11H2,1-3H3/t13-,16-/m1/s1 SJBIVHSZSSHVGK-CZUORRHYSA-N 12-Hydroxy-LSD, also known as 12-hydroxylysergic acid diethylamide, is a drug of the ergoline and lysergamide families and a derivative of lysergic acid diethylamide (LSD). M. Taeschler Pharmacology of Psychotomimetic Agents Brill H, Cole JO, Deniker P, Hippius H, Bradley PB 393–397 https://web.archive.org/web/20250318133331if_/https://bibliography.maps.org/resources/download/4386 Neuro-psycho-pharmacology: Proceedings of the Fifth International Congress of the Collegium Internationale Neuropsychopharmacologicum. Washington, D.C., 28-31 March 1966 1967 International Congress Series 129 Excerpta Medica Amsterdam 0531-5131 458719 https://books.google.com/books?id=_atTPgAACAAJ 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. [...] Usdin E, Efron DH Psychotropic Drugs and Related Compounds 1972 96,100 B002X3CDIY National Institute of Mental Health https://books.google.com/books?id=0rq7AAAAIAAJ&pg=PA100 Smith MV [Chapter 7:] LSD Psychedelic Chemistry Loompanics Unlimited 1981 978-0-915179-10-7 https://books.google.com/books?id=WYzZAAAAMAAJ 18 March 2025 103–137 (136) 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. Cooper DA Future Synthetic Drugs of Abuse 79–103 (81) https://erowid.org/archive/rhodium/chemistry/future_drugs.html 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 1989 978-0-932115-09-6 https://books.google.com/books?id=vGV4xLv_WE8C 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).Nichols DE, Oberlender R, McKenna DJ Stereochemical Aspects of Hallucinogenesis Watson RR Biochemistry and Physiology of Substance Abuse 3 CRC Press Boca Raton, Fla. 1991 978-0-8493-4463-3 26748320 1–39 https://archive.org/details/biochemistryphys0003unse/ https://bitnest.netfirms.com/external/Books/BiochemistryPhysiologySubstanceAbuse3.1 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. 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.Ergoline-8-beta-carboxamide, 9,10-didehydro-N,N-diethyl-12-hydroxy-6-methyl- PubChem https://pubchem.ncbi.nlm.nih.gov/compound/3042820 20 March 2025 12-Hydroxy-LSD produces psychedelic-like effects in animals, whereas reports on its activities in humans are very limited and have been conflicting. Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Pharmacology 12-Hydroxy-LSD is known to be pharmacologically active in animal studies. The drug's effects in rabbits include antiserotonergic activity (25% of that of LSD) and hyperthermia (dose ratio relative to LD50 median lethal dose of 1:44 for 12-hydroxy-LSD and 1:725 for LSD). In addition, like LSD, it is highly potent in terms of lethality, with a median lethal dose (LD50) of 0.3mg/kg i.v. intravenous administration in rabbits (relative to 0.1mg/kg for LSD). 12-Hydroxy-LSD also produces LSD-like electroencephalogram (EEG) changes in rabbits. Siddik ZH, Barnes RD, Dring LG, Smith RL, Williams RT 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 October 1979 117811 10.1016/0006-2952(79)90618-x 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. According to Robert C. Pfaff and David E. Nichols and colleagues, 12-hydroxy-LSD substitutes for LSD in rodent drug discrimination tests. Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE Lysergamides revisited NIDA Research Monograph 146 52–73 1994 8742794 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=dbc3139042e2b2baf5a2e6c65edc6afe9b131f79 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). Hence, it appears to show psychedelic-like effects in animals. 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. Its reduced potency compared to LSD could be due to its increased polarity and associated pharmacokinetic differences. It was reported in the 1960s that 12-hydroxy-LSD does not produce hallucinogenic effects in humans. 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". 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. Chemistry Synthesis The chemical synthesis of 12-hydroxy-LSD is described as being very difficult. Analogues An analogue of 12-hydroxy-LSD is 12-methoxy-LSD, which would be structurally akin to 5-MeO-DMT. As with 12-hydroxy-LSD, it has been reported that 12-methoxy-LSD is inactive as a psychedelic in humans. History 12-Hydroxy-LSD was first described in the scientific literature by 1962. Slaytor MB, Wright SE The metabolites of ergometrine and lysergic acid diethylamide in rat bile Journal of Medicinal and Pharmaceutical Chemistry 5 3 483–491 May 1962 14056385 10.1021/jm01238a008 Stadler PA, Frey AJ, Troxler F, Hofmann A 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 Helvetica Chimica Acta 47 3 1964 0018-019X 10.1002/hlca.19640470309 756–769 https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/files/5254-Selektive-Reduktions-und-Oxydationsreaktionen-an-lysergsaure-Derivaten.-23-Dihydro-und-12-Hydroxy-lysergsaureamide22d0.pdf Inoue T, Niwaguchi T, Murata T 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 May 1980 7415216 10.3109/00498258009033766 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. Subsequently, it was further described in the 1970s and 1980s. Mangner TJ Ph.D. University of Michigan Potential Psychotomimetic Antagonists. N,n -diethyl-1-methyl-3-aryl-1, 2, 5, 6-tetrahydropyridine-5-carboxamides. 1978 10.7302/11268 https://www.proquest.com/openview/f845a6810749d00f70305960adfde737/ https://web.archive.org/web/20250330031605/https://media.proquest.com/media/hms/ORIG/2/9yQxJ?cit%3Aauth=MANGNER%2C+THOMAS+JOSEPH&cit%3Atitle=POTENTIAL+PSYCHOTOMIMETIC+ANTAGONISTS.+N%2CN+...&cit%3Apub=ProQuest+Dissertations+and+Theses&cit%3Avol=&cit%3Aiss=&cit%3Apg=&cit%3Adate=1978&ic=true&cit%3Aprod=ProQuest+Dissertations+%26+Theses+Global&_a=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&_s=QP3F3liRMGFAbHtX3wDWE8eO1gs%3D#page=22 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. David E. Nichols and colleagues reported that 12-hydroxy-LSD produces psychedelic-like effects in animals in 1994. It was initially thought that 12-hydroxy-LSD might be a metabolite of LSD, Rutschmann J, Stadler PA Chemical Background Berde B, Schild HO Ergot Alkaloids and Related Compounds Springer Berlin Heidelberg Berlin, Heidelberg 1978 978-3-642-66777-0 10.1007/978-3-642-66775-6_2 29–85 Handbook of Experimental Pharmacology (HEP) 49 [...] 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. but this proved not to be the case. Parli CJ, Schmidt B, Shaar CJ Metabolism of lergotrile to 13-hydroxy lergotrile, a potent inhibitor of prolactin release in vitro Biochemical Pharmacology 27 9 1405–1408 May 1978 29651 10.1016/0006-2952(78)90131-4 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 https://www.proquest.com/docview/303382332 20 March 2025 303382332 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. See also Substituted lysergamide 12-Methoxy-LSD 13-Hydroxy-LSD 14-Hydroxy-LSD 2-Bromo-LSD Bufotenin (5-HO-DMT) References External links 12-Hydroxy-LSD - Isomer Design Category:Diethylamides Category:Hydroxyarenes Category:Psychedelic lysergamides Category:Serotonin receptor modulators