12-Hydroxy-LSD

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 {{Abbrlink|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 0.3{{nbsp}}mg/kg {{Abbrlink|i.v.|intravenous administration}} in rabbits (relative to 0.1{{nbsp}}mg/kg for LSD). 12-Hydroxy-LSD also produces LSD-like electroencephalogram (EEG) changes in rabbits.{{cite journal | vauthors = Siddik ZH, Barnes RD, Dring LG, Smith RL, Williams RT | title = 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 | journal = Biochemical Pharmacology | volume = 28 | issue = 20 | pages = 3093–3101 | date = October 1979 | pmid = 117811 | doi = 10.1016/0006-2952(79)90618-x | quote = 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.{{cite journal | vauthors = Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE | title = Lysergamides revisited | journal = NIDA Research Monograph | volume = 146 | issue = | pages = 52–73 | date = 1994 | pmid = 8742794 | doi = | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=dbc3139042e2b2baf5a2e6c65edc6afe9b131f79 | quote = 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% of the potency of LSD. 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.

The chemical synthesis of 12-hydroxy-LSD is described as being very difficult.

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.

12-Hydroxy-LSD was first described in the scientific literature by 1962.{{cite journal | vauthors = Slaytor MB, Wright SE | title = The metabolites of ergometrine and lysergic acid diethylamide in rat bile | journal = Journal of Medicinal and Pharmaceutical Chemistry | volume = 5 | issue = 3| pages = 483–491 | date = May 1962 | pmid = 14056385 | doi = 10.1021/jm01238a008 }}{{cite journal | vauthors = Stadler PA, Frey AJ, Troxler F, Hofmann A | title=Selektive Reduktions- und Oxydationsreaktionen an lysergsäure- Derivaten. 2.3-Dihydro- und 12-Hydroxy-lysergsäureamide. 59. Mitteilung über Mutterkornalkaloide | trans-title=Selective reduction and oxidation reactions of lysergic acid derivatives. 2,3-Dihydro- and 12-Hydroxy-lysergic acid amides. 59th Report on ergot alkaloids | journal=Helvetica Chimica Acta | volume=47 | issue=3 | date=1964 | issn=0018-019X | doi=10.1002/hlca.19640470309 | pages=756–769 | url=https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/files/5254-Selektive-Reduktions-und-Oxydationsreaktionen-an-lysergsaure-Derivaten.-23-Dihydro-und-12-Hydroxy-lysergsaureamide22d0.pdf}}{{cite journal | vauthors = Inoue T, Niwaguchi T, Murata T | title = Enzymic formation of dehydrogenated and hydroxylated metabolites from lysergic acid diethylamide by rat liver microsomes | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 10 | issue = 5 | pages = 343–348 | date = May 1980 | pmid = 7415216 | doi = 10.3109/00498258009033766 | quote = 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.{{cite thesis | vauthors = Mangner TJ | degree = Ph.D. | publisher = University of Michigan | title=Potential Psychotomimetic Antagonists. N,n -diethyl-1-methyl-3-aryl-1, 2, 5, 6-tetrahydropyridine-5-carboxamides. | date=1978 | doi=10.7302/11268 | url=https://www.proquest.com/openview/f845a6810749d00f70305960adfde737/ | archive-url=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 | archive-date=30 March 2025 | quote = 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,{{cite book | vauthors = Rutschmann J, Stadler PA | chapter=Chemical Background | veditors=Berde B, Schild HO | title=Ergot Alkaloids and Related Compounds | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | date=1978 | isbn=978-3-642-66777-0 | doi=10.1007/978-3-642-66775-6_2 | pages=29–85 | series=Handbook of Experimental Pharmacology (HEP) | volume=49 | quote=[...] 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.{{cite journal | vauthors = Parli CJ, Schmidt B, Shaar CJ | title = Metabolism of lergotrile to 13-hydroxy lergotrile, a potent inhibitor of prolactin release in vitro | journal = Biochemical Pharmacology | volume = 27 | issue = 9 | pages = 1405–1408 | date = May 1978 | pmid = 29651 | doi = 10.1016/0006-2952(78)90131-4 | quote = 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. }}{{cite thesis | author=Barbara L. Jones Ebersole | title=Interaction of D-LSD with Binding Sites in Brain: A Study In Vivo and In Vitro | website=ProQuest | url=https://www.proquest.com/docview/303382332 | access-date=20 March 2025 | id={{ProQuest|303382332}} | quote=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.}}

• 12-Methoxy-LSD
• 13-Hydroxy-LSD
• 2-Bromo-LSD
• Bufotenin (5-HO-DMT)

{{Reflist}}

• [https://isomerdesign.com/pihkal/explore/15412 12-Hydroxy-LSD - Isomer Design]

{{Psychedelics}}

{{Serotonin receptor modulators}}

{{Ergolines}}

Category:Diethylamino compounds

Category:Hydroxyarenes

Category:Psychedelic lysergamides

Category:Serotonin receptor modulators