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2-Oxo-LSD

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2-Oxo-LSD
Clinical data
Other names2-Oxy-LSD; O-LSD; 2-Keto-LSD; N,N-Diethyl-6-methyl-2-oxo-9,10-didehydro-2,3-dihydroergoline-8β-carboxamide
ATC code
  • None
Identifiers
  • (6aR,9R)-N,N-diethyl-7-methyl-5-oxo-4,5a,6,6a,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide
PubChem CID
Chemical and physical data
FormulaC20H25N3O2
Molar mass339.439 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)[C@H]1CN([C@@H]2CC3C4=C(C2=C1)C=CC=C4NC3=O)C
  • InChI=1S/C20H25N3O2/c1-4-23(5-2)20(25)12-9-14-13-7-6-8-16-18(13)15(19(24)21-16)10-17(14)22(3)11-12/h6-9,12,15,17H,4-5,10-11H2,1-3H3,(H,21,24)/t12-,15?,17-/m1/s1
  • Key:LEPCXKMUXAQZKG-XURPUJGUSA-N

2-Oxo-LSD, also known as 2-oxy-LSD or 2-keto-LSD, is a lysergamide and metabolite of the psychedelic drug lysergic acid diethylamide (LSD).[1][2][3][4] It is a metabolite of LSD in both humans and various animal species,[1][2][3][5] although there are important differences in LSD metabolism and relative proportions of metabolites between species.[2][6][5]

It is formed directly from LSD in the body and is also possibly an intermediate in the generation of LSD's major metabolite 2-oxo-3-hydroxy-LSD (O-H-LSD), which is present in urine at concentrations 4 to 40 times those of LSD in humans.[7][3][8][9][10] However, O-H-LSD may also form from other metabolites, such as 3-hydroxy-LSD.[3][10][7] The specific enzymes responsible for the generation of individual LSD metabolites like 2-oxo-LSD are largely unknown.[8][9][3][6] However, several cytochrome P450 enzymes were investigated and implicated in the formation of O-H-LSD in 2019.[11]

2-Oxo-LSD showed absence of various pharmacological effects in animals.[12][13] In contrast to LSD and certain other metabolites like 13-hydroxy-LSD, 2-oxo-LSD failed to produce LSD-like electroencephalogram (EEG) changes in rabbits.[5] 2-Oxo-LSD at a dose of 300 μg orally produced no psychoactive effects in a human subject who had previously responded to 30 μg LSD.[4][12][14][13] It was concluded that 2-oxo-LSD shows no LSD-like activity in the central nervous system and hence is inactive.[13][12][2][15] 2-Oxo-LSD's derivative O-H-LSD showed profound loss of activity at the serotonin 5-HT2 receptors compared to LSD in vitro.[11] 2-Oxo-LSD is said to readily enter the brain.[15]

2-Oxo-LSD was first described in the scientific literature by Julius Axelrod and colleagues in 1957.[1][13][16][17]

See also

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References

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  1. ^ a b c Nichols DE (October 2018). "Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)" (PDF). ACS Chem Neurosci. 9 (10): 2331–2343. doi:10.1021/acschemneuro.8b00043. PMID 29461039. It was first established by Axelrod in 1957, using in vitro studies, that LSD is metabolized by NADH-dependent microsomal liver enzymes from the guinea pig to the inactive 2-oxo-LSD and 2-oxo-3-hydroxy LSD (Figure 1).53,54 [...] The major metabolites in rats and guinea pigs (urine and bile) were glucuronic acid conjugates of 13- and 14-hydroxy-LSD. guinea pigs excreted significant amounts of 2-oxo-LSD in urine and bile. Lysergic acid ethylamide (LAE) was a minor urinary metabolite in both species. In rat livers perfused with [14C]-LSD, Siddik et al.59 identified the glucuronides of 13- and 14-hydroxyLSD, as well as 2-oxo-LSD, LAE, and nor-LSD. [...] Canezin et al.63 found the following LSD metabolites in human urine: nor-LSD, LAE, 2-oxo-LSD, 2-oxy-3-hydroxy-LSD, 13- and 14-hydroxy-LSD as glucuronides, lysergic acid ethyl-2- hydroxyethylamide (LEO), and "trioxylated LSD." The major metabolite in urine is 2-oxy-3-OH-LSD, which could not be detected in blood plasma. [...] In addition, recently described in vitro metabolites, including LAE, lysergic acid LEO, 2-oxo-LSD, trioxylatedLSD, and 13- and 14-hydroxy-LSD, could be identified. [...] Iso-LSD, 2-oxo-3-OH-LSD, nor-LSD, LAE, LEO, 13/14-hydroxy-LSD, and 2-oxo-LSD could be detected only sporadically, and concentrations were too low for quantification. [...]
  2. ^ a b c d Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A (2008). "The pharmacology of lysergic acid diethylamide: a review". CNS Neurosci Ther. 14 (4): 295–314. doi:10.1111/j.1755-5949.2008.00059.x. PMC 6494066. PMID 19040555. The metabolism of [14C]-LSD has been investigated in rats (1 mg/kg i.p.), guinea pigs (1 mg/kg i.p.), and rhesus monkeys (0.15 mg/kg i.m.) by Siddik et al. [103]. [...] The metabolites identified were 13- and 14-hydroxy-LSD and their glucuronic acid conjugates, 2-oxo-LSD, nor-LSD, as well as a not further specified naphthostyril derivative. However, important differences in the nature and amounts of the various metabolites occur in different species. The major metabolites in rats and guinea pigs (found in urine and bile) were glucuronic acid conjugates of 13- and 14-hydroxy-LSD. Guinea pigs excrete significant amounts of 2-oxo-LSD in urine and bile. [...] It was first established through in vitro studies that LSD is metabolized in humans by some NADH-dependent microsomal liver enzymes to the inactive 2-oxy-LSD [97,104] and 2-oxo-3-hydroxy LSD. Metabolites were first detected in urine with infrared spectroscopy [93]. [...] Klette et al. [106] and Canezin et al. [107] found the following LSD metabolites in human urine: norLSD, LAE, 2-oxo-LSD, 2-oxy-3-hydroxy-LSD, 13- and 14-hydroxy-LSD as glucoronides, lysergic acid ethyl-2- hydroxyethylamide (LEO), and trioxylated LSD. The major metabolite in urine is 2-oxy-3-hydroxy-LSD (which could not be detected in blood plasma).
  3. ^ a b c d e Yu AM (June 2008). "Indolealkylamines: biotransformations and potential drug-drug interactions". AAPS J. 10 (2): 242–253. doi:10.1208/s12248-008-9028-5. PMC 2751378. PMID 18454322. LSD is extensively metabolized in laboratory animals and only a trivial fraction of the parent drug is excreted in urine. Major metabolites of LSD detected in the rat and guinea pig urines were the 13- and 14-hydroxy-LSD (HOLSD) and their corresponding glucuronic acid conjugates (54). Other metabolites included 2-oxo-LSD, lysergic acid ethylamide (LSE) and N-desmethyl-LSD (nor-LSD). [...] Indeed, at least four metabolites have been identified in urine from human users of LSD, which include 2-oxo-3-hydroxy-LSD (2-oxo-3-HO-LSD), nor-LSD, 13- and 14- hydroxy-LSD glucuronides (57) (Fig. 4). Although other metabolites such as LSE were produced as major metabolites from LSD incubated with human liver microsomes (58), 2-oxo-3-HO-LSD was shown to be the main human urinary metabolite, which may be present at 4- to 41-times higher concentration than urinary LSD (59). [...] The detection of 2-oxo-LSD in human body fluids indicates that 2-oxo-3-HO-LSD may be formed in two steps via the 2-oxo-LSD intermediate. Recent studies on LSD metabolism in human liver microsomes and hepatocytes not only confirmed the formation of 2-oxo-3-HO-LSD but also identified a 2,3-dihydroxy-LSD metabolite (60). This finding suggests that 2-oxo-3-HO-LSD could be produced through dehydrogenation of the 2,3-dihydroxy-LSD intermediate, which is presumably formed from LSD 2,3-epoxide. [...] Fig. 4. Metabolism of LSD. Note that the 2-oxo-3-hydroxy-LSD (2-oxo-3-HO-LSD) has been shown as a principal metabolite in the LSD-positive human urine samples [...] Due to limited studies on LSD metabolism in humans, further well-controlled studies are warranted to validate whether 2-oxo-3-HO-LSD is indeed the major metabolite (59) and to delineate the particular mechanisms that are involved in the formation of this metabolite (60). Furthermore, almost nothing is known regarding the contribution of specific drug-metabolizing enzyme to the production of individual LSD metabolites in humans.
  4. ^ a b Dolder, Patrick (2017). The Pharmacology of d-Lysergic Acid Diethylamide (LSD) (PDF) (Thesis). University of Basel. doi:10.5451/UNIBAS-006786123. However, the formation of an additional metabolite formed out of 2-oxo-LSD was described, and named "naphthostyril compound" (43). This compound could be the precursor of the recently identified major human metabolite, 2-oxo-3-hydroxy-LSD (46). [...] [...] oral administration of 300 µg 2-oxo-LSD did not induce any psychological effects (44). [...] Indeed, more recent in-vitro studies using human liver microsomes and analysis of human urine samples have confirmed the presence of LAE, 2-oxo-LSD, 13- and 14-hydroxyLSD, and further identified nor-LSD, lysergic-acid-ethyl-2-hydroxyethylamide (LEO), tri-oxo-LSD and 2-oxo-3-hydroxy-LSD as potential human metabolites (54, 55). However, systematic information about their presence after controlled intake is still missing. [...] 44. Boyd ES. Metabolism of lysergic acid diethylamide. Arch. Int. Pharmacodyn. 1959;120:292.
  5. ^ a b c 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. [...] Preliminary studies have indicated that some of the metabolites of LSD, as well as the drug itself, produce an activation of the EEG of the conscious rabbit suggesting they may have central activity. These findings will be published elsewhere.
  6. ^ a b Araújo AM, Carvalho F, Bastos Mde L, Guedes de Pinho P, Carvalho M (August 2015). "The hallucinogenic world of tryptamines: an updated review". Arch Toxicol. 89 (8): 1151–1173. doi:10.1007/s00204-015-1513-x. PMID 25877327. Major metabolites detected in the rat and guinea pigs urine were the 13- and 14-hydroxy-LSD and their corresponding glucuronide conjugates (Siddik et al. 1979). Other metabolites included 2-oxo-LSD, lysergic acid ethylamide and N-desmethyl-LSD. However, significant differences in LSD metabolism between laboratory animals and humans have been observed. In fact, the analysis of urine from LSD users identified five metabolites, namely the 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, N-desmethyl-LSD, 13- and 14-hydroxy-LSD glucuronides (Fig. 4) (Poch et al. 1999; Reuschel et al. 1999; Sklerov et al. 2000). The 2-oxo-3-hydroxy-LSD showed to be a major human urinary metabolite with concentrations several times greater than LSD itself (Poch et al. 1999, 2000; Reuschel et al. 1999; Sklerov et al. 2000). In vitro studies in human liver microsomes and hepatocytes confirmed the formation of 2-oxo-3-hydroxy-LSD, being 2,3-dihydroxyLSD also identified (Klette et al. 2000), suggesting that 2-oxo-3-hydroxy-LSD could be produced through dehydrogenation of the 2,3-dihydroxy-LSD intermediate, which is presumably formed from LSD 2,3-epoxide. The contribution and importance of specific metabolizing enzymes in the formation of the LSD main metabolites, such as 2-oxo-3-hydroxy-LSD, remain hitherto unclear.
  7. ^ a b Hintzen, Annelie; Passie, Torsten (10 June 2010). The Pharmacology of LSD. OUP/Beckley Foundation Press. p. 29. ISBN 978-0-19-958982-1. Fig. 2.7 Metabolites of LSD. [...]
  8. ^ a b Meyer MR, Maurer HH (February 2011). "Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse". Pharmacogenomics. 12 (2): 215–233. doi:10.2217/pgs.10.171. PMID 21332315. It is rapidly metabolized to the following five metabolites which have been identified in urine or blood from human users: N-demethyl-LSD (nor-LSD), 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, 13-hydroxyLSD and 14-hydroxy-LSD [187–189]. The 13- and 14-hydroxy metabolites are additionally excreted as glucuronides [188]. However, 2-oxo-LSD may be an intermediate in the formation of 2-oxo-3-hydroxy-LSD. Following the incubation of LSD with HLM and hepatocytes, 2,3-dihydroxy-LSD could be identified [190]. 2-oxo-3-hydroxy-LSD was shown to be the main human urinary metabolite with concentrations four- to 40-times higher than that of LSD [187,188,191]. As concluded by Yu in his review on indolalkylamines, almost nothing is known regarding the contribution of specific drug-metabolizing enzymes to the production of individual LSD metabolites in humans.
  9. ^ a b Meyer, Markus R.; Maurer, Hans H. (18 April 2012). "Drugs of Abuse (Including Designer Drugs)". Metabolism of Drugs and Other Xenobiotics. Wiley. pp. 429–463. doi:10.1002/9783527630905.ch16. ISBN 978-3-527-32903-8. It is metabolized to the following five metabolites: N-demethyl-LSD (nor-LSD), 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, 13-hydroxy-LSD, and 14-hydroxy-LSD [72–74]. The 13- and 14-hydroxy metabolites are additionally excreted as glucuronides [74]. 2-Oxo-3-hydroxy-LSD was shown to be the main human urinary metabolite with concentrations 4–40 times higher than that of LSD [73–75]. In incubations of LSD with human liver microsomes and hepatocytes, 2,3-dihydroxy-LSD could be identified [71]. So far, the contribution and importance of specific enzymes in the formation of the LSD main metabolites such as 2-oxo-3-hydroxy-LSD still remains unclear.
  10. ^ a b Libânio Osório Marta RF (August 2019). "Metabolism of lysergic acid diethylamide (LSD): an update". Drug Metab Rev. 51 (3): 378–387. doi:10.1080/03602532.2019.1638931. PMID 31266388. In vitro studies using liver microsomes and human cryopreserved hepatocytes showed that O-HLSD is a product of LSD biotransformation whose amount increases in a time-dependent manner. In the same study was detected another metabolite in a time-dependent manner upon incubation, the dihydroxy-LSD (Klette et al. 2000). Therefore, LSD is oxidized to 2-oxo-LSD, which undergoes subsequent hydroxylation to O-H-LSD. Although the formation of O-H-LSD may occur via intermediate metabolite dihydroxy-LSD (Figure 1) (Klette et al. 2002).
  11. ^ a b Luethi D, Hoener MC, Krähenbühl S, Liechti ME, Duthaler U (June 2019). "Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use". Biochem Pharmacol. 164: 129–138. doi:10.1016/j.bcp.2019.04.013. PMID 30981875. 2-Oxo-3-hydroxy‐LSD (O-H-LSD) is the major urinary metabolite of LSD [5–9], which can also be detected in plasma [10–12]. Other identified metabolites are 6-norlysergic acid diethylamide (nor-LSD), lysergic acid ethylamide, 2‐oxo‐LSD, trioxylated LSD, lysergic acid ethyl-2-hydroxyethylamide, and 13 and 14-hydroxy-LSD as glucuronide conjugates [1,5,7,10,11]. [...] Table 4 Serotonin receptor binding affinities and activation potencies. [...]
  12. ^ a b c Hoffer A (1965). "D-Lysergic acid diethylamide (LSD): A review of its present status". Clin Pharmacol Ther. 6: 183–255. doi:10.1002/cpt196562183. PMID 14288188. Most of the LSD undergoes chemical change. Paper chromatography showed that bile contained three different 'radioactive substances. One of the derivatives of LSD was 2-oxy LSD.30,129 This substance in doses of 300 mcg. did not alter spontaneous cortical activity and had no psychological effect. Axelrod and co-workers'" found that the half-life in cat blood was 130 minutes, and in monkeys 100 minutes.
  13. ^ a b c d Axelrod J, Brady RO, Witkop B, Evarts EV (March 1957). "The distribution and metabolism of lysergic acid diethylamide". Ann N Y Acad Sci. 66 (3): 435–444. doi:10.1111/j.1749-6632.1957.tb40739.x. PMID 13425233.
  14. ^ 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. Two other variations at the 2-position of LSD include an isolated metabolite of LSD, 2-oxy-LSD (37), which did not produce any psychological effects after oral administration of 300 μg,63 and the 2,3-dihydro-LSD (38) which was found to be one-sixth to one-eighth as potent as LSD with a slower onset of action.64
  15. ^ a b Snyder SH, Merril CR (July 1965). "A relationship between the hallucinogenic activity of drugs and their electronic configuration". Proc Natl Acad Sci U S A. 54 (1): 258–266. doi:10.1073/pnas.54.1.258. PMC 285831. PMID 5216361. It is, therefore, interesting to note that 2-Brom-LSD3 and 2-oxy-LSD,28 which contain sterically obstructing substituents at the #2 carbon, are devoid of hallucinogenic effect, even though they readily enter the brain.
  16. ^ Boyd ES (July 1959). "The metabolism of lysergic acid diethylamide". Arch Int Pharmacodyn Ther. 120: 292–311. PMID 13803540.
  17. ^ Slaytor M, Pennefather JN, Wright SE (March 1959). "Metabolites of LSD and ergometrine". Experientia. 15 (3): 111. doi:10.1007/BF02166704. PMID 13652949.
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