2-Oxo-LSD

2-Oxo-LSD
Clinical data
Other names2-Oxy-LSD; O-LSD; 2-Keto-LSD; 2-Oxo-2,3-dihydro-LSD; N,N-Diethyl-6-methyl-2-oxo-9,10-didehydro-2,3-dihydroergoline-8β-carboxamide
ATC code
  • None
Identifiers
IUPAC name
  • (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)
SMILES
  • CCN(CC)C(=O)[C@H]1CN([C@@H]2CC3C4=C(C2=C1)C=CC=C4NC3=O)C
InChI
  • 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, or more fully as 2-oxo-2,3-dihydro-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]

  1. ^ a b Nichols DE (October 2018). "Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)" (PDF). ACS Chemical Neuroscience. 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 Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A (2008). "The pharmacology of lysergic acid diethylamide: a review". CNS Neuroscience & Therapeutics. 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 Yu AM (June 2008). "Indolealkylamines: biotransformations and potential drug-drug interactions". The AAPS Journal. 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. ^ Dolder P (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 Cite error: The named reference Siddik_1979 was invoked but never defined (see the help page).
  6. ^ Cite error: The named reference Araujo_2015 was invoked but never defined (see the help page).
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