The specificenzymes responsible for the formation of O-H-LSD from LSD are unclear.[5][7][8][3] However, subsequent research found involvement of severalcytochrome P450 enzymes.[9] O-H-LSD is thought to form from other LSD metabolites like2-oxo-LSD and 3-hydroxy-LSD.[6][3][7][8][10]
^abcDolder PC, Schmid Y, Haschke M, Rentsch KM, Liechti ME (June 2015)."Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans".The International Journal of Neuropsychopharmacology.19 (1) pyv072.doi:10.1093/ijnp/pyv072.PMC4772267.PMID26108222.In the present study, 13% of the orally administered LSD was recovered from urine as O-H-LSD within 24 hours. LSD is metabolized to O-H-LSD by cytochrome P450 enzymes, but the specific enzymes and mechanisms are unknown (Klette et al., 2000). To our knowledge, it is unknown whether O-H-LSD is pharmacologically active.
^abcMeyer 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.PMID21332315.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.
^abcMeyer MR, Maurer HH (18 April 2012). "Drugs of Abuse (Including Designer Drugs)".Metabolism of Drugs and Other Xenobiotics. Wiley. pp. 429–463.doi:10.1002/9783527630905.ch16.ISBN978-3-527-32903-8.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.
^abLuethi 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".Biochemical Pharmacology.164:129–138.doi:10.1016/j.bcp.2019.04.013.PMID30981875.
^Libânio Osório Marta RF (August 2019). "Metabolism of lysergic acid diethylamide (LSD): an update".Drug Metabolism Reviews.51 (3):378–387.doi:10.1080/03602532.2019.1638931.PMID31266388.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).
^Vu-Duc T, Vernay A, Calanca A (December 1991). "Détection de l'acide lysergique diéthylamide (LSD) dans l'urine humaine: élimination, dépistage et confirmation analytique" [Detection of lysergic acid diethylamide in human urine: elimination, screening and analytical confirmation].Schweizerische Medizinische Wochenschrift (in French).121 (50):1887–1890.PMID1759150.
^Li Z, Goc-Szkutnicka K, McNally AJ, Pilcher I, Polakowski S, Vitone S, et al. (1997). "New synthesis and characterization of (+)-lysergic acid diethylamide (LSD) derivatives and the development of a microparticle-based immunoassay for the detection of LSD and its metabolites".Bioconjugate Chemistry.8 (6):896–905.doi:10.1021/bc9700594.PMID9404664.
