Metabolism of Lysergic Acid Diethylamide (LSD) to 2-Oxo-3-Hydroxy LSD (O-H-LSD)in Human Liver Microsomes and Cryopreserved Human Hepatocytes

The metabolism of LSD into a compound called O-H-LSD occurs in human liver cells. O-H-LSD is found in human urine at 16 to 43 times the concentration of LSD itself, and earlier work ruled out its formation during sample handling or storage. This study incubated human liver microsomes and hepatocytes with LSD and used liquid chromatography-mass spectrometry to analyze the products. O-H-LSD was positively identified in all samples treated with LSD but not in any controls. The results definitively show that O-H-LSD is produced as a metabolic product of LSD in human liver tissue.

Study at a glance

Abstract

The metabolism of lysergic acid diethylamide (LSD) to 2-oxo-3-hydroxy lysergic acid diethylamide (O-H-LSD) was investigated in liver microsomes and cyropreserved hepatocytes from humans. Previous studies have demonstrated that O-H-LSD is present in human urine at concentrations 16-43 times greater than LSD, the parent compound. Additionally, these studies have determined that O-H-LSD is not generated during the specimen extraction and analytical processes or due to parent compound degradation in aqueous urine samples. However, these studies have not been conclusive in demonstrating that O-H-LSD is uniquely produced during in vivo metabolism. Phase I drug metabolism was investigated by incubating human liver microsomes and cryopreserved human hepatocytes with LSD. The reaction was quenched at various time points, and the aliquots were extracted using liquid partitioning and analyzed by liquid chromatography-mass spectrometry. O-H-LSD was positively identified in all human liver microsomal and human hepatocyte fractions incubated with LSD. In addition, O-H-LSD was not detected in any microsomal or hepatocyte fraction not treated with LSD nor in LSD specimens devoid of microsomes or hepatocytes. This study provides definitive evidence that O-H-LSD is produced as a metabolic product following incubation of human liver microsomes and hepatocytes with LSD.