Development and validation of an LC‐MS/MS method to quantify lysergic acid diethylamide (LSD), iso‐LSD, 2‐oxo‐3‐hydroxy‐LSD, and nor‐LSD and identify novel metabolites in plasma samples in a controlled clinical trial

A liquid chromatography tandem mass spectrometry method was developed and validated to measure lysergic acid diethylamide (LSD) and several of its metabolites in human plasma. After controlled administration of 100 μg LSD to 24 healthy subjects, the method accurately and precisely quantified LSD in all plasma samples, with a quantification limit of 0.05 ng/mL. Other compounds—iso-LSD, 2-oxo-3-hydroxy LSD, nor-LSD, lysergic acid monoethylamide, lysergic acid ethyl-2-hydroxyethylamide, 2-oxo-LSD, trioxylated-LSD, and 13/14-hydroxy-LSD—were only sporadically detected at levels too low for quantification.

Study at a glance

Abstract

Background Lysergic acid diethylamide ( LSD ) is a widely used recreational drug. The aim of this study was to develop and validate a liquid chromatography tandem mass spectrometry ( LC ‐ MS / MS ) method for the quantification of LSD , iso‐ LSD , 2‐oxo‐3‐hydroxy LSD (O‐H‐ LSD ), and nor‐ LSD in plasma samples from 24 healthy subjects after controlled administration of 100 μg LSD in a clinical trial. In addition, metabolites that have been recently described in in vitro studies, including lysergic acid monoethylamide ( LAE ), lysergic acid ethyl‐2‐hydroxyethylamide ( LEO ), 2‐oxo‐ LSD , trioxylated‐ LSD , and 13/14‐hydroxy‐LSD, should be identified. Methods Separation of LSD and its metabolites was achieved on a reversed phase chromatography column after turbulent‐flow online extraction. For the identification and quantification, a triple‐stage quadrupole LC ‐ MS / MS instrument was used. Results The validation data showed slight matrix effects for LSD , iso‐ LSD , O‐H‐ LSD , or nor‐ LSD . Mean intraday and interday accuracy and precision were 105%/4.81% and 105%/4.35% for LSD , 98.7%/5.75% and 99.4%/7.21% for iso‐ LSD , 106%/4.54% and 99.4%/7.21% for O‐H‐ LSD , and 107%/5.82% and 102%/5.88% for nor‐ LSD , respectively. The limit of quantification was 0.05 ng/mL for LSD , iso‐ LSD , and nor‐ LSD and 0.1 ng/mL for O‐H‐ LSD . The limit of detection was 0.01 ng/mL for all compounds. Conclusion The method described herein was accurate, precise, and the calibration range within the range of expected plasma concentrations. LSD was quantified in the plasma samples of the 24 subjects of the clinical trial, whereas iso‐ LSD , O‐H‐ LSD , nor‐ LSD , LAE , LEO , 13/14‐hydroxy‐LSD, and 2‐oxo‐LSD could only sporadically be detected but were too low for quantification.