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In vitro metabolic fate of nine LSD-based new psychoactive substances and their analytical detectability in different urinary screening procedures

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Abstract

The market of new psychoactive substances (NPS) is characterized by a high turnover and thus provides several challenges for analytical toxicology. The analysis of urine samples often requires detailed knowledge about metabolism given that parent compounds either may be present only in small amounts or may not even be excreted. Hence, knowledge of the metabolism of NPS is a prerequisite for the development of reliable analytical methods. The main aim of this work was to elucidate for the first time the pooled human liver S9 fraction metabolism of the nine d-lysergic acid diethylamide (LSD) derivatives 1-acetyl-LSD (ALD-52), 1-propionyl-LSD (1P-LSD), 1-butyryl-LSD (1B-LSD), N6-ethyl-nor-LSD (ETH-LAD), 1-propionyl-N6-ethyl-nor-LSD (1P-ETH-LAD), N6-allyl-nor-LSD (AL-LAD), N-ethyl-N-cyclopropyl lysergamide (ECPLA), (2′S,4′S)-lysergic acid 2,4-dimethylazetidide (LSZ), and lysergic acid morpholide (LSM-775) by means of liquid chromatography coupled to high-resolution tandem mass spectrometry. Identification of the monooxygenase enzymes involved in the initial metabolic steps was performed using recombinant human enzymes and their contribution confirmed by inhibition experiments. Overall, N-dealkylation and hydroxylation, as well as combinations of these steps predominantly catalyzed by CYP1A2 and CYP3A4, were found. For ALD-52, 1P-LSD, and 1B-LSD, deacylation to LSD was observed. The obtained mass spectral data of all metabolites are essential for reliable analytical detection particularly in urinalysis and for differentiation of the LSD-like compounds as biotransformations also led to structurally identical metabolites. However, in urine of rats after the administration of expected recreational doses and using standard urine screening approaches, parent drugs or metabolites could not be detected.

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Acknowledgments

The authors would like to thank Armin A. Weber and the Stiftelsen för Klinisk farmakologi & farmakoterapi for support.

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Authors and Affiliations

  1. Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Kirrberger Str. 100, 66421, Homburg, Germany

    Lea Wagmann, Lilian H. J. Richter, Tobias Kehl, Franziska Wack, Madeleine Pettersson Bergstrand, Hans H. Maurer & Markus R. Meyer

  2. Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden

    Madeleine Pettersson Bergstrand

  3. Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, 17177, Stockholm, Sweden

    Madeleine Pettersson Bergstrand

  4. School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byron Street, Liverpool, L33AF, UK

    Simon D. Brandt

  5. Synex Synthetics BV, Karveelweg 20, 6222NH, Maastricht, The Netherlands

    Alexander Stratford

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  1. Lea Wagmann
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  2. Lilian H. J. Richter
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Correspondence to Markus R. Meyer.

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The studies have been approved by an ethics committee (Landesamt für Verbraucherschutz, Saarbrücken, Germany).

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Published in the topical collection Young Investigators in (Bio-)Analytical Chemistry with guest editors Erin Baker, Kerstin Leopold, Francesco Ricci, and Wei Wang.

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Wagmann, L., Richter, L.H.J., Kehl, T. et al. In vitro metabolic fate of nine LSD-based new psychoactive substances and their analytical detectability in different urinary screening procedures. Anal Bioanal Chem 411, 4751–4763 (2019). https://doi.org/10.1007/s00216-018-1558-9

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