Differential alterations in peripheral tryptophan pathways in methamphetamine versus MDMA users are linked to their contrasting psychiatric symptoms.

Overview

1. Experimental Pharmacopsychology and Psychological Addiction Research, Department of Adult Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich,Zurich, Switzerland
2. Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University,Aarhus, Denmark
3. Institute of Forensic Medicine, University of Zurich,Zurich, Switzerland
4. Neuroscience Center Zurich, Joint Center of University of Zurich and Swiss Federal Institute of Technology Zurich,Zurich, Switzerland
5. Translational Psychiatry Lab, University Psychiatric Clinics Basel, University of Basel,Basel, Switzerland
6. Department of Child and Adolescent Psychiatry, TU Dresden,Dresden, Germany

Abstract

Methamphetamine (METH, “Crystal Meth”) and 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) are two types of substituted amphetamines that share structural-chemical similarities but exhibit contrasting acute and chronic effects including addictive liability. Tryptophan (TRY) pathways are involved in pleiotropic physiological functions at the interface of brain-body connections. Preclinical evidence suggests that amphetamines may modulate these pathways and, thus, indirectly influence brain functions via persistent alterations of peripheral metabolites. However, little is known about alterations of TRY-related metabolites in the blood and their clinical implications in chronic users of MDMA and METH. Hence, we characterized serum levels of TRY-related metabolites in a comparative cross-sectional study including n = 36 chronic MDMA users, n = 33 chronic METH users, and n = 71 sex-matched, healthy controls. An ultra–high performance liquid chromatography–mass spectrometry method was used to determine TRY metabolites. Combining metabolite levels, metabolic ratios, and network analysis we found robust evidence of divergent pathway alterations between METH and MDMA users. Chronic METH use was particularly associated with a depletion of serum TRY and serotonin levels, and a general activation of kynurenine pathways, while chronic MDMA use was linked to a selective activation of the OH-kynurenine metabolic branch. Metabolite changes were associated with the severity of psychopathology in the depression and psychosis domains across groups. Altogether, our findings demonstrate differential changes of serum TRY pathways in chronic MDMA and METH users. Persistent alterations of these pathways might contribute to the contrasting clinical profile of the substances and constitute a peripheral dimension of neurochemical plasticity with relevant implications for therapeutic targets.

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Analyses were conducted in Python using standard statistical libraries. No custom algorithms were developed; scripts used for data processing and analysis are available from the corresponding author.

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The data that support the findings of this study are available from the corresponding author upon reasonable request, subject to appropriate ethical and institutional approvals.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 2 keywords, 12 MeSH terms, 1 funder, 69 references.

Cite

This paper

Bavato, F., Steuer, A., Jacobsen, A. M., Zacher, A., Zimmermann, J., Cole, D. M., Opitz, A., Baumgartner, M. R., Stock, A.-K., Beste, C., & Quednow, B. B. (2026). Differential alterations in peripheral tryptophan pathways in methamphetamine versus MDMA users are linked to their contrasting psychiatric symptoms. Translational psychiatry, 16(1), 358. https://doi.org/10.1038/s41398-026-04069-4

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