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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                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200936 chronic MDMA users,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200933 chronic METH users, and\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200971 sex-matched, healthy controls. An ultra\u2013high performance liquid chromatography\u2013mass 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.\n                  <\/jats:p>","DOI":"10.1038\/s41398-026-04069-4","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T03:05:46Z","timestamp":1779332746000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential alterations in peripheral tryptophan pathways in methamphetamine versus MDMA users are linked to their contrasting psychiatric symptoms"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3787-6706","authenticated-orcid":false,"given":"Francesco","family":"Bavato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Steuer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Jacobsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelie","family":"Zacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josua","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Cole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Opitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0979-931X","authenticated-orcid":false,"given":"Markus R.","family":"Baumgartner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Kathrin","family":"Stock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Beste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7933-2865","authenticated-orcid":false,"given":"Boris B.","family":"Quednow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"4069_CR1","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1111\/add.12570","volume":"109","author":"C Ort","year":"2014","unstructured":"Ort C, van Nuijs AL, Berset JD, Bijlsma L, Castiglioni S, Covaci A, et al. 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