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Untargeted metabolomics screening approaches can determine biochemical changes after drug exposure and can reveal new pathways, which might be involved in the pharmacology and toxicology of a drug of abuse. We analyzed plasma samples from a placebo-controlled crossover study of a single intake of MDMA. Plasma samples from a time point before and three time points after the intake of a single dose of 125 mg MDMA were screened for changes of endogenous metabolites. An untargeted metabolomics approach on a high-resolution quadrupole time-of-flight mass spectrometer coupled to liquid chromatography with two different chromatographic systems (reversed-phase and hydrophobic interaction liquid chromatography) was applied. Over 10\u202f000 features of the human metabolome were detected. Hence, 28 metabolites were identified, which showed significant changes after administration of MDMA compared with placebo. The analysis revealed an upregulation of cortisol and pregnenolone sulfate 4 h after MDMA intake, suggesting increased stress and serotonergic activity. Furthermore, calcitriol levels were decreased after the intake of MDMA. Calcitriol is involved in the upregulation of trophic factors, which have protective effects on brain dopamine neurons. The inflammation mediators hydroxyeicosatetraenoic acid, dihydroxyeicosatetraenoic acid, and octadecadienoic acid were found to be upregulated after the intake of MDMA compared with placebo, which suggested a stimulation of inflammation pathways.<\/jats:p>","DOI":"10.1021\/acs.jproteome.8b00438","type":"journal-article","created":{"date-parts":[[2018,6,27]],"date-time":"2018-06-27T06:05:12Z","timestamp":1530079512000},"page":"2900-2907","source":"Crossref","is-referenced-by-count":23,"title":["Human Metabolome\nChanges after a Single Dose of 3,4-Methylenedioxymethamphetamine\n(MDMA) with Special Focus on Steroid Metabolism and Inflammation Processes"],"prefix":"10.1021","volume":"17","author":[{"given":"Martina\nI.","family":"Boxler","sequence":"first","affiliation":[{"name":"University of Zurich , , ,","place":["Zurich, Switzerland, 8057"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel L.","family":"Streun","sequence":"additional","affiliation":[{"name":"University of Zurich , , ,","place":["Zurich, Switzerland, 8057"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias E.","family":"Liechti","sequence":"additional","affiliation":[{"name":"University Hospital Basel, University of Basel , , ,","place":["Basel, Switzerland, 4031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Schmid","sequence":"additional","affiliation":[{"name":"University Hospital Basel, University of Basel , , ,","place":["Basel, Switzerland, 4031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3283-606X","authenticated-orcid":true,"given":"Thomas","family":"Kraemer","sequence":"additional","affiliation":[{"name":"University of Zurich , , ,","place":["Zurich, Switzerland, 8057"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-2353","authenticated-orcid":true,"given":"Andrea E.","family":"Steuer","sequence":"additional","affiliation":[{"name":"University of Zurich , , ,","place":["Zurich, Switzerland, 8057"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,6,27]]},"reference":[{"key":"2026081723142503300_cit1","doi-asserted-by":"publisher","first-page":"e36476","DOI":"10.1371\/journal.pone.0036476","article-title":"Duloxetine inhibits effects of MDMA (\u2033ecstasy\u2033) in\nvitro and in humans in a randomized placebo-controlled laboratory\nstudy","volume":"7","author":"Hysek","year":"2012","journal-title":"PLoS One"},{"key":"2026081723142503300_cit2","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1017\/S1461145713001132","article-title":"Pharmacokinetic and pharmacodynamic effects\nof methylphenidate and\nMDMA administered alone or in combination","volume":"17","author":"Hysek","year":"2014","journal-title":"Int.\nJ. Neuropsychopharmacol."},{"key":"2026081723142503300_cit3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.psyneuen.2014.04.006","article-title":"Plasma oxytocin\nconcentrations following MDMA or intranasal oxytocin in humans","volume":"46","author":"Kirkpatrick","year":"2014","journal-title":"Psychoneuroendocrinology"},{"key":"2026081723142503300_cit4","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1159\/000364879","article-title":"Acute effects of 3,4-methylenedioxymethamphetamine\nand methylphenidate\non circulating steroid levels in healthy subjects","volume":"100","author":"Seibert","year":"2014","journal-title":"Neuroendocrinology"},{"key":"2026081723142503300_cit5","doi-asserted-by":"publisher","first-page":"2844","DOI":"10.1210\/jc.2011-1143","article-title":"Sex differences in the effects of\nMDMA (ecstasy) on plasma copeptin in healthy subjects","volume":"96","author":"Simmler","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2026081723142503300_cit6","doi-asserted-by":"publisher","first-page":"e0145635","DOI":"10.1371\/journal.pone.0145635","article-title":"Stress-Induced In Vivo\nRecruitment of Human Cytotoxic Natural Killer\nCells Favors Subsets with Distinct Receptor Profiles and Associates\nwith Increased Epinephrine Levels","volume":"10","author":"Bigler","year":"2015","journal-title":"PLoS One"},{"key":"2026081723142503300_cit7","first-page":"917","article-title":"The pharmacology\nand toxicology of \u201cecstasy\u201d (MDMA) and related drugs","volume":"165","author":"Kalant","year":"2001","journal-title":"Can. Med. Assoc. J."},{"key":"2026081723142503300_cit8","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1124\/jpet.103.061374","article-title":"Paroxetine inhibits acute effects of 3,4-methylenedioxymethamphetamine\non the immune system in humans","volume":"309","author":"Pacifici","year":"2004","journal-title":"J. Pharmacol.\nExp. 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Neurochem."},{"key":"2026081723142503300_cit11","doi-asserted-by":"publisher","first-page":"3310","DOI":"10.1021\/acs.jproteome.7b00294","article-title":"First Time\nView on Human Metabolome Changes after a Single Intake of 3,4-Methylenedioxymethamphetamine\nin Healthy Placebo-Controlled Subjects","volume":"16","author":"Boxler","year":"2017","journal-title":"J. Proteome\nRes."},{"key":"2026081723142503300_cit12","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1021\/acs.jproteome.5b01023","article-title":"A Metabolomics Study of Retrospective Forensic Data\nfrom Whole Blood Samples of Humans Exposed to 3,4-Methylenedioxymethamphetamine:\nA New Approach for Identifying Drug Metabolites and Changes in Metabolism\nRelated to Drug Consumption","volume":"15","author":"Nielsen","year":"2016","journal-title":"J. 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Ther."},{"key":"2026081723142503300_cit30","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.neubiorev.2012.10.005","article-title":"Neurosteroids,\nstress and depression: potential therapeutic opportunities","volume":"37","author":"Zorumski","year":"2013","journal-title":"Neurosci. Biobehav. Rev."},{"key":"2026081723142503300_cit31","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.jsbmb.2015.09.030","article-title":"Neurosteroids\nand potential therapeutics: Focus on pregnenolone","volume":"160","author":"Vallee","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"2026081723142503300_cit32","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1007\/s00213-002-1131-1","article-title":"Subjective and hormonal effects of\n3,4-methylenedioxymethamphetamine\n(MDMA) in humans","volume":"162","author":"Harris","year":"2002","journal-title":"Psychopharmacology"},{"key":"2026081723142503300_cit33","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.euroneuro.2014.11.020","article-title":"Effects of methylphenidate\nand MDMA on appraisal of erotic stimuli\nand intimate relationships","volume":"25","author":"Schmid","year":"2015","journal-title":"Eur. Neuropsychopharmacol."},{"key":"2026081723142503300_cit34","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1176\/jnp.13.3.396","article-title":"Neuroactive\nsteroid levels in patients\nwith generalized anxiety disorder","volume":"13","author":"Semeniuk","year":"2001","journal-title":"J. Neuropsychiatry\nClin. Neurosci."},{"key":"2026081723142503300_cit35","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1017\/S0033291702005238","article-title":"Low pregnenolone sulphate plasma concentrations in\npatients with generalized social phobia","volume":"32","author":"Heydari","year":"2002","journal-title":"Psychol.\nMed."},{"key":"2026081723142503300_cit36","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1126\/science.8493557","article-title":"GDNF: a glial\ncell line-derived neurotrophic factor for midbrain dopaminergic neurons","volume":"260","author":"Lin","year":"1993","journal-title":"Science"},{"key":"2026081723142503300_cit37","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1196\/annals.1369.023","article-title":"Calcitriol protects against the dopamine-\nand serotonin-depleting effects of neurotoxic doses of methamphetamine","volume":"1074","author":"Cass","year":"2006","journal-title":"Ann. N. Y. Acad. 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Mol.\nBiol."},{"key":"2026081723142503300_cit40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/biof.5520270101","article-title":"Free radicals in biology and medicine:\nfrom inflammation to biotechnology","volume":"27","author":"Aruoma","year":"2006","journal-title":"BioFactors"},{"key":"2026081723142503300_cit41","doi-asserted-by":"publisher","first-page":"E337","DOI":"10.1208\/aapsj080238","article-title":"Causes and consequences\nof methamphetamine and MDMA\ntoxicity","volume":"8","author":"Quinton","year":"2006","journal-title":"AAPS J."},{"key":"2026081723142503300_cit42","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/s11481-012-9420-x","article-title":"MDMA increases\nglutamate release and reduces parvalbumin-positive GABAergic cells\nin the dorsal hippocampus of the rat: role of cyclooxygenase","volume":"8","author":"Anneken","year":"2013","journal-title":"Journal of neuroimmune pharmacology: the official journal\nof the Society on NeuroImmune Pharmacology"},{"key":"2026081723142503300_cit43","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.neuropharm.2013.06.014","article-title":"Protection\nof dopaminergic neurons by 5-lipoxygenase inhibitor","volume":"73","author":"Kang","year":"2013","journal-title":"Neuropharmacology"},{"key":"2026081723142503300_cit44","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1165\/ajrcmb.12.3.7873191","article-title":"5-Hydroxyeicosatetraenoic\nacid (HETE)-induced neutrophil\ntranscellular migration is dependent upon enantiomeric structure","volume":"12","author":"Bittleman","year":"1995","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2026081723142503300_cit45","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1016\/j.bcp.2007.05.027","article-title":"13-Oxo-ODE is an endogenous\nligand for PPARgamma in human colonic\nepithelial cells","volume":"74","author":"Altmann","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"2026081723142503300_cit46","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.ejphar.2011.10.033","article-title":"Effects of MDMA and\nrelated analogs on plasma 5-HT: relevance to\n5-HT transporters in blood and brain","volume":"674","author":"Yubero-Lahoz","year":"2012","journal-title":"Eur. J.\nPharmacol."}],"container-title":["Journal of Proteome Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jproteome.8b00438","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/17\/8\/2900\/6690678\/pr8b00438.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/17\/8\/2900\/6690678\/pr8b00438.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:41:23Z","timestamp":1787042483000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jprobs\/article\/17\/8\/2900\/677468\/Human-Metabolome-Changes-after-a-Single-Dose-of-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,27]]},"references-count":46,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2018,6,27]]},"published-print":{"date-parts":[[2018,8,3]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jproteome.8b00438","relation":{},"ISSN":["1535-3893","1535-3907"],"issn-type":[{"value":"1535-3893","type":"print"},{"value":"1535-3907","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,27]]}}}