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<p>In 2024, 3-Chloromethcathinone (3-CMC) accounted for over 63% of all New Psychoactive Substances seized in Europe, yet its human pharmacology remains poorly understood. This observational, uncontrolled, naturalistic study involved 16 regular psychostimulant users to evaluate and compare 3-CMC metabolism, and distribution in urine and oral fluid (OF) following oral and intranasal administration. Two groups, each consisting of 8 participants (6 males, 2 females) self-administered 3-CMC in two separate sessions: 100–150&#xa0;mg orally and 60–80&#xa0;mg intranasally. Urine was collected in two pooled intervals (0–2&#xa0;h and 2–5&#xa0;h). Samples were analyzed via four untargeted HPLC-HRMS/MS methods in full MS and ddMS<sup>2</sup> to characterize the unknown metabolites supported by Compound Discoverer™ software with an established workflow. The data were grouped into four groups concerning the route of administration and the time intervals and the average area were statistically compared with a one-way ANOVA. The parent drug was detected in all the samples at different levels. In total, nine metabolites were observed, of those 4 were phase I and 5 phase II metabolites. Considering the route of administration, distinct metabolic patterns emerged: three metabolites, including two N-acetylated forms and a carboxylated metabolite, were found only after oral intake, suggesting N-acetylation occurs primarily via this route. In contrast, β-OH-3-CMC accumulated more after intranasal use. Furthermore, 3-CMC N- glucuronidation was hypothesized for the first time. These findings indicate that the administration route significantly influences 3-CMC metabolism, highlighting the need for tailored forensic and toxicological assessments.</p> Graphical Abstract <p></p>

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The Influence of Routes of Administration on 3-chloromethcathinone Urinary Biomarkers Disposition: Preliminary In Vivo Study of Unknown Metabolites Profiling on Healthy Volunteers

  • 期刊论文

  • 发表日期：

    2026年1月8日

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  • Annagiulia Di Trana,
  • Nunzia La Maida,
  • Silvia Graziano,
  • Simona Pichini,
  • Olga Hladun,
  • Lourdes Poyatos,
  • Mireia Ventura,
  • Esther Papaseit,
  • Magi Farré,
  • Clara Perez-Maña

摘要

In 2024, 3-Chloromethcathinone (3-CMC) accounted for over 63% of all New Psychoactive Substances seized in Europe, yet its human pharmacology remains poorly understood. This observational, uncontrolled, naturalistic study involved 16 regular psychostimulant users to evaluate and compare 3-CMC metabolism, and distribution in urine and oral fluid (OF) following oral and intranasal administration. Two groups, each consisting of 8 participants (6 males, 2 females) self-administered 3-CMC in two separate sessions: 100–150 mg orally and 60–80 mg intranasally. Urine was collected in two pooled intervals (0–2 h and 2–5 h). Samples were analyzed via four untargeted HPLC-HRMS/MS methods in full MS and ddMS2 to characterize the unknown metabolites supported by Compound Discoverer™ software with an established workflow. The data were grouped into four groups concerning the route of administration and the time intervals and the average area were statistically compared with a one-way ANOVA. The parent drug was detected in all the samples at different levels. In total, nine metabolites were observed, of those 4 were phase I and 5 phase II metabolites. Considering the route of administration, distinct metabolic patterns emerged: three metabolites, including two N-acetylated forms and a carboxylated metabolite, were found only after oral intake, suggesting N-acetylation occurs primarily via this route. In contrast, β-OH-3-CMC accumulated more after intranasal use. Furthermore, 3-CMC N- glucuronidation was hypothesized for the first time. These findings indicate that the administration route significantly influences 3-CMC metabolism, highlighting the need for tailored forensic and toxicological assessments.

Graphical Abstract