Methoxphenidine (MXP) is classified as a new psychoactive substance that has recently emerged on the illicit drug market. Understanding the pharmacological and behavioural profiles of newly emerging drugs is essential for a better understanding of their psychotropic effects and potential toxicity. Therefore, in this study, we investigated a broad range of effects of acute MXP administration: pharmacokinetics in the brain and serum; behaviour (open field and prepulse inhibition), systemic toxicity (lethal dose; LD 50), and histopathology changes in parenchymal organs of Wistar rats. MXP rapidly crossed the blood-brain barrier, reaching peak median concentrations in both serum and brain 30 min post-administration, followed by an elimination phase with a half-life of 2.15 h. Locomotor activity in the open field test displayed a dose-response effect at low to moderate doses (10-20 mg/kg MXP). At higher doses (40 mg/kg), locomotor activity decreased. All doses of MXP significantly disrupted prepulse inhibition and the effect was present during the onset of its action as well as 60 min after treatment. Additionally, MXP demonstrated moderate acute toxicity, with an estimated LD50 of 500 mg/kg when administered subcutaneously. In summary, MXP exhibited a profile similar to typical dissociative anesthetics, producing stimulant and anxiogenic effects at lower doses, sedative effects at higher doses, and disrupting sensorimotor gating. The accumulation of MXP in brain tissue is likely to contribute to acute intoxication in humans, potentially leading to negative experiences. Our findings highlight the potentially dangerous effects of recreational MXP use and underscore the risks of inducing serious adverse health outcomes.

Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds University of Chemistry and Technology Technická 5 Prague 6 166 28 Czech Republic

Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds University of Chemistry and Technology Technická 5 Prague 6 166 28 Czech Republic; Department of Analytical Chemistry University of Chemistry and Technology Technická 5 Prague 6 166 28 Czech Republic

Institute of Pathology 1 Faculty of Medicine Charles University Studničkova 2 Prague 2 128 00 Czech Republic

Institute of Pharmacology 1 Faculty of Medicine Charles University and General University Hospital Prague Albertov 4 Prague 2 128 00 Czech Republic

Psychedelics Research Centre National Institute of Mental Health Topolová 748 Klecany 250 67 Czech Republic

Psychedelics Research Centre National Institute of Mental Health Topolová 748 Klecany 250 67 Czech Republic; 3 Faculty of Medicine Charles University Ruská 87 Prague 10 100 00 Czech Republic

Psychedelics Research Centre National Institute of Mental Health Topolová 748 Klecany 250 67 Czech Republic; Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds University of Chemistry and Technology Technická 5 Prague 6 166 28 Czech Republic

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