METHOXPHENIDINE, A DESIGNER DRUG OR A POSSIBLE ROUTE FOR RESEARCH TO DEPRESSION TREATMENT?
Authors: Jurásek *Bronislav , Vágnerová Magdalena , Walaská Hana , Mazochová Kristýna , Kuchař Martin 
Published: February 2025

Abstract

Background
Methoxphenidine (MXP) is a new psychoactive substance that belongs to the group of arylethylamines. Even though MXP has a different pharmacophore than ketamine, both of these substances belong to the dissociatives. To date, MXP has been associated with several intoxications and despite it being banned in most countries it is still available over the internet.1

Aims & Objectives
Even though MXP started to be abused approximately a decade ago, there is still a lack of data about it. Considering the knowledge gap on MXP toxicological data, its mostly unknown metabolism and overall the significant potential of dissociative anaesthetics for depression treatment, we aimed to thoroughly evaluate this substance.

Method
The MXP, nor-MXP and MXP-d3 were in-house synthesized and characterized using an 400 MHz NMR spectrometer (JEOL, Japan) and HRMS (LTQ Orbitrap Velos, ThermoFisher, USA), which was also used for the untargeted screening. The targeted screening was performed using the LC system Dionex Ultimate 3000 (Thermo-Fisher, USA) and the chromatographic separation was performed using Poroshell 120, Phenyl Hexyl (2.1 × 100 mm, 2.7 μ m) column (Agilent, USA). The behavioural experiments were performed on Wistar rats acquired from VELAZ (Prague, CZ). The open field test (OFT) was done in a sound-proof and evenly lit chamber with low levels of light intensity and pre-pulse inhibition (PPI) took place in startle chambers (SR-LAB, San Diego Instruments, USA). The rats were decapitated after 0.5, 1, 2, 4, 8 and 24 hours.

Results
The MXP (60 mg/kg s.c.) was administered to the Wistar rats, the urine was collected and analysed. Using the untargeted screening we proposed structures of several metabolites and we synthesized the nor-MXP metabolite and deuterium labelled analogue for the upcoming pharmacokinetics. The MXP was administered to the Wistar rats (10, 20 and 40 mg/kg s.c.) for behavioural experiments in which we studied locomotor effects in OFT and sensorimotor gating in PPI. The obtained serum and brain were analysed using targeted LC/MS screening and the concentrations were used for calculation of the pharmacokinetics.

Discussion & Conclusion
The maximal effect of the MXP was observed around 30 minutes after administration and the maximal effect prevailed another 0.5 hour. These data were consistent with the pharmacokinetic data, in which the concentration of MXP and its nor-MXP metabolite rapidly increased with a maximum of around 1 hour. The pharmacokinetic profile MXP and the nor-MXP suggest a slower metabolism and excretion of the MXP compared to the ketamine. Lower doses (10 and 20 mg/kg) induced significant locomotor stimulation suggesting MXP has a stimulating effect, which is typical for other dissociative anaesthetics, on the other hand, the higher dose increased the time spent in the centre of the arena, which suggests rather sedating effects. Even though MXP is a substance with a high potential for abuse, further research is needed to provide deep insight into its antidepressant effects.
Acknowledgement
This study was funded by the Ministry of Interior of the Czech Republic (New psychoactive substances: forensic-toxicology research center, VK01010212).

References
Jurá sek, B. et al. (2023) 'A structural spectroscopic study of dissociative anaesthetic methoxphenidine’, New Journal of Chemistry, 47(9), pp. 4543–4551. doi: 10.1039/D2NJ06126K.