Intriguing Cytotoxicity of the Street Dissociative Anesthetic Methoxphenidine: Unexpected Impurities Spotted
Jazyk angličtina Země Švýcarsko Médium electronic
Typ dokumentu časopisecké články
PubMed
35216198
PubMed Central
PMC8879332
DOI
10.3390/ijms23042083
PII: ijms23042083
Knihovny.cz E-zdroje
- Klíčová slova
- X-ray powder diffraction, crystal structure, cytotoxicity, dissociative anesthetic, inorganic impurity, methoxphenidine, new psychoactive substances, novel synthetic drug,
- MeSH
- anestetika disociativní škodlivé účinky MeSH
- difrakce rentgenového záření metody MeSH
- kultivované buňky MeSH
- lidé MeSH
- piperidiny škodlivé účinky MeSH
- psychotropní léky škodlivé účinky MeSH
- zakázané drogy škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 1-(1-(2-methoxyphenyl)-2-phenylethyl)piperidine MeSH Prohlížeč
- anestetika disociativní MeSH
- piperidiny MeSH
- psychotropní léky MeSH
- zakázané drogy MeSH
The black market for new psychoactive substances has been constantly evolving and the substances that appear on this market cause a considerable number of issues, in extreme cases leading to human deaths. While monitoring the drug black market, we detected a sample of a dissociative anesthetic methoxphenidine, the salt of which contained an unusual anion in the form of bromo- and chloro-zincate complex. Concerning the unknown and potentially hazardous properties of this sample, we performed an in vitro cytotoxicity screening in cell lines of various origins (e.g., kidney, liver, bladder) which was compared with the toxicity results of the methoxphenidine standard prepared for this purpose. The street methoxphenidine sample exhibited markedly higher toxicity than the standard, which was probably caused by the anion impurity. Since it is not usual to analyze anions in salts of novel psychoactive substances, but such samples may be commonly available at the drug black market, we have developed a method for their identification with X-ray powder diffraction (XRPD), which also enabled us to distinguish between different polymorphs/solvates of methoxphenidine that were crystallized in the laboratory. XRPD offers additional data about samples, which may not be discovered by routine techniques, and in some cases, they may help to find out essential information.
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European Monitoring Centre for Drugs and Drug Addiction . European Drug Report 2021: Trends and Developments. European Monitoring Centre for Drugs and Drug Addiction; Luxembourg: 2021.
Jurásek B., Kuchař M. Methoxfenidin. Drugs Forensics Bull. 2017;23:3–7.
Zanos P., Moaddel R., Morris P.J., Georgiou P., Fischell J., Elmer G.I., Alkondon M., Yuan P., Pribut H.J., Singh N.S., et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–486. doi: 10.1038/nature17998. PubMed DOI PMC
Yang Y., Cui Y., Sang K., Dong Y., Ni Z., Ma S., Hu H. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–322. doi: 10.1038/nature25509. PubMed DOI
Li N., Lee B., Liu R.J., Banasr M., Dwyer J.M., Iwata M., Li X.Y., Aghajanian G., Duman R.S. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–964. doi: 10.1126/science.1190287. PubMed DOI PMC
Dolgin E. Rapid antidepressant effects of ketamine ignite drug discovery. Nat. Med. 2013;19:8. doi: 10.1038/nm0113-8. PubMed DOI
Zanos P., Gould T.D. Mechanisms of ketamine action as an antidepressant. Mol. Psychiatry. 2018;23:801–811. doi: 10.1038/mp.2017.255. PubMed DOI PMC
Zhang K., Fujita Y., Hashimoto K. Lack of metabolism in (R)-ketamine’s antidepressant actions in a chronic social defeat stress model. Sci. Rep. 2018;8:4007. doi: 10.1038/s41598-018-22449-9. PubMed DOI PMC
Wood D.M., Davies S., Puchnarewicz M., Johnston A., Dargan P.I. Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine. Eur. J. Clin. Pharmacol. 2012;68:853–856. doi: 10.1007/s00228-011-1199-9. PubMed DOI
Dargan P.I., Tang H.C., Liang W., Wood D.M., Yew D.T. Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice. Clin. Toxicol. 2014;52:176–180. doi: 10.3109/15563650.2014.892605. PubMed DOI
Wallach J., Kang H., Colestock T., Morris H., Bortolotto Z.A., Collingridge G.L., Lodge D., Halberstadt A.L., Brandt S.D., Adejare A. Pharmacological investigations of the dissociative ‘legal highs’ diphenidine, methoxphenidine and analogues. PLoS ONE. 2016;11:e0157021. doi: 10.1371/journal.pone.0157021. PubMed DOI PMC
Berger M.L., Schweifer A., Rebernik P., Hammerschmidt F. NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds. Bioorg. Med. Chem. 2009;17:3456–3462. doi: 10.1016/j.bmc.2009.03.025. PubMed DOI
Luethi D., Hoener M.C., Liechti M.E. Effects of the new psychoactive substances diclofensine, diphenidine, and methoxphenidine on monoaminergic systems. Eur. J. Pharmacol. 2018;819:242–247. doi: 10.1016/j.ejphar.2017.12.012. PubMed DOI
Gray N.M., Cheng B.K. Preparation of 1,2-Diarylethylamines for Treatment of Neurotoxic Injury. Patent EP346791A1. 1989 December 20;
McLaughlin G., Morris N., Kavanagh P.V., Power J.D., O’Brien J., Talbot B., Elliott S.P., Wallach J., Hoang K., Morris H., et al. Test purchase, synthesis, and characterization of 2-methoxydiphenidine (MXP) and differentiation from its meta-and para-substituted isomers. Drug Test. Anal. 2016;8:98–109. doi: 10.1002/dta.1800. PubMed DOI
European Monitoring Centre for Drugs and Drug Addiction . Early Warning System: Unpublished Reports. European Monitoring Centre for Drugs and Drug Addiction; Luxembourg: 2017.
Helander A., Beck O., Bäckberg M. Intoxications by the dissociative new psychoactive substances diphenidine and methoxphenidine. Clin. Toxicol. 2015;53:446–453. doi: 10.3109/15563650.2015.1033630. PubMed DOI
Hofer K.E., Degrandi C., Müller D.M., Zürrer-Härdi U., Wahl S., Rauber-Lüthy C., Ceschi A. Acute toxicity associated with the recreational use of the novel dissociative psychoactive substance methoxphenidine. Clin. Toxicol. 2014;52:1288–1291. doi: 10.3109/15563650.2014.974264. PubMed DOI
Stachel N., Jacobsen-Bauer A., Skopp G.A. Methoxydiphenidine-impaired driver. Int. J. Leg. Med. 2016;130:405–409. doi: 10.1007/s00414-015-1280-5. PubMed DOI
Elliott S.P., Brandt S.D., Wallach J., Morris H., Kavanagh P.V. First reported fatalities associated with the “research chemical” 2-methoxydiphenidine. J. Anal. Toxicol. 2015;39:287–293. doi: 10.1093/jat/bkv006. PubMed DOI
Erowid Contributors Methoxphenidine Reports. [(accessed on 10 January 2021)]. Available online: https://www.erowid.org/experiences/subs/exp_Methoxphenidine.shtml.
PsychonautWiki Contributors Methoxphenidine. [(accessed on 10 January 2021)]. Available online: https://psychonautwiki.org/wiki/Methoxphenidine.
Lam R.P.K., Yip W.L., Tsui M.S.H., Ng S.W., Ching C.K., Mak T.W.L. Severe rhabdomyolysis and acute kidney injury associated with methoxphenidine. Clin. Toxicol. 2016;54:464–465. doi: 10.3109/15563650.2016.1157724. PubMed DOI
Winstock A.R., Mitcheson L., Gillatt D.A., Cottrell A.M. The Prevalence and Natural History of Urinary Symptoms among Recreational Ketamine Users. BJU Int. 2012;110:1762–1766. doi: 10.1111/j.1464-410X.2012.11028.x. PubMed DOI
Kjellgren A., Jonsson K. Methoxetamine (MXE)—A Phenomenological Study of Experiences Induced by a “Legal High” from the Internet. J. Psychoact. Drugs. 2013;45:276–286. doi: 10.1080/02791072.2013.803647. PubMed DOI PMC
Hur K., Kim S., Ma S., Lee B., Ko Y., Seo J., Kim S., Kim Y., Sung S., Lee Y., et al. Methoxphenidine (MXP) Induced Abnormalities: Addictive and Schizophrenia-related Behaviours Based on an Imbalance of Neurochemicals in the Brain. Br. J. Pharmacol. 2021;178:3869–3887. doi: 10.1111/bph.15528. PubMed DOI
Champeau W., Eiden C., Gambier J., Peyriere H. Methoxphenidine Use Disorder. J. Clin. Psychopharmacol. 2017;37:376–377. doi: 10.1097/JCP.0000000000000684. PubMed DOI
Stodůlková E., Man P., Kolařík M., Flieger M. High-performance liquid chromatography–off line mass spectrometry analysis of anthraquinones produced by Geosmithia lavendula. J. Chromatogr. A. 2010;1217:6296–6302. doi: 10.1016/j.chroma.2010.08.009. PubMed DOI
Stodůlková E., Císařová I., Kolařík M., Chudíčková M., Novák P., Man P., Kuzma M., Pavlů B., Černý J., Flieger M. Biologically Active Metabolites Produced by the Basidiomycete Quambalaria cyanescens. PLoS ONE. 2015;10:e0118913. doi: 10.1371/journal.pone.0118913. PubMed DOI PMC
Jurásek B., Bartůněk V., Huber Š., Kuchař M. X-ray powder diffraction—A non-destructive and versatile approach for the identification of new psychoactive substances. Talanta. 2019;195:414–418. doi: 10.1016/j.talanta.2018.11.063. PubMed DOI
Haddad A., Comanescu M.A., Green O., Kubic T.A., Lombardi J.R. Detection and quantitation of trace fentanyl in heroin by surface-enhanced Raman spectroscopy. Anal. Chem. 2018;90:12678–12685. doi: 10.1021/acs.analchem.8b02909. PubMed DOI
Isaacs R.C.A. A structure–reactivity relationship driven approach to the identification of a color test protocol for the presumptive indication of synthetic cannabimimetic drugs of abuse. Forensic Sci. Int. 2014;242:135–141. doi: 10.1016/j.forsciint.2014.06.027. PubMed DOI
Schneider S., Meys F. Analysis of illicit cocaine and heroin samples seized in Luxembourg from 2005–2010. Forensic Sci. Int. 2011;212:242–246. doi: 10.1016/j.forsciint.2011.06.027. PubMed DOI
Morelato M., Franscella D., Esseiva P., Broséus J. When does the cutting of cocaine and heroin occur? The first large-scale study based on the chemical analysis of cocaine and heroin seizures in Switzerland. Int. J. Drug Policy. 2019;73:7–15. doi: 10.1016/j.drugpo.2019.07.025. PubMed DOI
Peck Y., Clough A.R., Culshaw P.N., Liddell M.J. Multi-drug cocktails: Impurities in commonly used illicit drugs seized by police in Queensland, Australia. Drug Alcohol Depend. 2019;201:49–57. doi: 10.1016/j.drugalcdep.2019.03.019. PubMed DOI
American Addiction Centres What Is Meth Cut with? [(accessed on 20 October 2021)]. Available online: https://americanaddictioncenters.org/meth-treatment/cut-with.
Wang X., Baumann M.H., Xu H., Rothman R.B. 3,4-Methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein. Synapse. 2004;53:240–248. doi: 10.1002/syn.20058. PubMed DOI
National Crime Agency . Recent Deaths Possibly Linked to Fentanyl. National Crime Agency; London, UK: 2017.
Morris H., Wallach J. From PCP to MXE: A comprehensive review of the non-medical use of dissociative drugs. Drug Test. Anal. 2014;6:614–632. doi: 10.1002/dta.1620. PubMed DOI
Verweij A.M. Impurities in illicit drug preparations: Amphetamine and methamphetamine. Forensic Sci. Rev. 1989;1:1–11. PubMed
United Nations Office on Drugs and Crime . Cocaine: A Spectrum of Products, Cocaine Insights2. United Nations Office on Drugs and Crime; Vienna, Austria: 2021.
American Addiction Centres What Is Cocaine Cut with. [(accessed on 9 January 2021)]. Available online: https://americanaddictioncenters.org/cocaine-treatment/cut-with.
Triclinic Labs Inorganic Materials Analysis and Phase Identification Services. [(accessed on 9 January 2021)]. Available online: https://tricliniclabs.com/page-directory/materials-analysis-services/inorganic-materials-analysis-phase-identification-by-triclinic-labs.html.
Jurásek B., Bartůněk V., Huber Š., Fagan P., Setnička V., Králík F., Dehaen W., Svozil D., Kuchař M. Can X-Ray powder diffraction be a suitable forensic method for illicit drug identification? Front. Chem. 2020;8:499. doi: 10.3389/fchem.2020.00499. PubMed DOI PMC
Kotrlý M. Application of X-ray diffraction in forensic science; Proceedings of the Ninth European Powder Diffraction Conference; Prague, Czech Republic. 2–5 September 2004; München, Germany: Oldenbourg Wissenschaftsverlag; 2006. pp. 35–40.
Thatcher P.J., Briner G.P. The application of X-Ray powder diffraction to forensic science. Powder Diffr. 1986;1:320–324. doi: 10.1017/S0885715600011994. DOI
Folen V.A. X-Ray powder diffraction data for some drugs, excipients, and adulterants in illicit samples. J. Forensic Sci. 1975;20:348–372. doi: 10.1520/JFS10282J. PubMed DOI
Newman A. X-Ray powder diffraction in solid form screening and selection. Am. Pharm. Rev. 2011;14:44.
Bulska E., Bachliński R., Cyrański M.K., Michalska-Kacymirow M., Kośnik W., Małecki P., Grela K., Dobrowolski M.A. Comprehensive protocol for the identification and characterization of new psychoactive substances in the service of law enforcement agencies. Front. Chem. 2020;8:693. doi: 10.3389/fchem.2020.00693. PubMed DOI PMC
Disregard Everything I Say MXP, Broken Down and Described. [(accessed on 10 January 2021)]. Available online: https://disregardeverythingisay.com/post/79851082420/mxp-broken-down-and-described#.
Reddit MXP, Broken Down and Described (New Novel Dissociative) [(accessed on 9 January 2021)]. Available online: https://www.reddit.com/r/Psychonaut/comments/20m5j8/mxp_broken_down_and_described_new_novel/