Abstract

According to the Chief Sanitary Inspectorate, 75% of the compounds identified as new psychoactive substances in Poland are represented by synthetic cathinones. The aim of the presented paper is to describe the pharmacological profile of synthetic cathinones, including the structure-activity relationship and its impact on their biological effects. This article also includes a review of the literature on fatal and non-fatal intoxication cases associated with the administration of well-described synthetic cathinones, as well as their new derivatives. This review also characterises the influence of the amendment to the Act of August 2018 concerning the prevention of drug abuse on the process of banning new drugs and the current legal situation related to the abuse of new psychoactive substances.

References

• 1. Adebamiro A., Perazella M.A.: Recurrent acute kidney injury followingbath salts intoxication. Am. J. Kidney Dis., 2012; 59: 273–275
  Google Scholar
• 2. Al-Motarreb A., Al-Habori M., Broadley K.J.: Khat chewing, cardiovasculardisease and other internal medical problems; the currentsituation and directions for future research. J. Ethnopharmacol.,2010; 132: 540–548
  Google Scholar
• 3. Antonowicz J.L., Metzger A.K., Ramanujam S.L.: Paranoid psychosisinduced by consumption of methylenedioxypyrovalerone: twocases. Gen. Hosp. Psychiatry, 2011; 33: 640.e5–640.e6
  Google Scholar
• 4. Baumann M.H., Bulling S., Benaderet T.S., Saha K., Ayestas M.A.,Partilla J.S., Ali S.F., Stockner T., Rothman R.B., Sandtner W., SitteH.H.: Evidence for a role of transporter-mediated currents in thedepletion of brain serotonin induced by serotonin transporter substrates.Neuropsychopharmacology, 2014; 39: 1355–1365
  Google Scholar
• 5. Baumann M.H., Walters H.M., Niello M., Sitte H.H.: Neuropharmacologyof synthetic cathinones. Handb. Exp. Pharmacol., 2018;252: 113–142
  Google Scholar
• 6. Bonano J.S., Banks M.L., Kolanos R., Sakloth F., Barnier M.L., GlennonR.A., Cozzi N.V., Partilla J.S., Baumann M.H., Negus S.S..: Quantitativestructure-activity relationship analysis of the pharmacologyof para-substituted methcathinone analogues. Br. J. Pharmacol.,2015; 172: 2433–2444
  Google Scholar
• 7. Borek H.A., Holstege C.P.: Hyperthermia and multiorgan failureafter abuse of “bath salts” containing 3,4-methylenedioxypyrovalerone.Ann. Emerg. Med., 2012; 60: 103–105
  Google Scholar
• 8. Boulanger-Gobeil C., St-Onge M., Laliberté M., Auger P.L.: Seizuresand hyponatremia related to ethcathinone and methylone poisoning.J. Med. Toxicol., 2012; 8: 59–61
  Google Scholar
• 9. Busardò F.P., Kyriakou C., Napoletano S., Marinelli E., Zaami S.:Mephedrone related fatalities: a review. Eur. Rev. Med. Pharmacol.Sci., 2015; 19: 3777–3790
  Google Scholar
• 10. Carbone P.N., Carbone D.L., Carstairs S.D., Luzi S.A.: Suddencardiac death associated with methylone use. Am. J. Forensic Med.Pathol., 2013; 34: 26–28
  Google Scholar
• 11. Chapman M.H., Kajihara M., Borges G., O’Beirne J., Patch D.,Dhillon A.P., Crozier A., Morgan M.Y.: Severe, acute liver injury andkhat leaves. N. Engl. J. Med., 2010; 362: 1642–1644
  Google Scholar
• 12. Cozzi N.V., Brandt S.D., Daley P.F., Partilla J.S., Rothman R.B.,Tulzer A., Sitte H.H., Baumann M.H.: Pharmacological examinationof trifluoromethyl ring-substituted methcathinone analogs. Eur. J.Pharmacol., 2013; 699: 180–187
  Google Scholar
• 13. Dargan P., Wood D.: Technical report on mephedrone. W: Reporton the risk assessment of mephedrone in the framework of theCouncil Decision on new psychoactive substances., red.: R. Sedefov A. Gallegos. European Monitoring Centre for Drugs and Drug Addiction(EMCDDA), Lisbon 2011, 49–100
  Google Scholar
• 14. Derungs A., Schietzel S., Meyer M.R., Maurer H.H., KrähenbühlS, Liechti M.E..: Sympathomimetic toxicity in a case of analyticallyconfirmed recreational use of naphyrone (naphthylpyrovalerone).Clin. Toxicol., 2011; 49: 691–693
  Google Scholar
• 15. Eshleman A.J., Wolfrum K.M., Hatfield M.G., Johnson R.A., MurphyK.V., Jankowsky A.: Substituted methcathinones differ in transporterand receptor interactions. Biochem. Pharmacol., 2013; 85: 1803–1815
  Google Scholar
• 16. Eshleman A.J., Wolfrum K.M., Reed J.F., Kim S.O., Swanson T.,Johnson R.A., Jankowsky A..: Structure-activity relationships of substitutedcathinones, with transporter binding, uptake, and release.J. Pharmacol. Exp. Ther., 2017; 360: 33–47
  Google Scholar
• 17. European Monitoring Centre for Drugs and Drug Addiction: Fentanilsand synthetic cannabinoids: driving greater complexity into thedrug situation. An update from the EU Early Warning System (June2018). Publications Office of the European Union, Luxembourg 2018
  Google Scholar
• 18. Falgiani M., Desai B., Ryan M.: “Bath salts” intoxication: a casereport. Case Rep. Emerg. Med., 2012; 2012: 976314
  Google Scholar
• 19. Fleckenstein A.E., Volz T.J., Riddle E.L., Gibb, J.W., Hanson G.R.:New insights into the mechanism of action of amphetamines. Annu.Rev. Pharmacol. Toxicol., 2007; 47: 681–698
  Google Scholar
• 20. Fröhlich S., Lambe E., O’Dea J.: Acute liver failure following recreationaluse of psychotropic “head shop” compounds. Ir. J. Med.Sci., 2011; 180: 263–264
  Google Scholar
• 21. Gannon B.M., Rice K.C., Collins G.T.: Reinforcing effects ofabused ‘bath salts’ constituents 3,4-methylenedioxypyrovaleroneand α-pyrrolidinopentiophenone and their enantiomers. Behav.Pharmacol., 2017; 28: 578–581
  Google Scholar
• 22. Gannon B.M., Williamson A., Suzuki M., Rice K.C., FantegrossiW.E.: Stereoselective effects of abused “bath salt” constituent3,4-methylenedioxypyrovalerone in mice: drug discrimination, locomotoractivity, and thermoregulation. J. Pharmacol. Exp. Ther.,2016; 356: 615–623
  Google Scholar
• 23. German C.L., Fleckenstein A.E., Hanson G.R.: Bath salts and syntheticcathinones: an emerging designer drug phenomenon. LifeSci., 2014; 97: 2–8
  Google Scholar
• 24. Glennon R.A., Dukat M.: Synthetic cathinones: A brief overviewof overviews with applications to the forensic sciences. Ann. ForensicRes. Anal., 2017; 4: 1040
  Google Scholar
• 25. Główny Inspektorat Sanitarny, Departament Nadzoru nad ŚrodkamiZastępczymi – na podstawie danych Zespołu ds. oceny ryzykazagrożeń dla zdrowia lub życia ludzi związanych z używaniem nowychsubstancji psychoaktywnych: Lista „TOP 5”. Substancje psychoaktywnenajczęściej identyfikowane w zabezpieczanych przez organyPaństwowej Inspekcji Sanitarnej tzw. „dopalaczach”. https://gis.gov.pl/wp-content/uploads/2018/04/lista_top_5-2017.pdf (18.04.2018)
  Google Scholar
• 26. Główny Inspektorat Sanitarny, Departament Nadzoru nad ŚrodkamiZastępczymi – na podstawie danych Zespołu ds. oceny ryzykazagrożeń dla zdrowia lub życia ludzi związanych z używaniem nowychsubstancji psychoaktywnych: Lista „TOP 10” Substancje psychoaktywne,najczęściej identyfikowane w „nowych narkotykach”:https://gis.gov.pl/wp-content/uploads/2019/01/TOP-10-2017-17-01-2019.pdf (17.01.2019)
  Google Scholar
• 27. Goshgarian A.M., Benford D.M., Caplan J.P.: Bath salt abuse:neuropsychiatric effects of cathinone derivatives. Psychosomatics,2011; 52: 593–594
  Google Scholar
• 28. Gunderson E.W., Kirkpatrick M.G., Willing L.M., Holstege C.P.:Intranasal substituted cathinone “bath salts” psychosis potentiallyexacerbated by diphenhydramine. J. Addict. Med., 2013; 7: 163–168
  Google Scholar
• 29. Gustavsson D., Escher C.: Mephedrone – Internet drug which seemsto have come and stay. Fatal cases in Sweden have drawn attention topreviously unknown substance. Lakartidningen., 2009; 106: 2769–2771
  Google Scholar
• 30. Hasegawa K., Wurita A., Minakata K., Gonmori K., Nozawa H.,Yamagishi I., Watanabe K., Suzuki O.: Postmortem distribution ofPV9, a new cathinone derivative, in human solid tissues in a fatalpoisoning case. Forensic Toxicol., 2015; 33: 141–147
  Google Scholar
• 31. Ikeji C., Sittambalam C.D., Camire L.M., Weisman D.S.: Fatal intoxicationwith N –ethylpentylone: a case report. J. CommunityHosp. Intern. Med. Perspect., 2018; 8: 307–310
  Google Scholar
• 32. Kasick D.P., McKnight C.A., Klisovic E.: “Bath salt” ingestionleading to severe intoxication delirium: two cases and a brief reviewof the emergence of mephedrone use. Am. J. Drug Alcohol Abuse,2012; 38: 176–180
  Google Scholar
• 33. Khan S., Shaheen F., Sarwar H., Molina J., Mushtaq S.: “Bathsalts”–induced psychosis in a young woman. Prim. Care CompanionCNS Disord., 2013; 15: PCC.12I01417
  Google Scholar
• 34. Kolanos R., Partilla J.S., Baumann M.H., Hutsell B.A., BanksM.L., Negus S.S., Glennon R.A.: Stereoselective actions of methylenedioxypyrovalerone(MDPV) to inhibit dopamine and norepinephrinetransporters and facilitate intracranial self-stimulationin rats. ACS Chem. Neurosci., 2015; 6: 771–777
  Google Scholar
• 35. Kolanos R., Solis E. Jr., Sakloth F., De Felice L.J., Glennon R.A.:“Deconstruction” of the abused synthetic cathinone methylenedioxypyrovalerone(MDPV) and an examination of effects at the humandopamine transporter. ACS Chem. Neurosci., 2013; 4: 1524–1529
  Google Scholar
• 36. Kristensen A.S., Andersen J., Jørgensen T.N., Sørensen L., EriksenJ., Loland C.J., Strømgaard K., Gether U.: SLC6 neurotransmittertransporters: structure, function and regulation. Pharmacol. Rev.,2011; 63: 585–640
  Google Scholar
• 37. Kudo K., Usumoto Y., Kikura-Hanajiri R., Sameshima N., Tsuji A.,Ikeda N..: A fatal case of poisoning related to new cathinone designerdrugs, 4-methoxy PV8, PV9, and 4-methoxy PV9, and a dissociativeagent, diphenidine. Leg. Med., 2015; 17: 421–426
  Google Scholar
• 38. Kuś P., Kusz J., Książek M., Pieprzyca E., Rojkiewicz M.: Spectroscopiccharacterization and crystal structures of two cathinonederivatives: N-ethyl-2-amino-1-phenylpropan-1-one (ethcathinone)hydrochloride and N-ethyl-2-amino-1-(4-chlorophenyl)propan-1-one (4-CEC) hydrochloride. Forensic Toxicol., 2017; 35: 114-124
  Google Scholar
• 39. Kyle P.B., Iverson R.B., Gajagowni R.G., Spencer L.: Illicit bathsalts: not for bathing. J. Miss. State Med. Assoc., 2011; 52: 375–377
  Google Scholar
• 40. Levine M., Levitan R., Skolnik A.: Compartment syndrome after“bath salts” use: a case series. Ann. Emerg. Med., 2013; 61: 480–483
  Google Scholar
• 41. Liechti M.: Novel psychoactive substances (designer drugs):overview and pharmacology of modulators of monoamine signaling.Swiss Med. Wkly., 2015; 145: w14043
  Google Scholar
• 42. Lusthof K.J., Oosting R., Maes A., Verschraagen M., Dijkhuizen A.,Sprong A.G.: A case of extreme agitation and death after the use ofmephedrone in the Netherlands. Forensic Sci. Int., 2011; 206: e93–e95
  Google Scholar
• 43. Maan Z.N., D’Souza A.R.: Spontaneous subcutaneous emphysema associatedwith mephedrone usage. Ann. R. Coll. Surg. Engl., 2012; 94: e38–e40
  Google Scholar
• 44. Mackay K., Taylor M., Bajaj N.: The adverse consequences of mephedroneuse: a case series. Psychiatrist, 2011; 35: 203–205
  Google Scholar
• 45. Majchrzak M., Celiński R., Kowalska T., Sajewicz M.: Fatal case of poisoningwith a new cathinone derivative: α-propylaminopentiophenone(N-PP). Forensic Toxicol., 2018; 36: 525–533
  Google Scholar
• 46. Majchrzak M., Celiński R., Kuś P., Kowalska T., Sajewicz M.: Thenewest cathinone derivatives as designer drugs: an analytical andtoxicological review. Forensic Toxicol., 2018; 36: 33–50
  Google Scholar
• 47. Marusich J.A., Antonazzo K.R., Wiley J.L., Blough B.E., PartillaJ.S., Baumann M.H.: Pharmacology of novel synthetic stimulantsstructurally related to the “bath salts” constituent 3,4-methylenedioxypyrovalerone(MDPV). Neuropharmacol., 2014; 87: 206–213
  Google Scholar
• 48. McClean J.M., Anspikian A., Tsuang J.W.: Bath salt use: a casereport and review of the literature. J. Dual Diagn., 2012; 8: 250–256
  Google Scholar
• 49. Meltzer P.C., Butler D., Deschamps J.R., Madras B.K.:1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone)analogues: a promising class of monoamine uptake inhibitors. J. Med.Chem., 2006; 49: 1420–1432
  Google Scholar
• 50. Negus S.S., Banks M.L.: Decoding the structure of abuse potentialfor new psychoactive substances: structure-activity relationships forabuse-related effects of 4-substituted methcathinone analogs. Curr.Top. Behav. Neurosci., 2017; 32: 119–131
  Google Scholar
• 51. Nicholson P.J., Quinn M.J., Dodd J.D.: Headshop heartache: acutemephedrone ‘meow’ myocarditis. Heart, 2010; 96: 2051–2052
  Google Scholar
• 52. Peevers C.G., Moorghen M., Collins P.L., Gordon F.H., McCuneC.A.: Liver disease and cirrhosis because of khat chewing in UK Somalimen: a case series. Liver Int., 2010; 30: 1242–1243
  Google Scholar
• 53. Penders T.M., Gestring R.E., Vilensky D.A.: Excited delirium followinguse of synthetic cathinones (bath salts). Gen. Hosp. Psychiatry,2012; 34: 647–650
  Google Scholar
• 54. Prosser J.M., Nelson L.S.: The toxicology of bath salts: a reviewof synthetic cathinones. J. Med. Toxicol., 2012; 8: 33–42
  Google Scholar
• 55. Regunath H., Ariyamuthu V.K., Dalal P., Misra M.: Bath salt intoxicationcausing acute kidney injury requiring hemodialysis. Hemodial.Int., 2012; 16: S47–S49
  Google Scholar
• 56. Reith M.E., Blough B.E., Hong W.C., Jones K.T., Schmitt K.C.,Baumann M.H., Partilla J.S., Rothman R.B., Katz J.L: Behavioral, biological,and chemical perspectives on atypical agents targeting thedopamine transporter. Drug Alcohol. Depend., 2015; 147: 1–19
  Google Scholar
• 57. Rickli A., Hoener M.C., Liechti M.E.: Monoamine transporterand receptor interaction profiles of novel psychoactive substances:para-halogenated amphetamines and pyrovalerone cathinones. Eur.Neuropsychopharmacol., 2015; 25: 365–376
  Google Scholar
• 58. Roelandt P., George C., d’Heygere F., Aerts R., Monbaliu D., LalemanW., Cassiman D., Verslype C., van Steenbergen W., Pirenne J.,Wilmer A., Nevens F..: Acute liver failure secondary to khat (Cathaedulis)-induced necrotic hepatitis requiring liver transplantation:case report. Transplant. Proc., 2011; 43: 3493–3495
  Google Scholar
• 59. Rojek S., Kłys M., Strona M., Maciów M., Kula K.: “Legal highs”–toxicity in the clinical and medico-legal aspect as exemplified by suicidewith bk-MBDB administration. Forensic. Sci. Int., 2012; 222: e1–e6
  Google Scholar
• 60. Rothman R.B., Clark R.D., Partilla J.S., Baumann M.H.: (+)-Fenfluramineand its major metabolite, (+)-norfenfluramine, are potentsubstrates for norepinephrine transporters. J. Pharmacol. Exp. Ther.,2003; 305: 1191–1199
  Google Scholar
• 61. Russo R., Marks N., Morris K., King H., Gelvin A., Rooney R.:Life-threatening necrotizing fasciitis due to ‘bath salts’ injection.Orthopedics, 2012; 35: e124–e127
  Google Scholar
• 62. Sammler E.M., Foley P.L., Lauder G.D., Wilson S.J., Goudie A.R.O’Riordan J.I.: A harmless high? Lancet, 2010; 376: 742
  Google Scholar
• 63. Schifano F., Albanese A., Fergus S., Stair J.L., Deluca P., CorazzaO., Davey Z., Corkery J., Siemann H., Scherbaum N., Farre’ M., TorrensM., Demetrovics Z., Ghodse A.H., Psychonaut Web Mapping,ReDNet Research Groups: Mephedrone (4- methylmethcathinone;‘meow meow’): chemical, pharmacological and clinical issues. Psychopharmacology,2011; 214: 593–602
  Google Scholar
• 64. Sharma T.R., Iskandar J.W., Ali R., Shah U.R.: Bath salts-induceddelirium and brief psychotic episode in an otherwise healthy youngman. Prim. Care Companion CNS Disord., 2012; 14: PCC.11I01224
  Google Scholar
• 65. Shekar A., Aguilar J.I., Galli G., Cozzi N.V., Brandt S.D., RuohoA.E., Baumann M.H., Matthies H.J., Galli A.: Atypical dopamine effluxcaused by 3,4-methylenedioxypyrovalerone (MDPV) via the humandopamine transporter. J. Chem. Neuroanat. 2017; 83–84: 69–74
  Google Scholar
• 66. Shimizu E., Watanabe H., Kojima T., Hagiwara H., Fujisaki M., MiyatakeR., Hashimoto K., Iyo M.: Combined intoxication with methyloneand 5-MeO-MIPT. Prog. Neuropsychopharmacol. Biol. Psychiatry,2007; 31: 288–291
  Google Scholar
• 67. Simmler L.D., Buser T.A., Donzelli M., Schramm Y., Dieu L.H.,Huwyler J., Chaboz S., Hoener M.C., Liechti M.E.: Pharmacologicalcharacterization of designer cathinones in vitro. Br. J. Pharmacol.,2013; 168: 458–470
  Google Scholar
• 68. Simmler L.D., Rickli A., Hoener M.C., Liechti M.E.: Monoaminetransporter and receptor interaction profiles of a new series of designercathinones. Neuropharmacology, 2014; 79: 152–160
  Google Scholar
• 69. Sitte H.H., Freissmuth M.: Amphetamines, new psychoactivedrugs and the monoamine transporter cycle. Trends Pharmacol.Sci., 2015; 36: 41–50
  Google Scholar
• 70. Striebel J.M., Pierre J.M.: Acute psychotic sequelae of “bathsalts”. Schizophr. Res., 2011; 133: 259–260
  Google Scholar
• 71. Thornton S.L., Gerona R.R., Tomaszewski C.A.: Psychosis froma bath salt product containing flephedrone and MDPV with serum,urine, and product quantification. J. Med. Toxicol., 2012; 8: 310–313
  Google Scholar
• 72. Tomczak E., Woźniak M.K., Kata M., Wiergowski M., Szpiech B.,Biziuk M.: Blood concentrations of a new psychoactive substance4-chloromethcathinone (4-CMC) determined in 15 forensic cases.Forensic Toxicol., 2018; 36: 476–485
  Google Scholar
• 73. Ustawa o przeciwdziałaniu narkomanii: Dz.U., 2010; nr 143: poz. 962
  Google Scholar
• 74. Ustawa o przeciwdziałaniu narkomanii: Dz.U., 2018: poz. 1030 i 1490
  Google Scholar
• 75. Valente M.J., Guedes de Pinho P., de Lourdes Bastos M., CarvalhoF., Carvalho M.: Khat and synthetic cathinones: a review. Arch.Toxicol., 2014; 88: 15–45
  Google Scholar
• 76. Wabe N.T.: Chemistry, pharmacology, and toxicology of khat(Catha Edulis forsk): A review. Addict. Health, 2011; 3: 137–149
  Google Scholar
• 77. Warrick B.J., Wilson J., Hedge M., Freeman S., Leonard K., AaronC.: Lethal serotonin syndrome after methylone and butylone ingestion.J. Med. Toxicol., 2012; 8: 65–68
  Google Scholar
• 78. Weinstein A.M., Rosca P., Fattore L., London E.D..: Syntheticcathinone and cannabinoid designer drugs pose a major risk forpublic health. Front. Psychiatry, 2017; 8: 156
  Google Scholar
• 79. Winder G.S., Stern N., Hosanagar A.: Are “bath salts” the nextgeneration of stimulant abuse? J. Subst. Abuse Treat., 2013; 44: 42–45
  Google Scholar
• 80. Winstock A.R., Mitcheson L.R., Deluca P., Davey Z., Corazza O., SchifanoF.: Mephedrone, new kid for the chop? Addiction, 2011; 106: 154–161
  Google Scholar
• 81. Winstock A.R., Mitcheson L., Marsden J.: Mephedrone: still availableand twice the price. Lancet, 2010; 376: 1537
  Google Scholar
• 82. Wood D.M., Davies S., Greene S.L., Button J., Holt D.W., RamseyJ., Dargan P.I.: Case series of individuals with analytically confirmedacute mephedrone toxicity. Clin. Toxicol., 2010; 48: 924–927
  Google Scholar
• 83. Wood D.M., Davies S., Puchnarewicz M., Button J., Archer R.,Ovaska H., Ramsey J., Lee T., Holt D.W., Dargan P.I.: Recreational useof mephedrone (4-methylmethcathinone, 4-MMC) with associatedsympathomimetic toxicity. J. Med. Toxicol., 2010; 6: 327-330
  Google Scholar
• 84. World Health Organization: Mephedrone, Critical Review Report,Agenda item 4.12, Expert Committee on Drug Dependence,Thirty-sixth Meeting, Geneva 2014
  Google Scholar
• 85. Young A.C., Schwarz E.S., Velez L.I., Gardner M.: Two cases ofdisseminated intravascular coagulation due to ‘‘bath salts’’ resultingin fatalities, with laboratory confirmation. Am. J. Emerg. Med.,2013; 31: 445.e3–445.e5
  Google Scholar
• 86. Zawilska J.B., Słomiak K., Wasiak M., Woźniak P., Massalski M.,Krupa E., Wojcieszak J.Ł.: Pochodne β-katynonu – nowa generacjaniebezpiecznych związków psychostymulujących z grupy „dopalaczy”.Przegl. Lek., 2013; 70: 386–391
  Google Scholar

Full text