Understanding the risks associated with the use of new psychoactive substances (NPS): High variability of active ingredients concentration, mislabelled preparations, multiple psychoactive substances in single products

Toxicology Letters

Volumn 229, Issue 1, 2014, Pages 220-228

  Zamengo, Luca ^a   Frison, Giampietro ^a   Bettin, Chiara ^a   Sciarrone, Rocco ^a  

^a Azienda ULSS 12 Veneziana   (Italy)

Author keywords

Health risks; New psycoactive substances; NPS

Indexed keywords

3 (1 NAPHTHOYL) 1 PENTYLINDOLE; 4' METHYLMETHCATHINONE; AMPHETAMINE; BENZILPIPERAZINE; CANNABINOID; CENTRAL STIMULANT AGENT; HERBACEOUS AGENT; METYLENDIOXIPROVALERONE; NEW PSYCHOACTIVE SUBSTANCE; PIPERAZINE DERIVATIVE; RECREATIONAL DRUG; UNCLASSIFIED DRUG;

ADVERSE DRUG REACTION; AGITATION; AMNESIA; ARTICLE; CLONUS; CONFUSION; DRUG ANALYSIS; DRUG INTOXICATION; DRUG MANUFACTURE; DRUG PACKAGING; DRUG SURVEILLANCE PROGRAM; FORENSIC TOXICOLOGY; HALLUCINATION; HOSPITAL ADMISSION; HUMAN; POWDER; PRIORITY JOURNAL; RISK ASSESSMENT; SEIZURE; SUBSTANCE ABUSE;

HEALTH RISKS; NEW PSYCOACTIVE SUBSTANCES; NPS;

ADOLESCENT; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CRITICAL ILLNESS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG COMBINATIONS; DRUG CONTAMINATION; DRUG LABELING; GAS CHROMATOGRAPHY-MASS SPECTROMETRY; HUMANS; MALE; METHAMPHETAMINE; PIPERAZINES; PLANT PREPARATIONS; PSYCHOTROPIC DRUGS; RISK; SEIZURES; STREET DRUGS; SUBSTANCE-RELATED DISORDERS;

EID: 84903633193     PISSN: 03784274     EISSN: 18793169     Source Type: Journal    
DOI: 10.1016/j.toxlet.2014.06.012     Document Type: Article

References (69)

1. Atwood B.K., Huffman J., Straiker A., Mackie K. JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br. J. Pharmacol. 2010, 160:585.
2. Brandt S.D., Sumnall H.R., Measham F., Cole J. Analyses of second-generation 'legal highs' in the UK: initial findings. Drug Test. Anal. 2010, 2:377.
3. Brents L.K., Zimmerman S.M., Saffell A.R., Prather P.L., Fantegrossi W.E. Differential drug-drug interactions of the synthetic cannabinoids JWH-018 and JWH-073: implications for drug abuse liability and pain therapy. J. Pharmacol. Exp. Ther. 2013, 346:61.
4. Coppola M., Mondola R. 3,4-methylenedioxypyrovalerone (MDPV): chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online. Toxicol. Lett. 2012, 208:12.
5. Corazza O., Assi S., Simonato P., Corkery J., Bersani F.S., Demetrovics Z., et al. Promoting innovation and excellence to face the rapid diffusion of novel psychoactive substances in the EU: the outcomes of the ReDNet project. Hum. Psychopharmcol. 2013, 28:317.
6. Corkery J., Claridge H., Loi Goodair B.C., Schifano F. Drug-related deaths in the UK: January-December 2012. National Programme on Substance Abuse Deaths (NPSAD) International Centre for Drug Policy (ICDP), Annual Report 2013, St George's, University of London, UK.
7. Council of the European Union., 2008. Council Decision on defining 1-benzylpiperazine (BZP) as a new psychoactive substance which is to be made subject to control measures and criminal provisions, Brussels, 29 February.
8. Dargan P., Wood D. European Monitoring Centre for Drugs and Drug Addiction. Risk Assessment Report of a New Psychoactive Substance: 4-methylmethcathinone (Mephedrone) 2010, EMCDDA, Lisbon.
9. Dresen S., Ferreirós N., Pütz M., Westphal F., Zimmermann R., Auwärter V. Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. J. Mass Spectrom. 2010, 45:1186.
10. Drug Combinations FAQ (accessed 14.03.06.). http://www.drugs-forum.com/forum/showthread.php%3Ft=185995.
11. Ellefsen K.N., Anizan S., Castaneto M.S., Desrosiers N.A., Martin T.M., Klette K.L., Huestis M.A. Validation of the only commercially available immunoassay for synthetic cathinones in urine: Randox Drugs of Abuse V Biochip Array Technology. Drug Test. Anal. 2014, (March). (epub ahead of print). 10.1002/dta.1633.
12. Elsohly M.A., Gul W., Wanas A.S., Radwan M.M. Synthetic cannabinoids: analysis and metabolites. Life Sci. 2014, 97:78.
13. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Controlling new psychoactive substances. Available at: (accessed 14.03.06.). http://www.emcdda.europa.eu/topics/pods/controlling%3Fnew%3Fpsychoactive%3Fsubstances.
14. European Monitoring Centre for Drugs and Drug Addiction Understanding the ' Spice' Phenomenon Luxembourg 2009.
15. Every-Palmer S. Synthetic cannabinoid JWH-018 and psychosis: an explorative study. Drug Alcohol Depend. 2011, 117:152.
16. Fantegrossi W.E., Moran J.H., Radominska-Pandya A., Prather P.L. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to δ9-THC: mechanism underlying greater toxicity?. Life Sci. 2014, 97:45.
17. Favretto D., Pascali J.P., Tagliaro F. New challenges and innovation in forensic toxicology: focus on the "new psychoactive substances". J. Chromatogr. A 2013, 26:1287.
18. Freeman M.J., Rose D.Z., Myers M.A., Gooch C.L., Bozeman A.C., Burgin W.S. Ischemic stroke after use of the synthetic marijuana "Spice". Neurology 2013, 81:2090.
19. Frison G., Gregio M., Zamengo L., Zancanaro F., Frasson S., Sciarrone R. Gas chromatography/mass spectrometry determination of mephedrone in drug seizures after derivatization with 2,2, 2-trichloroethyl chloroformate. Rapid Commun. Mass Spectrom. 2011, 25:387.
20. Frison G., Zamengo L., Zancanaro F., Tedeschi G., Bettin C., Frasson S., Sciarrone R. Potenzialità della spettrometria di massa ad elevata risoluzione ed elevata accuratezza nella caratterizzazione strutturale delle nuove sostanze psicoattive ad azione amfetamino-simile. Ital. J. Addict. 2014, 4:57. Available at: http://www.ija-dpa.it/journal/index.php/ija/article/view/123/ (accessed 03.06.14).
21. Gee Gilbert P.M., Richardson S., Moore G., Paterson S., Graham P. Toxicity from the recreational use of 1-benzylpiperazine. Clin. Toxicol. (Phila.) 2008, 46:802.
22. P.L. Gee Schep, 2013. 1-Benzylpiperazine and other Piperazine-based Derivatives in Novel Psychoactive Substances: Classification, Pharmacology and Toxicology edited by Paul Dargan, David Wood; 179-209.
23. Gunderson E.W., Haughey H.M., Ait-Daoud N., Joshi A.S., Hart C.L. "Spice" and "K2" herbal highs: a case series and systematic review of the clinical effects and biopsychosocial implications of synthetic cannabinoid use in humans. Am. J. Addict. 2012, 21:320.
24. Harris C.R., Brown A. Synthetic cannabinoid intoxication: a case series and review. J. Emerg. Med. 2013, 44:360.
25. Heath T.S., Burroughs Z., Thompson A.J., Tecklenburg F.W. Acute intoxication caused by a synthetic cannabinoid in two adolescents. J. Pediatr. Pharmacol. Ther. 2012, 17:177.
26. Hughes B., Winstock A.R. Controlling new drugs under marketing regulations. Addiction 2012, 107:1894.
27. Huppertz L.M., Kneisel S., Auwärter V., Kempf J. A comprehensive library-based, automated screening procedure for 46 synthetic cannabinoids in serum employing liquid chromatography-quadrupole ion trap mass spectrometry with high-temperature electrospray ionization. J. Mass Spectrom. 2014, 49:117.
28. JWH 250:203 Mix (accessed 14.03.06.). http://www.drugs-forum.com/forum/showthread.php%3Ft=161161.
29. JWH-018/073/081/250 combinations, ratios and recipes... (accessed 14.03.06.). http://www.drugs-forum.com/forum/showthread.php%3Ft=129501.
30. Jankovics P., Váradi A., Tölgyesi L., Lohner S., Németh-Palotás J., Koszegi-Szalai H. Identification and characterization of the new designer drug 4'-methylethcathinone (4-MEC) and elaboration of a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening method for seven different methcathinone analogs. Forensic Sci. Int. 2011, 210:213.
31. Kronstrand R., Brinkhagen L., Birath-Karlsson C., Roman M., Josefsson M. LC-QTOF-MS as a superior strategy to immunoassay for the comprehensive analysis of synthetic cannabinoids in urine. Anal. Bioanal. Chem. 2014, (epub ahead of print).
32. Lapoint J., James L.P., Moran C.L., Nelson L.S., Hoffman R.S., Moran J.H. Severe toxicity following synthetic cannabinoid ingestion. Clin. Toxicol. (Phila.) 2011, 49:760.
33. Leffler A.M., Smith P.B., de Armas A., Dorman F.L. The analytical investigation of synthetic street drugs containing cathinone analogs. Forensic Sci. Int. 2014, 234:50.
34. Lindigkeit R., Boehme A., Eiserloh I., Luebbecke M., Wiggermann M., Ernst L., Beuerle T. Spice: a never ending story?. Forensic Sci. Int. 2009, 191:58.
35. Marona-Lewicka D., Rhee G.S., Sprague J.E., Nichols D.E. Psychostimulant-like effects of p-fluoroamphetamine in the rat. Eur. J. Pharmacol. 1995, 287:105.
36. Ministero della Salute. D.M. 16 giugno 2010. Aggiornamento delle tabelle contenenti l'indicazione delle sostanze stupefacenti e psicotrope relative a composizioni medicinali, di cui al decreto del Presidente della Repubblica 9 ottobre 1990, n. 309 e successive modificazioni ed integrazioni con l'inserimento delle sostanze denominate JWH-018, JWH-073 e Mefedrone. (G.U. Serie Generale, n. 146 del 25 giugno 2010).
37. Ministero della Salute. Decreto 18 luglio 2007. Aggiornamento delle tabelle contenenti l'indicazione delle sostanze stupefacenti e psicotrope e relative composizioni medicinali, di cui al decreto del Presidente della Repubblica del 9 ottobre 1990, n. 309, e successive modificazioni ed integrazioni, recante il testo unico delle leggi in materia di disciplina degli stupefacenti e sostanze psicotrope e di prevenzione, cura e riabilitazione dei relativi stati di tossicodipendenza (G.U. Serie Generale, n. 173 del 27 luglio 2007).
38. Ministero della Salute. D.M. 11 maggio 2011. Aggiornamento e completamento delle tabelle contenenti l'indicazione delle sostanze stupefacenti e psicotrope, di cui al decreto del Presidente della Repubblica 9 ottobre 1990, n. 309 e successive modificazioni ed integrazioni. Inserimento nella tabella I delle sostanze 3,4-metilendiossipirovalerone (MDPV), JWH-250, JWH-122 ed analoghi di struttura derivanti dal 3-fenilacetilindolo e dal 3-(1-naftoil)indolo.
39. Ministero della Salute. D.M. 29 Dicembre 2011. Aggiornamento delle tabelle contenenti l'indicazione delle sostanze stupefacenti e psicotrope, di cui al decreto del Presidente della Repubblica 9 ottobre 1990, n. 309 e successive modificazioni ed integrazioni. Inserimento nella tabella I della sostanza Butilone o bk-MBDB, di taluni analoghi di struttura derivanti dal 2-amino-1-fenil-1-propanone e della sostanza AM-694 e analoghi di struttura derivanti dal 3-benzoilindolo (G.U. Serie Generale, n. 3 del 04 gennaio 2012) as modified by the Decreto 11 giugno 2012 (G.U. Serie Generale, n. 142 del 20 giugno 2012).
40. Mir Obafemi A.A., Young A., Kane C. Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics 2011, 128:1622.
41. Mocha. "Memoirs of an Overdose: experience with JWH-018 in combination with cannabis (ID 88093)". Erowid.org. Apr 28, 2011. http://erowid.org/exp/88093.
42. Nahoko U., Ruri K., Jun Yukihiro O.G. Chemical analysis of synthetic cannabinoids as designer drugs in herbal products. Forensic Sci. Int. 2010, 198:31.
43. Oral Cannabinoid Administration Guide (accessed 14.03.06.). http://www.drugs-forum.com/forum/showthread.php%3Ft=224299.
44. Overdose/ER report 5F-UR-144 (XLR-11) (accessed 14.03.06.). http://www.drugs-forum.com/forum/showthread.php%3Ft=205744.
45. Papanti D., Schifano F., Botteon G., Bertossi F., Mannix J., Vidoni D., et al. "Spiceophrenia": a systematic overview of "Spice"-related psychopathological issues and a case report. Hum. Psychopharmacol. 2013, 28:379.
46. Prosser J.M., Nelson L.S. The toxicology of bath salts: a review of synthetic cathinones. J. Med. Toxicol. 2012, 8:33.
47. Psyonic-One. "A Little Flip'd Out: An Experience with Piperazines - pFPP (ID 56641)". Erowid.org. Jun 26, 2007. http://erowid.org/exp/56641.
48. Rajasekaran M., Brents L.K., Franks L.N., Moran J.H., Prather P.L. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors. Toxicol. Appl. Pharmacol. 2013, 269:100.
49. Research Chemicals Index - Synthetic Cannabinoids (accessed 14.03.06.). http://www.drugs-forum.com/forum/showthread.php%3Ft=95656.
50. Scheidweiler K.B., Huestis M.A. Simultaneous quantification of 20 synthetic cannabinoids and 21 metabolites, and semi-quantification of 12 alkyl hydroxy metabolites in human urine by liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2014, 1327:105.
51. Schifano F., Albanese A., Fergus S., Stair J.L., Deluca P., Corazza O., Davey Z., et al. Psychonaut Web Mapping; ReDNet Research Groups. Mephedrone (4-methylmethcathinone; 'meow meow'): chemical, pharmacological and clinical issues. Psychopharmacology (Berl.) 2011, 214:593.
52. Seely K.A., Lapoint J., Moran J.H., Fattore L. Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2012, 39:234.
53. Seely K.A., Brents L.K., Radominska-Pandya A., Endres G.W., Keyes G.S., Moran J.H., et al. A major glucuronidated metabolite of JWH-018 is a neutral antagonist at CB1 receptors. Chem. Res. Toxicol. 2012, 25:825.
54. The New Zealand Ministry of Health. Misuse of Drugs (Classification of BZP) Amendment Bill. (accessed 14.03.06.). http://www.parliament.nz/en-nz/pb/legislation/bills/00DBHOH_BILL8220_1/misuse%3Fof%3Fdrugs%3Fclassification%3Fof%3Fbzp%3Famendment%3Fbill.
55. The New Zealand Ministry of Health. Psychoactive Substances Act 2013. (accessed 14.03.06.). http://www.legislation.govt.nz/act/public/2013/0053/latest/whole.html#DLM5043017.
56. Thompson I., Williams G., Caldwell B., Aldington S., Dickson S., Lucas N., et al. Randomised double-blind, placebo-controlled trial of the effects of the 'party pills' BZP/TFMPP alone and in combination with alcohol. J. Psychopharmacol. 2010, 24:1299.
57. Tips and Tricks to beating a synthetic cannabinoid overdose (accessed 14.03.06.). http://www.drugs-forum.com/forum/showthread.php%3Ft=180256.
58. Tomiyama K., Funada M. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death. Toxicol. Appl. Pharmacol. 2014, 274:17.
59. UNODC. Synthetic cannabinoids in herbal products. 2011. (accessed 14.03.06). http://www.unodc.org/documents/scientific/Synthetic_Cannabinoids.pdf.
60. UNODC. The challenge of new psychoactive substances. A Report from the Global SMART Programme. March 2013. Available at: (accessed 14.03.06.). http://www.unodc.org/documents/scientific/NPS_2013_SMART.pdf.
61. UNODC. World Drug Report. 2013. Available at: (accessed 14.03.06.). http://www.unodc.org/unodc/secured/wdr/wdr2013/World_Drug_Report_2013.pdf/.
62. Uchiyama N., Kikura-Hanajiri R., Kawahara N., Goda Y. Identification of a cannabimimetic indole as a designer drug in a herbal product. Forensic Toxicol. 2009, 27:61.
63. Vardakou I., Pistos C., Spiliopoulou Ch. Spice drugs as a new trend: mode of action, identification and legislation. Toxicol. Lett. 2010, 197:157.
64. Vardakou I., Pistos C., Spiliopoulou Ch. Drugs for youth via Internet and the example of mephedrone. Toxicol. Lett. 2011, 201:191.
65. World Health Organisation (WHO) Who Expert Committee on Drug Dependence Who Expert Committee on Drug Dependence Who Technical Report Series 2012, http://apps.who.int/iris/bitstream/10665/77747/1/WHO_trs_973_eng.pdf.
66. Young A.C., Schwarz E., Medina G., Obafemi A., Feng S.Y., Kane C., Kleinschmidt K. Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory confirmation. Am. J. Emerg. Med. 2012, 30:1320.
67. Young S.A., Thrimawithana T.R., Antia U., Fredatovich J.D., Na Y., Neale P.T., Roberts A.F., Zhou H., Russell B. Pharmaceutical quality of "party pills" raises additional safety concerns in the use of illicit recreational drugs. N. Z. Med. J. 2013, 126:61.
68. Zamengo L., Frison G., Gregio M., Orrù G., Sciarrone R. Determination of illicit drugs in seized materials: role of sampling and analysis in estimation of measurement uncertainty. Forensic Sci. Int. 2011, 208:108.
69. lsdteknology. "Needs Further Human Exploration: An Experience with Piperazines - MeOPP (ID 21625)". Erowid.org. Jun 30, 2005. http://erowid.org/exp/21625.