Advertisement

Forensic Toxicology

, Volume 37, Issue 1, pp 17–26 | Cite as

Toxic by design? Formation of thermal degradants and cyanide from carboxamide-type synthetic cannabinoids CUMYL-PICA, 5F-CUMYL-PICA, AMB-FUBINACA, MDMB-FUBINACA, NNEI, and MN-18 during exposure to high temperatures

  • Richard C. KevinEmail author
  • Alexander L. Kovach
  • Timothy W. Lefever
  • Thomas F. Gamage
  • Jenny L. Wiley
  • Iain S. McGregor
  • Brian F. Thomas
Original Article

Abstract

Purpose

The use of novel synthetic cannabinoids as intoxicants continues in spite of associated health risks. These compounds are typically smoked or vaporized, but many synthetic cannabinoids contain thermally labile chemical moieties. This study investigated the thermal stability of six carboxamide-type synthetic cannabinoids (CUMYL-PICA, 5F-CUMYL-PICA, AMB-FUBINACA, MDMB-FUBINACA, NNEI, and MN-18) in order to characterise potential user exposure to thermolysis products.

Methods

Compounds were heated sequentially to 200, 400, 600 and 800 °C using a thermolysis probe, and the resultant thermolysis products were analysed via gas chromatography–mass spectrometry. A secondary analysis quantified thermolytically generated cyanide via liquid chromatography–tandem mass spectrometry.

Results

All six synthetic cannabinoids underwent thermal degradation when heated above 400 °C, and released a variety of potentially toxic products, including toluene, naphthalene, and 1-naphthalamine. Compound-specific degradants were tentatively identified together with general degradative pathways for carboxamide-type synthetic cannabinoids, which proceed via indole- or indazole-amide formation and subsequent dehydration to an indole- or indazole-carbonitrile. These degradative pathways culminated in the thermolytic liberation of cyanide, in amounts up to 27 µg per mg of starting material.

Conclusions

People who smoke carboxamide-type synthetic cannabinoids are likely to be exposed to a range of potentially toxic thermal degradants, including cyanide. These degradants could have significant health impacts in human users.

Keywords

Synthetic cannabinoids Toxicity Carboxamides Thermolytic products Cyanide Degradants 

Notes

Acknowledgements

This work was supported by research grant funding to BFT from the National Institute on Drug Abuse (1R01DA-040460), and to JLW from the National Institutes of Health (DA-03672). ISM was supported by a National Health and Medical Research Council Fellowship.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

11419_2018_430_MOESM1_ESM.pdf (34 kb)
Supplementary material 1 (PDF 33 kb)

References

  1. 1.
    Banister SD, Moir M, Stuart J, Kevin RC, Wood KE, Longworth M, Wilkinson SM, Beinat C, Buchanan AS, Glass M, Connor M, McGregor IS, Kassiou M (2015) Pharmacology of indole and indazole synthetic cannabinoid designer drugs AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, and 5F-ADBICA. ACS Chem Neurosci 6:1546–1559CrossRefGoogle Scholar
  2. 2.
    Wiley JL, Marusich JA, Lefever TW, Grabenauer M, Moore KN, Thomas BF (2013) Cannabinoids in disguise: ∆9-tetrahydrocannabinol-like effects of tetramethylcyclopropyl ketone indoles. Neuropharmacology 75:145–154CrossRefGoogle Scholar
  3. 3.
    Huffman JW, Zengin G, Wu MJ, Lu J, Hynd G, Bushell K, Thompson AL, Bushell S, Tartal C, Hurst DP, Reggio PH, Selley DE, Cassidy MP, Wiley JL, Martin BR (2005) Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists. Bioorg Med Chem 13:89–112CrossRefGoogle Scholar
  4. 4.
    Banister SD, Longworth M, Kevin R, Sachdev S, Santiago M, Stuart J, Mack JBC, Glass M, McGregor IS, Connor M, Kassiou M (2016) Pharmacology of valinate and tert-leucinate synthetic cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues. ACS Chem Neurosci 7:1241–1254CrossRefGoogle Scholar
  5. 5.
    Mir A, Obafemi A, Young A, Kane C (2011) Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics 128:e1622–e1627CrossRefGoogle Scholar
  6. 6.
    Bhanushali GK, Jain G, Fatima H, Leisch LJ, Thornley-Brown D (2012) AKI associated with synthetic cannabinoids: a case series. Clin J Am Soc Nephrol 8:523–526CrossRefGoogle Scholar
  7. 7.
    Hermanns-Clausen M, Kneisel S, Szabo B, Auwärter V (2012) Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction 108:534–544CrossRefGoogle Scholar
  8. 8.
    Trecki J, Gerona RR, Schwartz MD (2015) Synthetic cannabinoid–related illnesses and deaths. N Engl J Med 373:103–107CrossRefGoogle Scholar
  9. 9.
    Buser GL, Gerona RR, Horowitz BZ, Vian KP, Troxell ML, Hendrickson RG, Houghton DC, Rozansky D, Su SW, Leman RF (2014) Acute kidney injury associated with smoking synthetic cannabinoid. Clin Toxicol 52:664–673CrossRefGoogle Scholar
  10. 10.
    Gunderson EW, Haughey HM, Ait-Daoud N, Joshi AS, Hart CL (2014) A survey of synthetic cannabinoid consumption by current cannabis users. Subst Abus 35:184–189CrossRefGoogle Scholar
  11. 11.
    Lefever TW, Marusich JA, Thomas BF, Barrus DG, Peiper NC, Kevin RC, Wiley JL (2017) Vaping synthetic cannabinoids: a novel preclinical model of e-cigarette use in mice. Subst Abus Res Treat 11:1178221817701739.  https://doi.org/10.1177/1178221817701739 Google Scholar
  12. 12.
    Adedinsewo DA, Odewole O, Todd T (2016) Acute rhabdomyolysis following synthetic cannabinoid ingestion. N Am J Med Sci 8:256–258CrossRefGoogle Scholar
  13. 13.
    Baker RR (1974) Temperature distribution inside a burning cigarette. Nature 247:405–406CrossRefGoogle Scholar
  14. 14.
    Adamowicz P, Zuba D, Sekuła K (2013) Analysis of UR-144 and its pyrolysis product in blood and their metabolites in urine. Forensic Sci Int 233:320–327CrossRefGoogle Scholar
  15. 15.
    Grigoryev A, Kavanagh P, Melnik A, Savchuk S, Simonov A (2013) Gas and liquid chromatography-mass spectrometry detection of the urinary metabolites of UR-144 and its major pyrolysis product. J Anal Toxicol 37:265–276Google Scholar
  16. 16.
    Thomas BF, Lefever TW, Cortes RA, Grabenauer M, Kovach AL, Cox AO, Patel PR, Pollard GT, Marusich JA, Kevin RC, Gamage TF, Wiley JL (2017) Thermolytic degradation of synthetic cannabinoids: chemical exposures and pharmacological consequences. J Pharmacol Exp Ther 361:162–171CrossRefGoogle Scholar
  17. 17.
    Schreiner C (2003) Genetic toxicity of naphthalene: a review. J Toxicol Environ Health B Crit Rev 6:161–183CrossRefGoogle Scholar
  18. 18.
    Raso S, Bell S (2017) Qualitative analysis and detection of the pyrolytic products of JWH-018 and 11 additional synthetic cannabinoids in the presence of common herbal smoking substrates. J Anal Toxicol 41:551–558CrossRefGoogle Scholar
  19. 19.
    Tsujikawa K, Yamamuro T, Kuwayama K, Kanamori T, Iwata YT, Inoue H (2014) Thermal degradation of a new synthetic cannabinoid QUPIC during analysis by gas chromatography–mass spectrometry. Forensic Toxicol 32:201–207CrossRefGoogle Scholar
  20. 20.
    Kavanagh P, Grigoryev A, Savchuk S, Mikhura I, Formanovsky A (2013) UR-144 in products sold via the Internet: identification of related compounds and characterization of pyrolysis products. Drug Test Anal 5:683–692CrossRefGoogle Scholar
  21. 21.
    Shevyrin V, Melkozerov V, Nevero A, Eltsov O, Morzherin Y, Shafran Y (2013) Identification and analytical properties of new synthetic cannabimimetics bearing 2,2,3,3-tetramethylcyclopropanecarbonyl moiety. Forensic Sci Int 226:62–73CrossRefGoogle Scholar
  22. 22.
    Asada A, Doi T, Tagami T, Takeda A, Satsuki Y, Kawaguchi M, Nakamura A, Sawabe Y (2017) Cannabimimetic activities of cumyl carboxamide-type synthetic cannabinoids. Forensic Toxicol 36:170–177CrossRefGoogle Scholar
  23. 23.
    Dobaja M, Grenc D, Kozelj G, Brvar M (2017) Occupational transdermal poisoning with synthetic cannabinoid cumyl-PINACA. Clin Toxicol 55:193–195CrossRefGoogle Scholar
  24. 24.
    Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R (2017) “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N Engl J Med 376:235–242CrossRefGoogle Scholar
  25. 25.
    Gamage TF, Farquhar CE, Lefever TW, Marusich JA, Kevin RC, McGregor IS, Wiley JL, Thomas BF (2018) Molecular and behavioral pharmacological characterization of abused synthetic cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA. J Pharmacol Exp Ther 365:437–446CrossRefGoogle Scholar
  26. 26.
    EMCDDA (2014) Annual report on the implementation of council decision 2005/387/JHA. http://www.emcdda.europa.eu/system/files/publications/1018/TDAN15001ENN.pdf. Accessed Nov 2017
  27. 27.
    Sasaki C, Saito T, Shinozuka T, Irie W, Murakami C, Maeda K, Nakamaru N, Oishi M, Nakamura S, Kurihara K (2015) A case of death caused by abuse of a synthetic cannabinoid N-1-naphthalenyl-1-pentyl-1H-indole-3-carboxamide. Forensic Toxicol 33:165–169CrossRefGoogle Scholar
  28. 28.
    Mottier N, Jeanneret F, Rotach M (2010) Determination of hydrogen cyanide in cigarette mainstream smoke by LC/MS/MS. J AOAC Int 93:1032–1038Google Scholar
  29. 29.
    Li B, Zhao LC, Wang L, Liu C, McAdam KG, Wang B (2016) Gas-phase pressure and flow velocity fields inside a burning cigarette during a puff. Thermochim Acta 623:22–28CrossRefGoogle Scholar
  30. 30.
    Stohs SJ, Ohia S, Bagchi D (2002) Naphthalene toxicity and antioxidant nutrients. Toxicology 180:97–105CrossRefGoogle Scholar
  31. 31.
    King MD (1982) Neurological sequelae of toluene abuse. Hum Toxicol 1:281–287CrossRefGoogle Scholar
  32. 32.
    Simeonova FP, Fishbein L, World Health Organization (2004) Hydrogen cyanide and cyanides: human health aspects. http://www.who.int/ipcs/publications/cicad/en/cicad61.pdf. Accessed Dec 2017
  33. 33.
    Zhang Z-W, Xu Y-B, Wang C-H, Chen K-B, Tong H-W, Liu S-M (2011) Direct determination of hydrogen cyanide in cigarette mainstream smoke by ion chromatography with pulsed amperometric detection. J Chromatogr A 1218:1016–1019CrossRefGoogle Scholar
  34. 34.
    Sobolevsky T, Prasolov I, Rodchenkov G (2010) Detection of JWH-018 metabolites in smoking mixture post-administration urine. Forensic Sci Int 200:141–147CrossRefGoogle Scholar
  35. 35.
    Nelson L (2006) Acute cyanide toxicity: mechanisms and manifestations. J Emerg Nurs 32:S8–S11CrossRefGoogle Scholar
  36. 36.
    Schwartz MD, Trecki J, Edison LA, Steck AR, Arnold JK, Gerona RR (2015) A common source outbreak of severe delirium associated with exposure to the novel synthetic cannabinoid ADB-PINACA. J Emerg Med 48:573–580CrossRefGoogle Scholar
  37. 37.
    Anonymous (2017) A look so far into my use of FUB-AMB. https://www.reddit.com/r/researchchemicals/comments/4dre6j/a_look_so_far_into_my_use_of_fubamb/. Accessed Dec 2017
  38. 38.
    Lundquist P, Rosling H, Sörbo B, Tibbling L (1987) Cyanide concentrations in blood after cigarette smoking, as determined by a sensitive fluorimetric method. Clin Chem 33:1228–1230Google Scholar
  39. 39.
    Åstrand A, Vikingsson S, Lindstedt D, Thelander G, Gréen H, Kronstrand R, Wohlfarth A (2018) Metabolism study for CUMYL-4CN-BINACA in human hepatocytes and authentic urine specimens: free cyanide is formed during the main metabolic pathway. Drug Test Anal.  https://doi.org/10.1002/dta.2373 Google Scholar

Copyright information

© Japanese Association of Forensic Toxicology and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Richard C. Kevin
    • 1
    Email author
  • Alexander L. Kovach
    • 2
  • Timothy W. Lefever
    • 2
  • Thomas F. Gamage
    • 2
  • Jenny L. Wiley
    • 2
  • Iain S. McGregor
    • 1
  • Brian F. Thomas
    • 2
  1. 1.School of PsychologyThe University of SydneySydneyAustralia
  2. 2.RTI InternationalResearch Triangle ParkUSA

Personalised recommendations