Skip to main content

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

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  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 6:1546–1559

    Article  CAS  PubMed  Google Scholar 

  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 75:145–154

    Article  CAS  PubMed  Google Scholar 

  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 13:89–112

    Article  CAS  PubMed  Google Scholar 

  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 7:1241–1254

    Article  CAS  PubMed  Google Scholar 

  5. Mir A, Obafemi A, Young A, Kane C (2011) Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics 128:e1622–e1627

    Article  PubMed  Google Scholar 

  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 8:523–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 108:534–544

    Article  PubMed  Google Scholar 

  8. Trecki J, Gerona RR, Schwartz MD (2015) Synthetic cannabinoid–related illnesses and deaths. N Engl J Med 373:103–107

    Article  CAS  PubMed  Google Scholar 

  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 52:664–673

    Article  CAS  Google Scholar 

  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 35:184–189

    Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  Google Scholar 

  12. Adedinsewo DA, Odewole O, Todd T (2016) Acute rhabdomyolysis following synthetic cannabinoid ingestion. N Am J Med Sci 8:256–258

    Article  PubMed  PubMed Central  Google Scholar 

  13. Baker RR (1974) Temperature distribution inside a burning cigarette. Nature 247:405–406

    Article  Google Scholar 

  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 233:320–327

    Article  CAS  PubMed  Google Scholar 

  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 37:265–276

    CAS  PubMed  Google Scholar 

  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 361:162–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schreiner C (2003) Genetic toxicity of naphthalene: a review. J Toxicol Environ Health B Crit Rev 6:161–183

    Article  CAS  PubMed  Google Scholar 

  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 41:551–558

    Article  CAS  PubMed  Google Scholar 

  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 32:201–207

    Article  CAS  Google Scholar 

  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 5:683–692

    Article  CAS  PubMed  Google Scholar 

  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 226:62–73

    Article  CAS  PubMed  Google Scholar 

  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 36:170–177

    Article  CAS  Google Scholar 

  23. Dobaja M, Grenc D, Kozelj G, Brvar M (2017) Occupational transdermal poisoning with synthetic cannabinoid cumyl-PINACA. Clin Toxicol 55:193–195

    Article  CAS  Google Scholar 

  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 376:235–242

    Article  CAS  PubMed  Google Scholar 

  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 365:437–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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 33:165–169

    Article  CAS  Google Scholar 

  28. Mottier N, Jeanneret F, Rotach M (2010) Determination of hydrogen cyanide in cigarette mainstream smoke by LC/MS/MS. J AOAC Int 93:1032–1038

    CAS  PubMed  Google Scholar 

  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 623:22–28

    Article  CAS  Google Scholar 

  30. Stohs SJ, Ohia S, Bagchi D (2002) Naphthalene toxicity and antioxidant nutrients. Toxicology 180:97–105

    Article  CAS  PubMed  Google Scholar 

  31. King MD (1982) Neurological sequelae of toluene abuse. Hum Toxicol 1:281–287

    Article  CAS  PubMed  Google Scholar 

  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. 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 1218:1016–1019

    Article  CAS  PubMed  Google Scholar 

  34. Sobolevsky T, Prasolov I, Rodchenkov G (2010) Detection of JWH-018 metabolites in smoking mixture post-administration urine. Forensic Sci Int 200:141–147

    Article  CAS  PubMed  Google Scholar 

  35. Nelson L (2006) Acute cyanide toxicity: mechanisms and manifestations. J Emerg Nurs 32:S8–S11

    Article  PubMed  Google Scholar 

  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 48:573–580

    Article  PubMed  Google Scholar 

  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. 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 33:1228–1230

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard C. Kevin.

Ethics declarations

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 33 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kevin, R.C., Kovach, A.L., Lefever, T.W. et al. 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. Forensic Toxicol 37, 17–26 (2019). https://doi.org/10.1007/s11419-018-0430-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11419-018-0430-0

Keywords

  • Synthetic cannabinoids
  • Toxicity
  • Carboxamides
  • Thermolytic products
  • Cyanide
  • Degradants