Skip to main content
SpringerLink
Log in

Detection of metabolites of two synthetic cannabimimetics, MDMB-FUBINACA and ADB-FUBINACA, in authentic human urine specimens by accurate mass LC–MS: a comparison of intersecting metabolic patterns

  • Original Article
  • Published:
Forensic Toxicology Aims and scope Submit manuscript

Abstract

The structures of two indazole-derived synthetic cannabimimetics, a methyl ester, MDMB-FUBINACA, and an amide, ADB-FUBINACA, differ only in the terminal groups on the side chains. Based upon liquid chromatography–quadrupole time-of-flight-mass spectrometry analysis of urine and blood samples collected from patients who were admitted to hospital with suspected drug intoxications and from postmortem forensic investigations, 38 metabolites were tentatively identified. Hydrolysis of the terminal groups (methyl ester and amide for MDMB-FUBINACA and ADB-FUBINACA, respectively) was found to be a common metabolic pathway for both compounds, leading to the formation of other common metabolites. Hydrolysed metabolites undergo subsequent monohydroxylation, dihydrodiol formation, fluorobenzyl loss and dehydrogenation. Most of the metabolites of MDMB-FUBINACA were products of ester hydrolysis. Metabolites formed by hydrolysis, additional monohydroxylation, dihydrodiol formation and fluorobenzyl loss were also detected in forms of glucuronides. Two unhydrolysed metabolites were identified as products of hydroxylation and fluorobenzyl loss with subsequent glucuronidation. In the case of ADB-FUBINACA, products of mono- and dihydroxylation, dihydrodiol formation, dihydrodiol formation combined with monohydroxylation, monohydroxylation combined with dehydrogenation and fluorobenzyl loss with monohydroxylation were identified. Monohydroxylated and dihydrodiol metabolites were also detected in the form of glucuronides. The most abundant metabolites were products of ester hydrolysis in free and glucuronidated forms (for MDMB-FUBINACA) and of dihydrodiol formation (for ADB-FUBINACA). These compounds are recommended for toxicological screening. To our knowledge, there are no reports dealing with the detection of metabolites of MBDB-FUBINACA and ADB-FUBINACA in authentic human urine specimens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. EMCDDA (2016) Perspectives on drugs. Synthetic cannabinoids in Europe. http://www.emcdda.europa.eu/attachements.cfm/att_212361_EN_Synthetic%20cannabinoids_updated2016.pdf. Accessed Sept 2016

  2. Reggio PH (ed) (2009) The cannabinoid receptors. Humana Press, New York

    Google Scholar 

  3. Zaurova M, Hoffman RS, Vlahov D, Manini AF (2016) Clinical effects of synthetic cannabinoid receptor agonists compared with marijuana in emergency department patients with acute drug overdose. J Med Toxicol 12:335–340

    Article  CAS  PubMed  Google Scholar 

  4. Waugh J, Najafi J, Hawkins L, Hill SL, Eddleston M, Vale JA, Thompson JP, Thomas SH (2016) Epidemiology and clinical features of toxicity following recreational use of synthetic cannabinoid receptor agonists: a report from the United Kingdom National Poisons Information Service. Clin Toxicol 54:512–518

    Article  CAS  Google Scholar 

  5. Labay LM, Caruso JL, Gilson TP, Phipps RJ, Knight LD, Lemos NP, McIntyre IM, Stoppacher R, Tormos LM, Wiens AL, Williams E, Logan BK (2016) Synthetic cannabinoid drug use as a cause or contributory cause of death. Forensic Sci Int 260:31–39

    Article  CAS  PubMed  Google Scholar 

  6. EMCDDA (2015) European Drug Report 2015: trends and developments, 2015. http://www.emcdda.europa.eu/attachements.cfm/att_239505_EN_TDAT15001ENN.pdf. Accessed Sept 2016

  7. Langer N, Lindigkeit R, Schiebel H-M, Papke U, Ernst L, Beuerle T (2015) Identification and quantification of synthetic cannabinoids in “spice-like” herbal mixtures: update of the German situation for the spring of 2015. Forensic Toxicol 34:94–107

    Article  Google Scholar 

  8. Namera A, Kawamura M, Nakamoto A, Saito T, Nagao M (2015) Comprehensive review of the detection methods for synthetic cannabinoids and cathinones. Forensic Toxicol 33:175–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Qian Z, Hua Z, Liu C, Jia W (2016) Four types of cannabimimetic indazole and indole derivatives, ADB-BINACA, AB-FUBICA, ADB-FUBICA, and AB-BICA, identified as new psychoactive substances. Forensic Toxicol 34:133–143

    Article  CAS  PubMed  Google Scholar 

  10. Presley BC, Gurney SM, Scott KS, Kacinko SL, Logan BK (2016) Metabolism and toxicological analysis of synthetic cannabinoids in biological fluids and tissues. Forensic Sci Rev 28:103–169

    CAS  PubMed  Google Scholar 

  11. Peterson BL, Couper FJ (2015) Concentrations of AB-CHMINACA and AB-PINACA and driving behavior in suspected impaired driving cases. J Anal Toxicol 39:642–647

    Article  CAS  PubMed  Google Scholar 

  12. 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 

  13. Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Watanabe K, Suzuki O (2015) Postmortem distribution of AB-CHMINACA, 5-fluoro-AMB, and diphenidine in body fluids and solid tissues in a fatal poisoning case: usefulness of adipose tissue for detection of the drugs in unchanged forms. Forensic Toxicol 33:45–53

    Article  CAS  Google Scholar 

  14. Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Watanabe K, Suzuki O (2015) Postmortem distribution of MAB-CHMINACA in body fluids and solid tissues of a human cadaver. Forensic Toxicol 33:380–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Znaleziona J, Ginterová P, Petr J, Ondra P, Válka I, Ševčík J, Chrastina J, Maier V (2015) Determination and identification of synthetic cannabinoids and their metabolites in different matrices by modern analytical techniques—a review. Anal Chim Acta 874:11–25

    Article  CAS  PubMed  Google Scholar 

  16. Grigoryev A, Kavanagh P, Pechnikov A (2016) Human urinary metabolite pattern of a new synthetic cannabimimetic, methyl 2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate. Forensic Toxicol 34:316–328

    Article  CAS  Google Scholar 

  17. Erratico C, Negreira N, Norouzizadeh H, Covaci A, Neels H, Maudens K, van Nuijs ALN (2015) In vitro and in vivo human metabolism of the synthetic cannabinoid AB-CHMINACA. Drug Test Anal 7:866–876

    Article  CAS  PubMed  Google Scholar 

  18. Sobolevsky T, Prasolov I, Rodchenkov G (2015) Study on the phase I metabolism of novel synthetic cannabinoids, APICA and its fluorinated analogue. Drug Test Anal 7:131–142

    Article  CAS  PubMed  Google Scholar 

  19. Wohlfarth A, Castaneto MS, Zhu M, Pang S, Scheidweiler KB, Kronstrand R, Huestis MA (2015) Pentylindole/pentylindazole synthetic cannabinoids and their 5-fluoro analogs produce different primary metabolites: metabolite profiling for AB-PINACA and 5F-AB-PINACA. AAPS J 17:660–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wohlfarth A, Gandhi AS, Pang S, Zhu M, Scheidweiler KB, Huestis MA (2014) Metabolism of synthetic cannabinoids PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte incubation and high-resolution mass spectrometry. Anal Bioanal Chem 406:1763–1780

    Article  CAS  PubMed  Google Scholar 

  21. Castaneto MS, Wohlfarth A, Pang S, Zhu M, Scheidweiler KB, Kronstrand R, Huestis MA (2015) Identification of AB-FUBINACA metabolites in human hepatocytes and urine using high-resolution mass spectrometry. Forensic Toxicol 33:295–310

    Article  CAS  Google Scholar 

  22. Vikingsson S, Gréen H, Brinkhagen L, Mukhtar S, Josefsson M (2016) Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry. Drug Test Anal 8:950–956

    Article  CAS  PubMed  Google Scholar 

  23. Takayama T, Suzuki M, Todoroki K, Inoue K, Min JZ, Kikura-Hanajiri R, Goda Y, Toyo’oka T (2014) UPLC/ESI-MS/MS-based determination of metabolism of several new illicit drugs, ADB-FUBINACA, AB-FUBINACA, AB-PINACA, QUPIC, 5F-QUPIC and α-PVT, by human liver microsome. Biomed Chromatogr 28:831–838

    Article  CAS  PubMed  Google Scholar 

  24. Vasiliev AB, Rizvanova LN, Bulygina IE, Gevelik OD, Novikov AP, Bondar’ IV, Didenko ES, Nadezhdin AV, Savchuk SA, Gizetdinova LA, Goffenberg MA, Dzhurko YA, Zheltkova LA, Labutin AV, Malyshkina AP, Nikitina NM, Osokin AR, Podolenko EV, Samyshkina NV, Simonov AB, Skrebkova KS, Snyatkov AV, Petchnikov AL (2014) Identification of cannabimimetic MDMB(N)Bz-F by gas chromatography–monoquadrupole-mass-spectrometry and high performance liquid chromatography–tandem mass spectrometry in case of mass poisoning in the city of Surgut (in Russian). Narcology 12:49–55

    Google Scholar 

  25. EMCDDA Europol (2014) Annual report on the implementation of Council Decision 2005/387/JHA. http://www.emcdda.europa.eu/system/files/publications/1018/TDAN15001ENN.pdf. Accessed Sept 2016

  26. Peace MR, Krakowiak RI, Wolf C, Poklis A, Poklis JL (2017) Identification of MDMB-FUBINACA in commercially available e-liquid formulations sold for use in electronic cigarettes. Forensic Sci Int 271:92–97

    Article  CAS  PubMed  Google Scholar 

  27. Uchiyama N, Matsuda S, Kawamura M, Kikura-Hanajiri R, Goda Y (2013) Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products. Forensic Toxicol 31:223–240

    Article  CAS  Google Scholar 

  28. EMCDDA Europol (2013) Annual report on the implementation of Council Decision 2005/387/JHA. http://www.emcdda.europa.eu/system/files/publications/814/TDAN14001ENN_475519.pdf. Accessed Sept 2016

  29. Shanks KG, Clark W, Behonick G (2016) Death associated with the use of the synthetic cannabinoid ADB-FUBINACA. J Anal Toxicol 40:236–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. Carlier J, Diao X, Wohlfarth A, Scheidweiler K, Huestis MA (2016) In vitro metabolite profiling of ADB-FUBINACA, a new synthetic cannabinoid. Curr Neuropharmacol. doi:10.2174/1570159X15666161108123419

    PubMed  Google Scholar 

  32. Thomsen R, Nielsen LM, Holm NB, Rasmussen HB, Linnet K, INDICES Consortium (2015) Synthetic cannabimimetic agents metabolized by carboxylesterases. Drug Test Anal 7:565–576

    Article  CAS  PubMed  Google Scholar 

  33. Bruker Daltonics (2012) Toxtyper™. https://www.bruker.com/products/mass-spectrometry-and-separations/lc-ms/ion-trap/toxtyper/overview.html. Accessed Sept 2016

  34. Zaikina OL, Kind AV, Grinshtejn IL, Grigoryev AM (2015) Features of glucuronidated metabolites of the synthetic cannabimimetics detection in urine by LC–MC (in Russian). Narcology 9:77–82

    Google Scholar 

  35. Franz F, Angerer V, Moosmann B, Auwärter V (2017) Phase I metabolism of the highly potent synthetic cannabinoid MDMB-CHMICA and detection in human urine samples. Drug Test Anal. doi:10.1002/dta.2049

    Google Scholar 

  36. Shipkova M, Armstrong VW, Oellerich MW (2003) Acyl glucuronide drug metabolites: toxicological and analytical implications. Ther Drug Monit 25:1–16

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Trinity College, School of Medicine, Dublin 8, Ireland

    Pierce Kavanagh

  2. Forensic-Chemical Division, Bureau of Forensic-Medical Expertise’s, Shhepkina str. 61/2, build. 8, Moscow, Russia

    Andrej Grigoryev & Natalia Krupina

Authors
  1. Pierce Kavanagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrej Grigoryev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natalia Krupina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrej Grigoryev.

Ethics declarations

Conflict of interest

There are no financial or other relations that could lead to a conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors. For this type of study, formal informed consent is not required.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1057 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kavanagh, P., Grigoryev, A. & Krupina, N. Detection of metabolites of two synthetic cannabimimetics, MDMB-FUBINACA and ADB-FUBINACA, in authentic human urine specimens by accurate mass LC–MS: a comparison of intersecting metabolic patterns. Forensic Toxicol 35, 284–300 (2017). https://doi.org/10.1007/s11419-017-0356-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11419-017-0356-y

Keywords

Search

Navigation