Skip to main content
SpringerLink
Log in

GHB-O-β-glucuronide in blood and urine is not a suitable tool for the extension of the detection window after GHB intake

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

Abstract

Because of its small detection window, uncovering drug-facilitated crime after gamma-hydroxybutyric acid (GHB) intake remains a problem. The aim of this experiment was to determine endogenous concentrations of GHB and GHB-O-β-glucuronide (GHB-Gluc) in plasma and urine samples and to compare them with concentrations after GHB intake in humans. Plasma and urine samples of volunteers (n = 50) who had never taken GHB during their lifetime (control group) were collected, and endogenous concentrations of GHB and GHB-Gluc were determined. In addition, plasma and urine samples of patients (n = 3) therapeutically taking sodium oxybate (GHB-sodium salt) were collected prior to and at different time points after the intake. GHB was determined via a liquid chromatography (LC)–tandem mass spectrometry system operated in multiple reaction monitoring mode. GHB-Gluc was detected by LC–quadrupole time-of-flight mass spectrometry. In plasma and urine samples of the control group (n = 50), endogenous concentrations of GHB-Gluc ranged from 0.011 to 0.067 mg/L and from 0.16 to 7.1 mg/L, respectively, while unconjugated GHB concentrations were less than 2 mg/L in both matrices. In contrast, after sodium oxybate administration, GHB concentrations increased markedly, and fell to below the commonly used cutoff value (plasma 4 mg/L and urine 10 mg/L) after 6–8 h in all patients. GHB-Gluc concentrations showed no significant time-dependent increase in plasma samples. In urine, GHB-Gluc concentrations increased after GHB intake, but were generally not higher than the endogenous concentrations of the control group. Therefore, it can be concluded that GHB-Gluc concentrations are not a suitable marker for extending the detection window after GHB intake.

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

Similar content being viewed by others

References

  1. Cash CD (1994) Gammahydroxybutyrate: an overview of the pros and cons for it being a neurotransmitter and/or a useful therapeutic agent. Neurosci Biobehav Rev 18:291–304. doi:10.1016/0149-7634(94)90031-0

    Article  CAS  PubMed  Google Scholar 

  2. Busardò FP, Jones AW (2015) GHB pharmacology and toxicology: acute intoxication, concentrations in blood and urine in forensic cases and treatment of the withdrawal syndrome. Curr Neuropharmacol 13:47–70. doi:10.2174/1570159X13666141210215423

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gibson KM, Hoffmann GF, Hodson AK, Bottiglieri T, Jakobs C (1998) 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics 29:14–22. doi:10.1055/s-2007-973527

    Article  CAS  PubMed  Google Scholar 

  4. Dauvilliers Y, Arnulf I, Mignot E (2007) Narcolepsy with cataplexy. Lancet 369:499–511. doi:10.1016/S0140-6736(07)60237-2

    Article  PubMed  Google Scholar 

  5. Mamelak M, Scharf MB, Woods M (1986) Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings. Sleep 9:285–289 (PMID: 3704454)

    Article  CAS  PubMed  Google Scholar 

  6. Jazz Pharmaceuticals (2015) Highlights of prescribing information. https://www.xyremrems.com/documents/XYREM_Prescribing_Information.pdf. Accessed 13 Dec 2016

  7. Takahara J, Yunoki S, Yakushiji W, Yamauchi J, Yamane Y (1977) Stimulatory effects of gamma-hydroxybutyric acid on growth hormone and prolactin release in humans. J Clin Endocrinol Metab 44:1014–1017

    Article  CAS  PubMed  Google Scholar 

  8. Kam PCA, Yoong FFY (1998) Gamma-hydroxybutyric acid: an emerging recreational drug. Anaesthesia 53:1195–1198. doi:10.1046/j.1365-2044.1998.00603.x

    Article  CAS  PubMed  Google Scholar 

  9. Stell JM, Ryan JM (1996) Ecstasy and neurodegeneration. gamma-Hydroxybutyrate is a new recreational drug that may lead to loss of consciousness. BMJ 313(7054):424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Laborit H (1964) Sodium 4-hydroxybutyrate. Int J Neuropharmacol 3:433–451. doi:10.1016/0028-3908(64)90074-7

    Article  CAS  PubMed  Google Scholar 

  11. Madea B, Musshoff F (2009) Knock-out drugs: their prevalence, modes of action, and means of detection. Dtsch Arztebl Int 106:341–347. doi:10.3238/arztebl.2009.0341

    PubMed  PubMed Central  Google Scholar 

  12. Brenneisen R, Elsohly MA, Murphy TP, Passarelli J, Russmann S, Salamone SJ, Watson DE (2004) Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects. J Anal Toxicol 28:625–630. doi:10.1093/jat/28.8.625

    Article  CAS  PubMed  Google Scholar 

  13. Bay T, Eghorn LF, Klein AB, Wellendorph P (2014) GHB receptor targets in the CNS: focus on high-affinity binding sites. Biochem Pharmacol 87:220–228. doi:10.1016/j.bcp.2013.10.028

    Article  CAS  PubMed  Google Scholar 

  14. Abanades S, Farré M, Segura M, Pichini S, Pastor A, Pacifici R, Pellegrini M, de la Torre R (2007) Disposition of gamma-hydroxybutyric acid in conventional and nonconventional biologic fluids after single drug administration: issues in methodology and drug monitoring. Ther Drug Monit 29:64–70. doi:10.1097/FTD.0b013e3180307e5e

    Article  CAS  PubMed  Google Scholar 

  15. LeBeau MA, Christenson RH, Levine B, Darwin WD, Huestis MA (2002) Intra- and interindividual variations in urinary concentrations of endogenous gamma-hydroxybutyrate. J Anal Toxicol 26:340–346. doi:10.1093/jat/26.6.340

    Article  CAS  PubMed  Google Scholar 

  16. Andresen H, Sprys N, Schmoldt A, Mueller A, Iwersen-Bergmann S (2010) Gamma-hydroxybutyrate in urine and serum: additional data supporting current cut-off recommendations. Forensic Sci Int 200:93–99. doi:10.1016/j.forsciint.2010.03.035

    Article  CAS  PubMed  Google Scholar 

  17. Elliott SR (2004) Further evidence for the presence of GHB in postmortem biological fluid : implications for the interpretation of findings. J Anal Toxicol 28:20–26. doi:10.1093/jat/28.1.20

    Article  CAS  PubMed  Google Scholar 

  18. Erdmann F, Zandt D, Auch J, Schütz H, Weiler G, Verhoff MA (2006) Investigations concerning the threshold value between endogenous and exogenous GHB (liquid ecstasy) (in German with English abstract). Arch Kriminol 217:129–136 (PMID: 16910296)

    PubMed  Google Scholar 

  19. Abanades S, Farré M, Segura M, Pichini S, Barral D, Pacifici R, Pellegrini M, Fonseca F, Langohr K, De La Torre R (2006) Gamma-hydroxybutyrate (GHB) in humans: pharmacodynamics and pharmacokinetics. Ann N Y Acad Sci 1074:559–576. doi:10.1196/annals.1369.065

    Article  CAS  PubMed  Google Scholar 

  20. Haller C, Thai D, Jacob III  P, Dyer JE (2006) GHB urine concentrations after single-dose administration in humans. J Anal Toxicol 30:360–364. doi:10.1093/jat/30.6.360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Petersen IN, Tortzen C, Kristensen JL, Pedersen DS, Breindahl T (2013) Identification of a new metabolite of GHB: gamma-hydroxybutyric acid glucuronide. J Anal Toxicol 37:291–297. doi:10.1093/jat/bkt027

    Article  CAS  PubMed  Google Scholar 

  22. Wang X, Linnet K, Johansen SS (2016) Development of a UPLC–MS/MS method for determining γ-hydroxybutyric acid (GHB) and GHB glucuronide concentrations in hair and application to forensic cases. Forensic Toxicol 34:51–60. doi:10.1007/s11419-015-0285-6

    Article  Google Scholar 

  23. Mehling L-M, Piper T, Dib J, Pedersen DS, Madea B, Hess C, Thevis M (2016) Development and validation of a HPLC–QTOF-MS method for the determination of GHB-β-O-glucuronide and GHB-4-sulfate in plasma and urine. Forensic Toxicol. doi:10.1007/s11419-016-0339-4

    Google Scholar 

  24. Petersen IN, Kristensen JL, Tortzen C, Breindahl T, Pedersen DS (2013) Synthesis and stability study of a new major metabolite of γ-hydroxybutyric acid. Beilstein J Org Chem 9:641–646. doi:10.3762/bjoc.9.72

    Article  CAS  Google Scholar 

  25. Lott S, Musshoff F, Madea B (2012) Estimation of gamma-hydroxybutyrate (GHB) co-consumption in serum samples of drivers positive for amphetamine or ecstasy. Forensic Sci Int 221:98–101. doi:10.1016/j.forsciint.2012.04.009

    Article  CAS  PubMed  Google Scholar 

  26. Borgen LA, Okerholm RA, Lai A, Scharf MB (2004) The pharmacokinetics of sodium oxybate oral solution following acute and chronic administration to narcoleptic patients. J Clin Pharmacol 44:253–257. doi:10.1177/0091270003262795

    Article  CAS  PubMed  Google Scholar 

  27. Mamelak M, Escriu JM, Stokan O (1977) The effects of gamma-hydroxybutyrate on sleep. Biol Psychiatry 12:273–288

    CAS  PubMed  Google Scholar 

  28. Broughton R, Mamelak M (1980) Effects of nocturnal gamma-hydroxybutyrate on sleep/waking patterns in narcolepsy–cataplexy. Can J Neurol Sci 7:23–31. doi:10.1017/S0317167100023659

    CAS  PubMed  Google Scholar 

  29. King C, Rios G, Green M, Tephly T (2000) UDP-glucuronosyltransferases. Curr Drug Metab 1:143–161. doi:10.2174/1389200003339171

    Article  CAS  PubMed  Google Scholar 

  30. Foti RS, Fisher MB (2005) Assessment of UDP-glucuronosyltransferase catalyzed formation of ethyl glucuronide in human liver microsomes and recombinant UGTs. Forensic Sci Int 153:109–116. doi:10.1016/j.forsciint.2004.12.003

    Article  CAS  PubMed  Google Scholar 

  31. Crunelle CL, Neels H, Maudens K, De Doncker M, Cappelle D, Matthys F, Dom G, Fransen E, Michielsen P, De Keukeleire S, Covaci A, Yegles M (2016) Influence of body mass index on hair ethyl glucuronide concentrations. Alcohol Alcohol. doi:10.1093/alcalc/agw079

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Ms. Alexandra Maas for making sample collection possible, Dr. Daniel Sejer Pedersen for providing the internal standard, and all volunteers for taking part in this study.

Author information

Authors and Affiliations

  1. Institute of Forensic Medicine, University Hospital, University of Bonn, Stiftsplatz 12, 53111, Bonn, Germany

    Lena-Maria Mehling, Burkhard Madea & Cornelius Hess

  2. Center for Preventive Doping Research, Institute of Biochemistry, German Sport University Cologne, Cologne, Germany

    Thomas Piper & Mario Thevis

  3. Department of Neurology, University Hospital, University of Bonn, Bonn, Germany

    Annika Spottke

  4. Division of Sleep Medicine and Neuromuscular Disorders, Department of Neurology, University Hospital, University of Münster, Münster, Germany

    Anna Heidbreder & Peter Young

Authors
  1. Lena-Maria Mehling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Piper
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annika Spottke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Heidbreder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Burkhard Madea
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mario Thevis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cornelius Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lena-Maria Mehling or Cornelius Hess.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants, who provided small amounts of blood and urine, were in accordance with the ethical standards of the institutional review board of the universities of Bonn and Münster and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 21 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehling, LM., Piper, T., Spottke, A. et al. GHB-O-β-glucuronide in blood and urine is not a suitable tool for the extension of the detection window after GHB intake. Forensic Toxicol 35, 263–274 (2017). https://doi.org/10.1007/s11419-016-0352-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11419-016-0352-7

Keywords

Search

Navigation