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Published in: International Journal of Legal Medicine 1/2015

01-01-2015 | Original Article

Endogenous gamma-hydroxybutyric acid (GHB) concentrations in post-mortem specimens and further recommendation for interpretative cut-offs

Authors: Hilke Andresen-Streichert, P. Jensen, J. Kietzerow, M. Schrot, N. Wilke, E. Vettorazzi, A. Mueller, S. Iwersen-Bergmann

Published in: International Journal of Legal Medicine | Issue 1/2015

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Abstract

When interpreting gamma-hydroxybutyric acid (GHB) concentrations in post-mortem specimens, a possible increase in GHB concentrations because of post-mortem generation must be considered. In this study, endogenous GHB concentrations in post-mortem biological fluids were investigated. Additionally, we review post-mortem GHB concentrations already published in the literature. Heart and peripheral blood samples, cerebrospinal fluid, urine, and vitreous humor were collected from 64 autopsies in subjects where the cause of death excluded GHB exposure. Sample analysis was carried out either on the day of autopsy or later after immediate freezing and storage at −20 °C. GHB concentrations in venous blood samples (n = 61) were <0.6–28.7 mg/L (mean 11.9 mg/L; median 10.6 mg/L), <0.6–65.3 mg/L (mean 15.2 mg/L; median 12.8 mg/L) in heart blood (n = 56), <0.6–25.1 mg/L (mean 6.0 mg/L; median 3.8 mg/L) in urine (n = 50), <0.6–39.0 mg/L (mean 9.6 mg/L; median 7.5 mg/L), in vitreous humor (n = 54), and <0.6–24.0 mg/L (mean 4.2 mg/L; median 3.2 mg/L) in cerebrospinal fluid (n = 52). There was no significant difference between GHB concentrations in cases where there were signs of beginning putrefaction at the time of autopsy (n = 9) and cases without obvious signs of putrefaction. In one case with advanced putrefaction, the GHB concentration in venous blood was 32.7 mg/L. In conclusion, for post-mortem venous blood, urine, and cerebrospinal fluid, an interpretative cut-off of 30 mg/L for GHB concentrations is suggested in cases where GHB analysis is conducted on the day of sample collection at autopsy or if samples have been stored at −20 °C immediately after collection.
Literature
1.
go back to reference Abanades S, Farré M, Barral D, Torrens M, Closas N, Langohr K, Pastor A, De la Torre R (2007) Relative abuse liability of gamma-hydroxybutyric acid, flunitrazepam, and ethanol in club drug users. J Clin Psychopharmacol 17:625–638CrossRef Abanades S, Farré M, Barral D, Torrens M, Closas N, Langohr K, Pastor A, De la Torre R (2007) Relative abuse liability of gamma-hydroxybutyric acid, flunitrazepam, and ethanol in club drug users. J Clin Psychopharmacol 17:625–638CrossRef
2.
go back to reference Abanades S, Farré M, Segura M, Pichini M, 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(1):64–70 Abanades S, Farré M, Segura M, Pichini M, 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(1):64–70
3.
go back to reference Miotto K, Darakjian J, Basch J, Murray S, Zogg J, Rawson R (2001) Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal. Am J Addict 10(3):232–241CrossRefPubMed Miotto K, Darakjian J, Basch J, Murray S, Zogg J, Rawson R (2001) Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal. Am J Addict 10(3):232–241CrossRefPubMed
4.
go back to reference Elliott S (2004) Nonfatal instances of intoxication with gamma-hydroxybutyrate in the United Kingdom. Ther Drug Monit 26(4):432–440CrossRefPubMed Elliott S (2004) Nonfatal instances of intoxication with gamma-hydroxybutyrate in the United Kingdom. Ther Drug Monit 26(4):432–440CrossRefPubMed
5.
go back to reference Couper FJ, Logan BK (2000) Determination of gamma-hydroxybutyrate (GHB) in biological specimens by gas chromatography-mass spectrometry. J Anal Toxicol 24:1–7CrossRefPubMed Couper FJ, Logan BK (2000) Determination of gamma-hydroxybutyrate (GHB) in biological specimens by gas chromatography-mass spectrometry. J Anal Toxicol 24:1–7CrossRefPubMed
6.
go back to reference Sporer K, Chin R, Dyer J, Lamb R (2003) Gamma-hydroxybutyrate serum levels and clinical syndrome after severe overdose. Ann Emerg Med 42:3–8CrossRefPubMed Sporer K, Chin R, Dyer J, Lamb R (2003) Gamma-hydroxybutyrate serum levels and clinical syndrome after severe overdose. Ann Emerg Med 42:3–8CrossRefPubMed
7.
go back to reference Mason P, Kerns W (2002) Gamma hydroxybutyric acid (GHB) intoxication. Acad Emerg Med 9(7):730–739CrossRefPubMed Mason P, Kerns W (2002) Gamma hydroxybutyric acid (GHB) intoxication. Acad Emerg Med 9(7):730–739CrossRefPubMed
8.
go back to reference Duer WC, Byers KL, Martin JV (2001) Application of a convenient extraction procedure to analyze gamma-hydroxybutyric acid in fatalities involving gamma-hydroxybutyric acid, gamma-butyrolactone, and 1,4-butanediol. J Anal Toxicol 25:576–582CrossRefPubMed Duer WC, Byers KL, Martin JV (2001) Application of a convenient extraction procedure to analyze gamma-hydroxybutyric acid in fatalities involving gamma-hydroxybutyric acid, gamma-butyrolactone, and 1,4-butanediol. J Anal Toxicol 25:576–582CrossRefPubMed
9.
go back to reference Mazarr-Proo S, Kerrigan S (2005) Distribution of GHB in tissues and fluids following a fatal overdose. J Anal Toxicol 29:398–400CrossRefPubMed Mazarr-Proo S, Kerrigan S (2005) Distribution of GHB in tissues and fluids following a fatal overdose. J Anal Toxicol 29:398–400CrossRefPubMed
10.
go back to reference Kintz P, Villain M, Pélisser A-L, Cirimele V, Leonetti G (2005) Unusually high concentrations in a fatal GHB case. J Anal Toxicol 29:582–585CrossRefPubMed Kintz P, Villain M, Pélisser A-L, Cirimele V, Leonetti G (2005) Unusually high concentrations in a fatal GHB case. J Anal Toxicol 29:582–585CrossRefPubMed
11.
go back to reference Kalasinsky K, Dixon M, Schmunk G, Kish S (2001) Blood, brain, and hair GHB concentrations following fatal ingestion. J Forensic Sci 46(3):728–730CrossRefPubMed Kalasinsky K, Dixon M, Schmunk G, Kish S (2001) Blood, brain, and hair GHB concentrations following fatal ingestion. J Forensic Sci 46(3):728–730CrossRefPubMed
12.
go back to reference Knudsen K, Jonsson U, Abrahamsson J (2010) Twenty-three deaths with γ-hydroxybutyrate overdose in Western Sweden between 2000 and 2007. Acta Anaesthesiol Scand 54(8):987–992CrossRefPubMed Knudsen K, Jonsson U, Abrahamsson J (2010) Twenty-three deaths with γ-hydroxybutyrate overdose in Western Sweden between 2000 and 2007. Acta Anaesthesiol Scand 54(8):987–992CrossRefPubMed
13.
go back to reference Zvosec D, Smith S, Porrata T, Strobl A, Dyer J (2011) Case series of 226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am J Emerg Med 29(3):319–332CrossRefPubMed Zvosec D, Smith S, Porrata T, Strobl A, Dyer J (2011) Case series of 226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am J Emerg Med 29(3):319–332CrossRefPubMed
14.
go back to reference Kugelberg F, Holmgren A, Eklund A, Jones A (2010) Forensic toxicology findings in deaths involving gamma-hydroxybutyrate. Int J Legal Med 124(1):1–6CrossRefPubMed Kugelberg F, Holmgren A, Eklund A, Jones A (2010) Forensic toxicology findings in deaths involving gamma-hydroxybutyrate. Int J Legal Med 124(1):1–6CrossRefPubMed
15.
go back to reference Lenz D, Rothschild M, Kroener L (2008) Intoxications due to ingestion of gamma-butyrolactone: organ distribution of gamma-hydroxybutyric acid and gamma-butyrolactone. Ther Drug Monit 30(6):755–761CrossRefPubMed Lenz D, Rothschild M, Kroener L (2008) Intoxications due to ingestion of gamma-butyrolactone: organ distribution of gamma-hydroxybutyric acid and gamma-butyrolactone. Ther Drug Monit 30(6):755–761CrossRefPubMed
16.
go back to reference Zvosec DL, Smith SW, McCutcheon R, Spillane J, Hall BJ, Peacock E (2001) Adverse events, including death, associated with the use of 1, 4-butanediol. N Engl J Med 344:87–94CrossRefPubMed Zvosec DL, Smith SW, McCutcheon R, Spillane J, Hall BJ, Peacock E (2001) Adverse events, including death, associated with the use of 1, 4-butanediol. N Engl J Med 344:87–94CrossRefPubMed
17.
go back to reference ElSohly MA, Salamone SJ (1999) Prevalence of drug used in cases of alleged sexual assault. J Anal Toxicol 23:141–146CrossRefPubMed ElSohly MA, Salamone SJ (1999) Prevalence of drug used in cases of alleged sexual assault. J Anal Toxicol 23:141–146CrossRefPubMed
18.
go back to reference LeBeau MA, Andollo W, Hearn W, Baselt R, Cone E, Finkle B, Fraser D, Jenkins A, Mayer J, Negrusz A, Poklis A, Walls H, Raymon L, Robertson M, Saady J (1999) Recommendation for toxicological investigations of drug-facilitated sexual assaults. J Forensic Sci 44:227–230CrossRefPubMed LeBeau MA, Andollo W, Hearn W, Baselt R, Cone E, Finkle B, Fraser D, Jenkins A, Mayer J, Negrusz A, Poklis A, Walls H, Raymon L, Robertson M, Saady J (1999) Recommendation for toxicological investigations of drug-facilitated sexual assaults. J Forensic Sci 44:227–230CrossRefPubMed
19.
go back to reference Marinetti L, LeBeau M (2010) The use of GHB and analogs to facilitate sexual assault. Forensic Sci Rev 22:41PubMed Marinetti L, LeBeau M (2010) The use of GHB and analogs to facilitate sexual assault. Forensic Sci Rev 22:41PubMed
20.
go back to reference Roth RH, Giarman NJ (1970) Natural occurrence of gamma-hydroxybutyrate in mammalian brain. Biochem Pharmacol 19:1087–1093CrossRef Roth RH, Giarman NJ (1970) Natural occurrence of gamma-hydroxybutyrate in mammalian brain. Biochem Pharmacol 19:1087–1093CrossRef
21.
go back to reference Bessman S, Fishbein W (1963) Gamma-hydroxybutyrate, a normal brain metabolite. Nature 200:1207–1208CrossRefPubMed Bessman S, Fishbein W (1963) Gamma-hydroxybutyrate, a normal brain metabolite. Nature 200:1207–1208CrossRefPubMed
22.
go back to reference Elliott S (2003) Gamma hydroxybutyric acid (GHB) concentrations in humans and factors affecting endogenous production. Forensic Sci Int 133:9–16CrossRefPubMed Elliott S (2003) Gamma hydroxybutyric acid (GHB) concentrations in humans and factors affecting endogenous production. Forensic Sci Int 133:9–16CrossRefPubMed
23.
go back to reference Bosman IJ, Lusthof KJ (2003) Forensic cases involving the use of GHB in the Netherlands. Forensic Sci Int 133:17–21CrossRefPubMed Bosman IJ, Lusthof KJ (2003) Forensic cases involving the use of GHB in the Netherlands. Forensic Sci Int 133:17–21CrossRefPubMed
24.
go back to reference Elian AA (2002) Determination of endogenous gamma-hydroxybutyric acid (GHB) levels in antemortem urine and blood. Forensic Sci Int 128:120–122CrossRefPubMed Elian AA (2002) Determination of endogenous gamma-hydroxybutyric acid (GHB) levels in antemortem urine and blood. Forensic Sci Int 128:120–122CrossRefPubMed
25.
go back to reference Kavanagh P, Kenny P, Feely J (2001) The urinary excretion of gamma-hydroxybutyric acid in man. J Pharm Pharmacol 53:399–402CrossRefPubMed Kavanagh P, Kenny P, Feely J (2001) The urinary excretion of gamma-hydroxybutyric acid in man. J Pharm Pharmacol 53:399–402CrossRefPubMed
26.
go back to reference 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 200:93–99CrossRefPubMed 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 200:93–99CrossRefPubMed
27.
go back to reference Fieler EL, Coleman DE, Baselt RC (1998) Gamma-hydroxybutyrate concentrations in pre- and postmortem blood and urine. Clin Chem 44:692–693CrossRefPubMed Fieler EL, Coleman DE, Baselt RC (1998) Gamma-hydroxybutyrate concentrations in pre- and postmortem blood and urine. Clin Chem 44:692–693CrossRefPubMed
28.
go back to reference Kintz P, Villain M, Cirimele V, Ludes B (2004) GHB in postmortem toxicology. discrimination between endogenous production from exposure using multiple specimens. Forensic Sci Int 143:177–181CrossRefPubMed Kintz P, Villain M, Cirimele V, Ludes B (2004) GHB in postmortem toxicology. discrimination between endogenous production from exposure using multiple specimens. Forensic Sci Int 143:177–181CrossRefPubMed
29.
go back to reference Elliott S (2001) The presence of gamma-hydroxybutyric acid (GHB) in postmortem biological fluids. J Anal Toxicol 25:152CrossRef Elliott S (2001) The presence of gamma-hydroxybutyric acid (GHB) in postmortem biological fluids. J Anal Toxicol 25:152CrossRef
30.
go back to reference Moriya F, Hashimoto Y (2004) Endogenous gamma-hydroxybutyric acid levels in postmortem blood. Legal Med 6:47–51CrossRefPubMed Moriya F, Hashimoto Y (2004) Endogenous gamma-hydroxybutyric acid levels in postmortem blood. Legal Med 6:47–51CrossRefPubMed
31.
go back to reference Doherty J, Hattox S, Snead O, Roth R (1978) Identification of endogenous gamma-hydroxybutyrate in human and bovine brain and its regional distribution in human, guinea pig and rhesus monkey brain. J Pharmacol Exp Ther 207(1):130–139PubMed Doherty J, Hattox S, Snead O, Roth R (1978) Identification of endogenous gamma-hydroxybutyrate in human and bovine brain and its regional distribution in human, guinea pig and rhesus monkey brain. J Pharmacol Exp Ther 207(1):130–139PubMed
32.
go back to reference Or S, Liu C, Bearden L (1982) Studies on the relation of gamma-hydroxybutyric acid (GHB) to gamma-aminobutyric acid (GABA). Evidence that GABA is not the sole Source for GHB in Rat. Brain Biochem Pharmacol 31(23):3917–3923CrossRefPubMed Or S, Liu C, Bearden L (1982) Studies on the relation of gamma-hydroxybutyric acid (GHB) to gamma-aminobutyric acid (GABA). Evidence that GABA is not the sole Source for GHB in Rat. Brain Biochem Pharmacol 31(23):3917–3923CrossRefPubMed
33.
go back to reference Sakurada K, Kobayashi M, Iwase H, Yoshino M, Mukoyama H, Takatori T, Yoshida K (2002) Production of gamma-hydroxybutyric acid in postmortem liver increases with time after death. Toxicol Lett 129:207–217CrossRefPubMed Sakurada K, Kobayashi M, Iwase H, Yoshino M, Mukoyama H, Takatori T, Yoshida K (2002) Production of gamma-hydroxybutyric acid in postmortem liver increases with time after death. Toxicol Lett 129:207–217CrossRefPubMed
34.
go back to reference Seiler N, Schmidt-Glenewinkel T, Sarhan S (1979) On the formation of gamma-aminobutyric acid from putrescine in brain. J Biochem 86:277–278PubMed Seiler N, Schmidt-Glenewinkel T, Sarhan S (1979) On the formation of gamma-aminobutyric acid from putrescine in brain. J Biochem 86:277–278PubMed
35.
go back to reference Marinetti LJ, Isenschmid DS, Hepler BR, Kanluen S (2005) Analysis of GHB and 4-methyl-GHB in postmortem matrices after long-term storage. J Anal Toxicol 29:41–47CrossRefPubMed Marinetti LJ, Isenschmid DS, Hepler BR, Kanluen S (2005) Analysis of GHB and 4-methyl-GHB in postmortem matrices after long-term storage. J Anal Toxicol 29:41–47CrossRefPubMed
36.
go back to reference Petersen I, Tortzen C, Kristensen J, Pedersen D, Breindahl T (2013) Identification of a new metabolite of GHB: gamma-hydroxybutyric acid glucuronide. J Anal Toxicol 37:291–297CrossRefPubMed Petersen I, Tortzen C, Kristensen J, Pedersen D, Breindahl T (2013) Identification of a new metabolite of GHB: gamma-hydroxybutyric acid glucuronide. J Anal Toxicol 37:291–297CrossRefPubMed
37.
go back to reference Moriya F, Hashimoto Y (2005) Site-dependent production of gamma-hydroxybutyric acid in the early postmortem period. Forensic Sci Int 148:139–142CrossRefPubMed Moriya F, Hashimoto Y (2005) Site-dependent production of gamma-hydroxybutyric acid in the early postmortem period. Forensic Sci Int 148:139–142CrossRefPubMed
38.
go back to reference Elliott S (2004) Further evidence for the presence of GHB in postmortem biological fluid: implications for the interpretation of findings. J Anal Toxicol 28:20–26CrossRefPubMed Elliott S (2004) Further evidence for the presence of GHB in postmortem biological fluid: implications for the interpretation of findings. J Anal Toxicol 28:20–26CrossRefPubMed
39.
go back to reference Stephens B, Coleman D, Baselt R (1999) In vitro stability of endogenous gamma-hydroxybutyrate in postmortem blood. J Forensic Sci 44:231CrossRefPubMed Stephens B, Coleman D, Baselt R (1999) In vitro stability of endogenous gamma-hydroxybutyrate in postmortem blood. J Forensic Sci 44:231CrossRefPubMed
40.
go back to reference Kerrigan S (2002) In vitro production of gamma-hydroxybutyrate in antemortem urine samples. J Anal Toxicol 26:571–574CrossRefPubMed Kerrigan S (2002) In vitro production of gamma-hydroxybutyrate in antemortem urine samples. J Anal Toxicol 26:571–574CrossRefPubMed
41.
go back to reference Shah V, Midha K, Findlay J, Hill H, Hulse J, McGilveray I, McKay G, Miller K, Patnaik R, Powell M, Tonelli A, Viswanathan C, Yacobi A (2000) Bioanalytical method validation—a revisit with a decade of progress. Pharm Res 17(12):1551–1557CrossRefPubMed Shah V, Midha K, Findlay J, Hill H, Hulse J, McGilveray I, McKay G, Miller K, Patnaik R, Powell M, Tonelli A, Viswanathan C, Yacobi A (2000) Bioanalytical method validation—a revisit with a decade of progress. Pharm Res 17(12):1551–1557CrossRefPubMed
43.
go back to reference Erdmann F, Zandt D, Auch J, Schütz H, Weiler G, Verhoff M (2006) Investigations concerning the threshold value between endogenous and exogenous GHB (liquid ecstasy). Arch Kriminol 217(5–6):129–136, GermanPubMed Erdmann F, Zandt D, Auch J, Schütz H, Weiler G, Verhoff M (2006) Investigations concerning the threshold value between endogenous and exogenous GHB (liquid ecstasy). Arch Kriminol 217(5–6):129–136, GermanPubMed
44.
go back to reference Anderson D, Kuwahara T (1997) Endogenous GHB concentrations in postmortem specimens. Presented at the California Association of Toxicologists Meeting, Las Vegas, NV Anderson D, Kuwahara T (1997) Endogenous GHB concentrations in postmortem specimens. Presented at the California Association of Toxicologists Meeting, Las Vegas, NV
45.
go back to reference Eklund A, Eriksson M (2000) GHB endogenous concentrations, abuse, traffic accidents and death. Poster presented at the International Association of Forensic Toxicologists Meeting, Helsinki, Finland Eklund A, Eriksson M (2000) GHB endogenous concentrations, abuse, traffic accidents and death. Poster presented at the International Association of Forensic Toxicologists Meeting, Helsinki, Finland
46.
go back to reference Quattrocchi F, Sullivan L, Gray K (2001) Postmortem data review of gamma-hydroxybutyrate levels. Poster presented at the American Academy of Forensic Science Meeting, Seattle, WA Quattrocchi F, Sullivan L, Gray K (2001) Postmortem data review of gamma-hydroxybutyrate levels. Poster presented at the American Academy of Forensic Science Meeting, Seattle, WA
47.
go back to reference Kalasinsky KS, Dixon MM, Schmunk GA, Kish SJ (2001) Blood, brain and hair GHB concentrations following fatal ingestion. J Forensic Sci 46(3):728–730CrossRefPubMed Kalasinsky KS, Dixon MM, Schmunk GA, Kish SJ (2001) Blood, brain and hair GHB concentrations following fatal ingestion. J Forensic Sci 46(3):728–730CrossRefPubMed
48.
go back to reference Fjeld B, Burns M, Karinen R, Larssen B, Smith-Kielland A, Vindenes V (2012) Long-term stability of GHB in post-mortem samples and samples from living persons, stored at -20 °C, using fluoride preservatives. Forensic Sci Int 222(1–3):47–51CrossRefPubMed Fjeld B, Burns M, Karinen R, Larssen B, Smith-Kielland A, Vindenes V (2012) Long-term stability of GHB in post-mortem samples and samples from living persons, stored at -20 °C, using fluoride preservatives. Forensic Sci Int 222(1–3):47–51CrossRefPubMed
49.
go back to reference Elliott S, Lowe P, Amanda S (2004) The possible influence of micro-organisms and putrefaction in the production of GHB in post-mortem biological fluid. Forensic Sci Int 139:183–190CrossRefPubMed Elliott S, Lowe P, Amanda S (2004) The possible influence of micro-organisms and putrefaction in the production of GHB in post-mortem biological fluid. Forensic Sci Int 139:183–190CrossRefPubMed
50.
go back to reference Villain M, Cirimele V, Ludes B, Kintz P (2003) Ultra-rapid procedure to test for gamma-hydroxybutyric acid in blood and urine by gas chromatography-mass spectrometry. J Chromatogr 792:83–87 Villain M, Cirimele V, Ludes B, Kintz P (2003) Ultra-rapid procedure to test for gamma-hydroxybutyric acid in blood and urine by gas chromatography-mass spectrometry. J Chromatogr 792:83–87
Metadata
Title
Endogenous gamma-hydroxybutyric acid (GHB) concentrations in post-mortem specimens and further recommendation for interpretative cut-offs
Authors
Hilke Andresen-Streichert
P. Jensen
J. Kietzerow
M. Schrot
N. Wilke
E. Vettorazzi
A. Mueller
S. Iwersen-Bergmann
Publication date
01-01-2015
Publisher
Springer Berlin Heidelberg
Published in
International Journal of Legal Medicine / Issue 1/2015
Print ISSN: 0937-9827
Electronic ISSN: 1437-1596
DOI
https://doi.org/10.1007/s00414-014-1051-8

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