Skip to main content

Advertisement

SpringerLink
Log in

Effect of γ-hydroxybutyrate (GHB) on driving as measured by a driving simulator

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Gamma-hydroxybutyrate acid (GHB), a GABAB receptor agonist approved for treatment of narcolepsy, impairs driving ability, but little is known about doses and plasma concentrations associated with impairment and time course of recovery.

Objective

To assess effects of oral GHB (Xyrem®) upon driving as measured by a driving simulator, and to determine plasma concentrations associated with impairment and the time course of recovery.

Methods

Randomized, double-blind, two-arm crossover study, during which 16 participants received GHB 50 mg/kg orally or placebo. GHB blood samples were collected prior to and at 1, 3, and 6 h post dosing. Driving simulator sessions occurred immediately after blood sampling.

Results

Plasma GHB was not detectable at baseline or 6 h post dosing. Median GHB concentrations at 1 and 3 h were 83.1 mg/L (range 54–110) and 24.4 mg/L (range 7.2–49.7), respectively. Compared to placebo, at 1 h post GHB dosing, significant differences were seen for the life-threatening outcome collisions (p < 0.001) and off-road accidents (p = 0.018). Although driving was not faster, there was significantly more weaving and erratic driving with GHB as measured by speed deviation (p = 0.002) and lane position deviation (p = 0.004). No significant impairment regarding driving outcomes was found in the GHB group at 3 and 6 h post dose.

Conclusion

GHB in doses used to treat narcolepsy resulted in severe driving impairment at 1 h post dosing. After 3 to 6 h, there was full recovery indicating that safe driving is expected the next morning after bedtime therapeutic GHB use in the absence of other substances.

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

Similar content being viewed by others

References

  • 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 27(6):625–638

    Article  CAS  Google Scholar 

  • Akinwuntan AE, De Weerdt W, Feys H, Pauwels J, Baten G, Arno P, Kiekens C (2005) Effect of simulator training on driving after stroke: a randomized controlled trial. Neurology 65(6):843–850

    Article  CAS  Google Scholar 

  • Al-Samarraie MS, Karinen R, Mørland J, Stokke Opdal M (2010) Blood GHB concentrations and results of medical examinations in 25 car drivers in Norway. Eur J Clin Pharmacol 66(10):987–998

    Article  Google Scholar 

  • Anderson IB, Kim SY, Dyer JE, Burkhardt CB, Iknoian JC, Walsh MJ, Blanc PD (2006) Trends in gamma-hydroxybutyrate (GHB) and related drug intoxication: 1999 to 2003. Ann Emerg Med 47(2):177–183

    Article  Google Scholar 

  • Arnedt JT, Owens J, Crouch M, Stahl J, Carskadon MA (2005) Neurobehavioral performance of residents after heavy night call vs after alcohol ingestion. JAMA 294(9):1025–1033

    Article  CAS  Google Scholar 

  • Bania TC, Ashar T, Press G, Carey PM (2003) Gamma-hydroxybutyric acid tolerance and withdrawal in a rat model. Acad Emerg Med 10(7):697–704

    Article  Google Scholar 

  • Borgen LA, Cook HN, Hornfeldt CS, Fuller DE (2002) Sodium oxybate (GHB) for treatment of cataplexy. Pharmacotherapy 22(6):798–799 discussion 799

    Article  Google Scholar 

  • 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(3):253–257

    Article  CAS  Google Scholar 

  • Bosch OG, Eisenegger C, Gertsch J, von Rotz R, Dornbierer D, Gachet MS, Heinrichs M, Wetter TC, Seifritz E, Quednow BB (2015) Gamma-hydroxybutyrate enhances mood and prosocial behavior without affecting plasma oxytocin and testosterone. Psychoneuroendocrinology 62:1–10

    Article  CAS  Google Scholar 

  • Bosman IJ, Lusthof KJ (2003) Forensic cases involving the use of GHB in The Netherlands. Forensic Sci Int 133(1–2):17–21

    Article  CAS  Google Scholar 

  • 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(8):625–630

    Article  CAS  Google Scholar 

  • Burch HJ, Clarke EJ, Hubbard AM, Scott-Ham M (2013) Concentrations of drugs determined in blood samples collected from suspected drugged drivers in England and Wales. J Forensic Legal Med 20(4):278–289

    Article  Google Scholar 

  • 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(1):47–70

    Article  Google Scholar 

  • Carter LP, Richards BD, Mintzer MZ, Griffiths RR (2006) Relative abuse liability of GHB in humans: a comparison of psychomotor,subjective, and cognitive effects of supratherapeutic doses of triazolam,pentobarbital, and GHB. Neuropsychopharmacology 31(11):2537–2551

    Article  CAS  Google Scholar 

  • Carter LP, Griffiths RR, Mintzer MZ (2009) Cognitive, psychomotor, and subjective effects of sodium oxybate and triazolam in healthy volunteers. Psychopharmacology 206(1):141–154

    Article  CAS  Google Scholar 

  • Centola C, Giorgetti A, Zaami S, Giorgetti R (2018) Effects of GHB on psychomotor and driving performance. Curr Drug Metab. https://doi.org/10.2174/1389200219666180124113802

  • Couper FJ, Logan BK (2001) GHB and driving impairment. J Forensic Sci 46(4):919–923

    Article  CAS  Google Scholar 

  • Couper FJ, Logan BK (2004) Addicted to driving under the influence—a GHB/GBL case report. J Anal Toxicol 28(6):512–515

    Article  CAS  Google Scholar 

  • Couper FJ, Marinetti LJ (2002) γ-Hydroxybutyrate (GHB)—effects on human performance and behavior. Forensic Sci Rev 14(1–2):101–121

    CAS  PubMed  Google Scholar 

  • Dempsey D, Murphy N, Benowitz NL, Wiegand T, Wu L, Haller CA (2007) Respiratory effects of gamma-hydroxybutyrate (GHB) and ethanol. Clin Pharm Ther 81(Supplement 1):S51

    Google Scholar 

  • Drasbek KR, Christensen J, Jensen K (2006) Gamma-hydroxybutyrate—a drug of abuse. Acta Neurol Scand 114(3):145–156

    Article  CAS  Google Scholar 

  • Dresen S, Kempf J, Weinmann W (2007) Prevalence of gamma-hydroxybutyrate (GHB) in serum samples of amphetamine, metamphetamine and ecstasy impaired drivers. Forensic Sci Int 173(2–3):112–116

    Article  CAS  Google Scholar 

  • ElSohly MA, Salamone SJ (1999) Prevalence of drugs used in cases of alleged sexual assault. J Anal Toxicol 23(3):141–146

    Article  CAS  Google Scholar 

  • European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (2008) GHB and its precursor GBL: an emerging trend case study. http://wwwemcddaeuropaeu/system/files/publications/505/TP_GHB_and_GBL_107300pdf Accessed June 2018

  • Ferrara SD, Giorgetti R, Zancaner S, Orlando R, Tagliabracci A, Cavarzeran F, Palatini P (1999) Effects of single dose of gamma-hydroxybutyric acid and lorazepam on psychomotor performance and subjective feelings in healthy volunteers. Eur J Clin Pharmacol 54(11):821–827

    Article  CAS  Google Scholar 

  • Fritz CO, Morris PE, Richler JJ (2012) Effect size estimates: current use, calculations, and interpretation. J Exp Psychol Gen 141(1):2–18

    Article  Google Scholar 

  • Frucht SJ, Houghton WC, Bordelon Y, Greene PE, Louis ED (2005) A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor. Neurology 65(12):1967–1969

    Article  CAS  Google Scholar 

  • Fuller DE, Hornfeldt CS, Kelloway JS, Stahl PJ, Anderson TF (2004) The Xyrem risk management program. Drug Saf 27(5):293–306

    Article  CAS  Google Scholar 

  • Gonzalez A, Nutt DJ (2005) Gamma hydroxy butyrate abuse and dependency. J Psychopharmacol 19(2):195–204

    Article  CAS  Google Scholar 

  • Itzhak Y, Ali SF (2002) Repeated administration of gamma-hydroxybutyric acid (GHB) to mice: assessment of the sedative and rewarding effects of GHB. Ann N Y Acad Sci 965:451–460

    Article  CAS  Google Scholar 

  • Johnson MW, Griffiths RR (2013) Comparative abuse liability of GHB and ethanol in humans. Exp Clin Psychopharmacol 21(2):112–123

    Article  CAS  Google Scholar 

  • Jones AW, Holmgren A, Kugelberg FC (2007) Gamma-hydroxybutyrate concentrations in the blood of impaired drivers, users of illicit drugs, and medical examiner cases. J Anal Toxicol 31(9):566–572

    Article  CAS  Google Scholar 

  • Keating GM (2014) Sodium oxybate: a review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence. Clin Drug Investig 34(1):63–80

    Article  CAS  Google Scholar 

  • Lenne MG, Dietze P, Rumbold GR, Redman JR, Triggs TJ (2003) The effects of the opioid pharmacotherapies methadone, LAAM and buprenorphine, alone and in combination with alcohol, on simulated driving. Drug Alcohol Depend 72(3):271–278

    Article  CAS  Google Scholar 

  • Liakoni E, Walther F, Nickel CH, Liechti ME (2016) Presentations to an urban emergency department in Switzerland due to acute γ-hydroxybutyrate toxicity. Scand J Trauma Resusc Emerg Med 24(1):107

    Article  Google Scholar 

  • Liechti ME, Quednow BB, Liakoni E, Dornbierer D, von Rotz R, Gachet MS, Gertsch J, Seifritz E, Bosch OG (2016) Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects. Br J Clin Pharmacol 81(5):980–988

    Article  CAS  Google Scholar 

  • Mattila MJ, Palva E, Seppälä T, Ostrovskaya RU (1978) Actions and interactions with alcohol of drugs on psychomotor skills: comparison of diazepam and gamma-hydroxybutyric acid. Arch Int Pharmacodyn Ther 234(2):236–246

    CAS  PubMed  Google Scholar 

  • McElroy SL, Guerdjikova AI, Winstanley EL, O'Melia AM, Mori N, Jr Keck PE, Hudson JI (2011) Sodium oxybate in the treatment of binge eating disorder: an open-label, prospective study. Int J Eat Disord 44(3):262–268

    Article  Google Scholar 

  • Miró Ò, Galicia M, Dargan P, Dines AM, Giraudon I, Heyerdahl F, Hovda KE, Yates C, Wood DM, Euro-DEN Research Group (2017) Intoxication by gamma hydroxybutyrate and related analogues: clinical characteristics and comparison between pure intoxication and that combined with other substances of abuse. Toxicol Lett 277:84–91

    Article  Google Scholar 

  • Moskowitz H, Burns M, Fiorentino D, Smiley A, Zador P (2000) Driving characteristics and impairment at various BACs, DOT HS 809 075 (P. J. Tremont, ed.), US Department of Transportation, National Highway Traffice Safety Administration, pp. 1–60. www.nhtsa.dot.gov/people/injury/research/pub/impaired_driving/BAC/impairment.pdf Accessed March 2018

  • National Drug Intelligence Center (2002) Information bulletin: GHB analogs GBL, BD, GHV and GVL, National Drug Intelligence Center https://wwwjusticegov/archive/ndic/pubs1/1621/1621thtm Accessed March 2018

  • Oliveto A, Gentry WB, Pruzinsky R, Gonsai K, Kosten TR, Martell B, Poling J (2010) Behavioral effects of gamma-hydroxybutyrate in humans. Behav Pharmacol 21(4):332–342

    Article  CAS  Google Scholar 

  • Palatini P, Tedeschi L, Frison G, Padrini R, Zordan R, Orlando R, Gallimberti L, Gessa GL, Ferrara SD (1993) Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers. Eur J Clin Pharmacol 45(4):353–356

    Article  CAS  Google Scholar 

  • Pan YM, Gill GN, Tilson CS, Wall WH, McCurdy HH (2001) Improved procedure for the analysis of gamma-hydroxybutyrate and ethylene glycol in whole blood. J Anal Toxicol 25(5):328–332

    Article  CAS  Google Scholar 

  • Partinen M, Hirvonen K, Hublin C, Halavaara M, Hiltunen H (2003) Effects of after-midnight intake of zolpidem and temazepam on driving ability in women with non-organic insomnia. Sleep Med 4(6):553–561

    Article  CAS  Google Scholar 

  • Product Information: Xyrem® (2012) Oral solution, sodium oxybate oral solution. Jazz Pharmaceuticals (per FDA), Palo Alto

    Google Scholar 

  • Rumbach AF, Blitzer A, Frucht SJ, Simonyan K (2017) An open-label study of sodium oxybate in spasmodic dysphonia. Laryngoscope 127(6):1402–1407

    Article  CAS  Google Scholar 

  • Russell IJ, Perkins AT, Michalek JE (2009) Oxybate SXB-26 fibromyalgia syndrome. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum 60(1):299–309

    Article  CAS  Google Scholar 

  • Scharf MB, Lai AA, Branigan B, Stover R, Berkowitz DB (1998) Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients. Sleep 21(5):507–514

    Article  CAS  Google Scholar 

  • Schep LJ, Knudsen K, Slaughter RJ, Vale JA, Mégarbane B (2012) The clinical toxicology of γ-hydroxybutyrate, γ-butyrolactone and 1,4-butanediol. Clin Toxicol (Phila) 50(6):458–470

    Article  CAS  Google Scholar 

  • Schröck A, Hari Y, König S, Auwärter V, Schürch S, Weinmann W (2014) Pharmacokinetics of GHB and detection window in serum and urine after single uptake of a low dose of GBL—an experiment with two volunteers. Drug Test Anal 6(4):363–366

    Article  Google Scholar 

  • Snead OC III, Gibson KM (2005) Gamma-hydroxybutyric acid. N Engl J Med 352(26):2721–2732

    Article  CAS  Google Scholar 

  • Staner L, Ertle S, Boeijinga P, Rinaudo G, Arnal MA, Muzet A, Luthringer R (2005) Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring. Psychopharmacology 181(4):790–798

    Article  CAS  Google Scholar 

  • Stephens BG, Baselt RC (1994) Driving under the influence of GHB? J Anal Toxicol 18(6):357–358

    Article  CAS  Google Scholar 

  • Thai D, Dyer JE, Benowitz NL, Haller CA (2006) Gamma-hydroxybutyrate and ethanol effects and interactions in humans. J Clin Psychopharmacol 26(5):524–529

    Article  CAS  Google Scholar 

  • Thai D, Dyer JE, Jacob P, Haller CA (2007) Clinical pharmacology of 1,4-butanediol and gamma-hydroxybutyrate after oral 1,4-butanediol administration to healthy volunteers. Clin Pharmacol Ther 81(2):178–184

    Article  CAS  Google Scholar 

  • Turkington PM, Sircar M, Allgar V, Elliott MW (2001) Relationship between obstructive sleep apnoea, driving simulator performance, and risk of road traffic accidents. Thorax 56(10):800–805

    Article  CAS  Google Scholar 

  • Wallace DM, Maze T, Shafazand S (2011) Sodium oxybate-induced sleep driving and sleep-related eating disorder. J Clin Sleep Med 7(3):310–311

    PubMed  PubMed Central  Google Scholar 

  • Weiler JM, Bloomfield JR, Woodworth GG, Grant AR, Layton TA, Brown TL, McKenzie DR, Baker TW, Watson GS (2000) Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator. Ann Intern Med 132(5):354–363

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank the nurses and staff of the Clinical Research Center of San Francisco General Hospital for their help, and Newton Addo for statistical and technical support.

Funding

This study is supported by the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research, Grant Numbers MO1RR00083-44 and UL1 RR024131-01, NIDA DA14935, and DA12393.

Author information

Author notes

  1. Evangelia Liakoni and Delia A. Dempsey contributed equally to this work.

Authors and Affiliations

  1. Departments of Medicine and Bioengineering & Therapeutic Sciences, The University of California San Francisco, San Francisco, CA, USA

    Evangelia Liakoni, Delia A. Dempsey, Christopher Havel & Neal L. Benowitz

  2. Department of Pediatrics, Division of Adolescent Medicine, The University of California San Francisco, San Francisco, CA, USA

    Matthew Meyers

  3. Department of Emergency Medicine, Dalhousie University, Halifax, NS, Canada

    Nancy G. Murphy

  4. DF Consulting, Van Nuys, CA, USA

    Dary Fiorentino

  5. Ultragenyx Pharmaceutical Inc., Novato, CA, USA

    Christine Haller

Authors
  1. Evangelia Liakoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Delia A. Dempsey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew Meyers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nancy G. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dary Fiorentino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christopher Havel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christine Haller
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Neal L. Benowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Neal L. Benowitz.

Ethics declarations

This study was performed with informed consent and with the approval of the Committee on Human Research of the University of California, San Francisco.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(DOCX 15.9 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liakoni, E., Dempsey, D.A., Meyers, M. et al. Effect of γ-hydroxybutyrate (GHB) on driving as measured by a driving simulator. Psychopharmacology 235, 3223–3232 (2018). https://doi.org/10.1007/s00213-018-5025-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-018-5025-2

Keywords

Search

Navigation