Effect of chronic γ-hydroxybutyrate (GHB) administration on GHB toxicokinetics and GHB-induced respiratory depression

Am J Drug Alcohol Abuse. 2017 Nov;43(6):686-693. doi: 10.1080/00952990.2017.1339055. Epub 2017 Jun 29.


Background: γ-hydroxybutyrate (GHB) has a high potential for illicit use; overdose of this compound results in sedation, respiratory depression and death. Tolerance to the hypnotic/sedative and electroencephalogram effects of GHB occurs with chronic GHB administration; however, tolerance to respiratory depression has not been evaluated. GHB toxicodynamic effects are mediated predominantly by GABAB receptors. Chronic treatment may affect monocarboxylate transporters (MCTs) and alter the absorption, renal clearance and brain uptake of GHB.

Objectives: To determine effects of chronic GHB dosing on GHB toxicokinetics, GHB-induced respiratory depression, and MCT expression.

Methods: Rats were administered GHB 600 mg/kg intravenously daily for 5 days. Plasma, urine and tissue samples and respiratory measurements were obtained on days 1 and 5. Plasma and urine were analyzed for GHB by LC/MS/MS and tissue samples for expression of MCT1, 2 and 4 and their accessory proteins by QRT-PCR.

Results: No differences in GHB pharmacokinetics or respiratory depression were observed between days 1 and 5. Opposing changes in MCT1 and MCT4 mRNA expression were observed in kidney samples on day 5 compared to GHB-naïve animals, and MCT4 expression was increased in the intestine.

Conclusions: The lack of tolerance observed with GHB-induced respiratory depression, in contrast to the tolerance reported for the sedative/hypnotic and electroencephalogram effects, suggests that different GABAB receptor subtypes may be involved in different GABAB-mediated toxicodynamic effects of GHB. Chronic or binge users of GHB may be at no less risk for fatality from respiratory arrest with a GHB overdose than with a single dose of GHB.

Keywords: GHB; monocarboxylate transporter; pharmacokinetics; respiratory depression; tolerance; toxicodynamics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Hypnotics and Sedatives / adverse effects
  • Hypnotics and Sedatives / blood
  • Hypnotics and Sedatives / pharmacokinetics
  • Hypnotics and Sedatives / urine
  • Male
  • Monocarboxylic Acid Transporters / biosynthesis*
  • Rats
  • Respiratory Insufficiency / chemically induced*
  • Sodium Oxybate / adverse effects*
  • Sodium Oxybate / blood
  • Sodium Oxybate / pharmacokinetics*
  • Sodium Oxybate / urine
  • Time Factors
  • Toxicokinetics


  • Hypnotics and Sedatives
  • Monocarboxylic Acid Transporters
  • Sodium Oxybate