Pharmacokinetics and pharmacodynamics of γ‐hydroxybutyrate in healthy subjects
Matthias E. Liechti, Boris B. Quednow, Evangelia Liakoni, Dario Dornbierer, Robin von Rotz, M. Salomé Gachet, Jürg Gertsch, Erich Seifritz, Oliver G. Bosch
British Journal of Clinical Pharmacology December 11, 2015 DOI: 10.1111/bcp.12863 via OpenAlex
Summary
Gamma-hydroxybutyrate (GHB) produced mixed stimulant-sedative effects in healthy men, with higher doses causing more sedation and dizziness but no changes in heart rate or blood pressure. Plasma exposure to GHB rose disproportionately with dose—a 40% greater increase than expected from dose alone—indicating nonlinear pharmacokinetics. The psychotropic effects were closely tied to plasma concentrations, and no acute tolerance developed over time.
Study at a glance
| Characteristics | Randomized, placebo-controlled, cross-over design Peer reviewed |
|---|---|
| Sample size | 32 |
| Population | Healthy male subjects |
| Dose | 25 and 35 mg kg(-1) |
| Keywords | Pharmacokinetics Sedation Pharmacodynamics Stimulant Sedative |
| Citations | 57 |
| Key finding | GHB shows nonlinear dose-exposure relationship and produces dose-dependent sedative effects without acute tolerance. |
Abstract
AIMS: γ-Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as a recreational substance. Nevertheless, there are limited data on the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of GHB in humans. We characterized the pharmacokinetic profile and exposure-psychotropic effect relationship of GHB in humans. METHODS: Two oral doses of GHB (25 and 35 mg kg(-1) ) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo-controlled, cross-over design. RESULTS: Maximal concentrations of GHB were (geometric mean and 95% CI): 218 (176-270) nmol ml(-1) and 453 (374-549) nmol ml(-1) for the 25 and 35 mg kg(-1) GHB doses, respectively. The elimination half-lives (mean ± SD) were 36 ± 9 and 39 ± 7 min and the AUC∞ values (geometric mean and 95% CI) were 15 747 (12 854-19 290) and 40 113 (33 093-48 622) nmol∙min ml(-1) for the 20 and 35 mg kg(-1) GHB doses, respectively. Thus, plasma GHB exposure (AUC0-∞ ) rose disproportionally (+40%) with the higher dose. γ-Hydroxybutyrate produced mixed stimulant-sedative effects, with a dose-dependent increase in sedation and dizziness. It did not alter heart rate or blood pressure. A close relationship between plasma GHB exposure and its psychotropic effects was found, with higher GHB concentrations associated with higher subjective stimulation, sedation, and dizziness. No clockwise hysteresis was observed in the GHB concentration effect plot over time (i.e., no acute pharmacological tolerance). CONCLUSION: Evidence was found of a nonlinear dose-exposure relationship (i.e., no dose proportionality) at moderate doses of GHB. The effects of GHB on consciousness were closely linked to its plasma exposure and exhibited no acute tolerance.