Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects

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.

Keywords: GHB; liquid ecstasy; pharmacokinetic; sodium oxybate.

Figure 1

Pharmacokinetics of GHB. (A) The data represent the plasma concentrations of GHB (mean and SD) after GHB administration at doses of 20 or 35 mg kg⁻¹ in 16 subjects for each dose group. (B) The dashed lines in the semi‐log concentration–time plot represent the terminal linear elimination rate (λ_z). γ‐Hydroxybutyrate was administered at t = 0 min

Figure 2

Subjective effects of GHB. (A) γ‐Hydroxybutyrate produced significant general subjective drug effects and increased VAS scores of (B) sedation, (C) stimulation, and (D) dizziness. The higher dose of GHB produced significantly greater sedation and dizziness compared with the lower dose. γ‐Hydroxybutyrate or placebo was administered at t = 0 min. The data are expressed as mean and SD in 16 subjects per group

Figure 3

Effects of GHB on vital signs. γ‐Hydroxybutyrate had no significant effects on (A) heart rate, (B) systolic blood pressure, or (C) diastolic blood pressure. γ‐Hydroxybutyrate or placebo was administered at t = 0 min. The data are expressed as mean and SEM in 16 subjects per group

Figure 4

Effects of GHB plotted against GHB plasma concentrations (hysteresis curves). The values are expressed as the mean and SD in 16 subjects per dose group. Separate plots are shown for the two doses of GHB. The time of sampling is noted next to each point in minutes after drug administration. Close relationships were observed between the plasma levels of GHB and its subjective drug effects. (A–D) Overall, higher concentrations of GHB were associated with higher subjective effects of GHB. (B) Maximal subjective sedation coincided with maximal plasma levels of GHB 35–60 min after drug administration. A slight delay was observed for VAS (C) stimulation and (D) dizziness, in which the maximal responses occurred at 60 min when plasma levels were already declining. This slight counterclockwise hysteresis was likely attributable to drug distribution to the effect compartment. No evidence of acute pharmacological tolerance to the effects of GHB was found (i.e., no clockwise hysteresis)