Pharmacokinetics and pharmacodynamics of γ‐hydroxybutyrate in healthy subjects

Abstract

AIMSγ-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. METHODSTwo oral doses of GHB (25 and 35 mg kg À1 ) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo-controlled, cross-over design. RESULTSMaximal concentrations of GHB were (geometric mean and 95% CI): 218 (176-270) nmol ml À1 and 453 (374-549) nmol ml À1for the 25 and 35 mg kg À1 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 À1 for the 20 and 35 mg kg À1 GHB doses, respectively. Thus, plasma GHB exposure (AUC 0-∞ ) 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). CONCLUSIONEvidence 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• γ-Hydroxybutyrate (GHB) presents nonlinear elimination kinetics at higher doses in humans.• γ-Hydroxybutyrate produces mixed stimulant-sedative subjective effects. WHAT THIS STUDY ADDS• At moderate doses, GHB exhibited first-order elimination kinetics but a nonlinear dose-plasma exposure relationship.• A close relationship was found between the plasma GHB concentration and subjective effects of GHB over time, with no evidence of acute tolerance.

Prohedonic properties of gamma‐hydroxybutyrate are associated with changes in limbic resting‐state functional connectivity

“…Quantitatively, there were two peaks at 55 and 77 min due to visual stimulation, were sexual arousal was increased in both the GHB and the placebo group, resulting in no significant difference between the groups. Both profiles are in line with previous pharmacokinetic and pharmacodynamic studies (Abanades et al, ; Bosch et al, ; Brenneisen et al, ; Liechti et al, ). Depending on dosage and time, GHB frequently exerts biphasic effects such as euphoria in lower doses and in early stages of intoxication and sedation or coma with higher doses and in later stages of intoxication (Abanades et al, ; Madah‐Amiri, Myrmel, & Brattebo, ).…”

“…Both profiles are in line with previous pharmacokinetic and pharmacodynamic studies (Abanades et al, 2006;Bosch et al, 2015;Brenneisen et al, 2004;Liechti et al, 2016). Depending on dosage and time, GHB frequently exerts biphasic effects such as euphoria in lower doses and in early stages of intoxication and sedation or coma with higher doses and in later stages of intoxication (Abanades et al, 2006;Madah-Amiri, Myrmel, & Brattebo, 2017).…”

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

“…The effects of GHB on psychomotor function, and presumably on driving performance, are dose-related (Liechti 2016, Centola 2018). The mean dose administrated in our study was 3333 mg (45–50 mg/kg).…”

“…Although the one hour concentrations in our study (median 83.1 mg/L) are comparable to the reported DUI values, in the DUI cases, the blood samples were typically drawn one or more hours after the arrest. The half-life of GHB is reported to be between 20 and 50 minutes (Schep 2012; Liechti 2016; Brenneisen 2004; Schröck 2014; Thai 2006; Thai 2007), so it is assumed that the GHB concentrations were higher at the time of the arrest (Busardò 2015). …”

Recreational use of GHB is associated with alterations of resting state functional connectivity of the central executive and default mode networks

“…Gamma‐hydroxybutyrate acid (GHB) is a central nervous system depressant that has a mixed stimulant‐sedative effect (Bosch et al, ; Korf, Nabben, Benschop, Ribbink, & Van Amsterdam, ). Its capacity to induce euphoria, sociability, sexual arousal (in low doses), but also relaxation and altered states of consciousness (in higher doses), are accountable for its use as a recreational drug (Bosch et al, ; European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), ; Korf et al, ; Liechti et al, ). Despite the modest prevalence of GHB‐use in the population, GHB overdose with GHB‐induced coma is still the fourth most common drug‐related cause for emergency attendances in Europe (EMCDDA, ; Liakoni, Walther, Nickel, & Liechti, ; Miró et al, ; United Nations Office on Drugs and Crime, ).…”