Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): Time course and severity of withdrawal in baboons

Background: 1,4-Butanediol (1,4-BD) is a gamma-hydroxybutyrate (GHB) pro-drug, with multiple commercial uses, and a drug of abuse. Although there are case reports of a withdrawal syndrome following 1,4-BD use, no studies have evaluated the physical dependence potential of 1,4-BD and characterized the time course of withdrawal. Methods: Vehicle and then 1,4-BD were administered continuously 24. h/day via intragastric catheters in male baboons (Papio anubis, n=3). Dosing was initiated at 100. mg/kg and increased by 100. mg/kg/day to 400. mg/kg. After a stabilization period, doses of 500 and then 600. mg/kg/day were each maintained for 3-4 weeks. Plasma levels of 1,4-BD and GHB were determined for each dose condition. Physical dependence was assessed via administration of a GABA-B antagonist (precipitated withdrawal test) during administration of the 600. mg/kg dose and via abrupt termination of chronic 1,4-BD administration (spontaneous withdrawal test). Outcome measures included the number of food pellets earned, performance on a fine-motor task, observed behaviors, and plasma levels of GHB and 1,4-BD. Results: Following maintenance of 1,4-BD 600. mg/kg for 3 weeks, the number of food pellets earned was significantly decreased. At the end of chronic 1,4-BD dosing, the levels of GHB in plasma ranged from 1290 to 2300. μmol/L and levels of 1,4-BD in plasma ranged from 13.1 to 37.9. μmol/L. Signs of physical dependence were observed following precipitated and spontaneous withdrawal tests. Seizures were not observed. Conclusions: These data indicate chronic 1,4-BD produced physical dependence in baboons and the withdrawal syndrome can be characterized as mild to intermediate.