Gamma-hydroxybutyrate was introduced as an anesthetic agent in the 1960s and is still used in some countries, despite recognized disadvantages. More recently, it has emerged as a popular recreational drug. We report 3 cases of gamma-hydroxybutyrate overdose, the effects of which were reversed by the administration of low-dose intravenous physostigmine. The origins of this regimen and the case for physostigmine as a potential antidote are described.