DARK Classics in Chemical Neuroscience: Gamma-Hydroxybutyrate (GHB).

Gamma-hydroxybutyrate (GHB) is a naturally occurring short-chain fatty acid that rose to prominence as a popular club drug in the 1990s. Originally developed as an anesthetic in the early 1960s, it was later sold as an over-the-counter dietary supplement before becoming a rising substance of abuse in the following decades as one of the "date rape" drugs. Despite its abuse potential, there has been a recent surge in therapeutic interest in the drug due to its clinical viability in the treatment of narcolepsy and alcohol abuse/withdrawal. Its interactions with the GABAergic framework of higher mammals has made it the prototypical example for the study of the chief inhibitory mechanism in the human central nervous system. Though relatively obscure in terms of popular culture, it has a storied history with widespread usage in therapeutic, recreational ("Chemsex"), and some disturbingly nefarious contexts. This Review aims to capture its legacy through review of the history, synthesis, pharmacology, drug metabolism, and societal impact of this DARK classic in chemical neuroscience.