Barbiturates for the Management of Gamma-Hydroxybutyrate (GHB) Withdrawal: A Systematic Review

Gamma-hydroxybutyrate (GHB) withdrawal is an uncommon but potentially severe syndrome which may not respond to benzodiazepines, with no clear guidelines for treatment escalation. This systematic review examines the evidence of barbiturates as alternative or adjunct therapies in managing GHB withdrawal. PubMed was searched for articles published from 1964-2025 using terms related to GHB, its precursors, withdrawal, and barbiturates. Two independent reviewers screened articles, with a third resolving discrepancies. English-language primary reports involving barbiturate use for GHB withdrawal in humans were included; reviews were excluded. Of 1,398 articles identified, 16 were included, describing 30 cases. Data were analyzed using descriptive statistics and narrative synthesis. Phenobarbital was commonly used (n = 26), with daily doses from 30-1200 mg and cumulative doses from 60-8500 mg. Barbiturates were generally initiated after inadequate response to benzodiazepines, although no consistent thresholds for escalation were identified. Barbiturate use was not associated with complications and in several cases provided rapid symptom resolution. Comparisons and conclusions were limited by incomplete and inconsistent reporting of patient characteristics, interventions, and outcomes; co-administered treatments; and non-standardized dosing across small, heterogenous, retrospective studies (primarily case reports) describing patients with severe withdrawal. Controlled studies are needed to establish evidence-based protocols, including dosing, timing, and safety considerations.