AbstractSodium oxybate (γ-hydroxybutyrate, GHB) is an endogenous GHB/GABABreceptor agonist, clinically used to promote slow-wave sleep and reduce next-day sleepiness in disorders such as narcolepsy and fibromyalgia. The neurobiological signature of these unique therapeutic effects remains elusive. Promising current neuropsychopharmacological approaches to understand the neural underpinnings of specific drug effects address cerebral resting-state functional connectivity (rsFC) patterns and neurometabolic alterations. Hence, we performed a placebo-controlled, double-blind, randomized, cross-over pharmacological magnetic resonance imaging study with a nocturnal administration of GHB, combined with magnetic resonance spectroscopy of GABA and glutamate in the anterior cingulate cortex (ACC). In sum, 16 healthy male volunteers received 50 mg/kg GHB p.o. or placebo at 02:30 a.m. to maximize deep sleep enhancement and multi-modal brain imaging was performed at 09:00 a.m. of the following morning. Independent component analysis of whole-brain rsFC revealed a significant increase of rsFC between the salience network (SN) and the right central executive network (rCEN) after GHB intake compared with placebo. This SN-rCEN coupling was significantly associated with changes in GABA levels in the ACC (pall< 0.05). The observed neural pattern is compatible with a functional switch to a more extrinsic brain state, which may serve as a neurobiological signature of the wake-promoting effects of GHB.