Nocturnal sodium oxybate increases the anterior cingulate cortex magnetic resonance glutamate signal upon awakening

Summary Clinical guidelines recommend sodium oxybate (SXB; the sodium salt of γ‐hydroxybutyrate) for the treatment of disturbed sleep and excessive daytime sleepiness in narcolepsy, yet the underlying mode of action is elusive. In a randomised controlled trial in 20 healthy volunteers, we aimed at establishing neurochemical changes in the anterior cingulate cortex (ACC) following SXB‐enhanced sleep. The ACC is a core neural hub regulating vigilance in humans. At 2:30 a.m., we administered in a double‐blind cross‐over manner an oral dose of 50 mg/kg SXB or placebo, to enhance electroencephalography‐defined sleep intensity in the second half of nocturnal sleep (11:00 p.m. to 7:00 a.m.). Upon scheduled awakening, we assessed subjective sleepiness, tiredness and mood and measured two‐dimensional, J‐resolved, point‐resolved magnetic resonance spectroscopy (PRESS) localisation at 3‐Tesla field strength. Following brain scanning, we used validated tools to quantify psychomotor vigilance test (PVT) performance and executive functioning. We analysed the data with independent t tests, false discovery rate (FDR) corrected for multiple comparisons. The morning glutamate signal (at 8:30 a.m.) in the ACC was specifically increased after SXB‐enhanced sleep in all participants in whom good‐quality spectroscopy data were available ( n = 16; p FDR < 0.002). Further, global vigilance (10th–90th inter‐percentile range on the PVT) was improved ( p FDR < 0.04) and median PVT response time was shorter ( p FDR < 0.04) compared to placebo. The data indicate that elevated glutamate in the ACC could provide a neurochemical mechanism underlying SXB's pro‐vigilant efficacy in disorders of hypersomnolence.