Nocturnal Gamma-Hydroxybutyrate Reduces Cortisol-Awakening Response and Morning Kynurenine Pathway Metabolites in Healthy Volunteers

Abstract

Background Gamma-hydroxybutyrate (GHB; or sodium oxybate) is an endogenous GHB-/gamma-aminobutyric acid B receptor agonist. It is approved for application in narcolepsy and has been proposed for the potential treatment of Alzheimer’s disease, Parkinson’s disease, fibromyalgia, and depression, all of which involve neuro-immunological processes. Tryptophan catabolites (TRYCATs), the cortisol-awakening response (CAR), and brain-derived neurotrophic factor (BDNF) have been suggested as peripheral biomarkers of neuropsychiatric disorders. GHB has been shown to induce a delayed reduction of T helper and natural killer cell counts and alter basal cortisol levels, but GHB’s effects on TRYCATs, CAR, and BDNF are unknown. Methods Therefore, TRYCAT and BDNF serum levels, as well as CAR and the affective state (Positive and Negative Affect Schedule [PANAS]) were measured in the morning after a single nocturnal dose of GHB (50 mg/kg body weight) in 20 healthy male volunteers in a placebo-controlled, balanced, randomized, double-blind, cross-over design. Results In the morning after nocturnal GHB administration, the TRYCATs indolelactic acid, kynurenine, kynurenic acid, 3-hydroxykynurenine, and quinolinic acid; the 3-hydroxykynurenine to kynurenic acid ratio; and the CAR were significantly reduced (P < 0.05–0.001, Benjamini-Hochberg corrected). The quinolinic acid to kynurenic acid ratio was reduced by trend. Serotonin, tryptophan, and BDNF levels, as well as PANAS scores in the morning, remained unchanged after a nocturnal GHB challenge. Conclusions GHB has post-acute effects on peripheral biomarkers of neuropsychiatric disorders, which might be a model to explain some of its therapeutic effects in disorders involving neuro-immunological pathologies. This study was registered at ClinicalTrials.gov as NCT02342366.

Towards Extending the Detection Window of Gamma-Hydroxybutyric Acid—An Untargeted Metabolomics Study in Serum and Urine Following Controlled Administration in Healthy Men

“…MS/MS experiments were performed on selected samples in addition to full scan analysis for identification purposes. Serum and urine samples collected after randomized, placebo-controlled, crossover administration of GHB [ 25 ] were analyzed in randomized order and analytical performance controlled by regular system suitability tests (SST) and pooled plasma quality control samples (QC). Mean coefficients of variation (%CV) values of all compounds in the SST and median CV of all features exceeding 500 cps in the QC were within our acceptance criteria of <30% in all four methods.…”

“…Serum samples from 20 male volunteers were collected prior to the intake of the study medication at night in the middle of a sleep episode (t0) and then 4 h (t1) and 16.5 h (t2) after. Urine was sampled in the morning, approximately 4.5 h after GHB or placebo intake (Ut1) [ 25 ]. Additionally, early morning urine samples from an initial GHB pilot study from 15 male volunteers, where the study medication was administered in the evening prior to sleep, were collected in the morning, approximately 8 h after dosing (Ut2).…”

“…The study used a randomized, balanced, double-blinded placebo-controlled crossover design given in detail in reference [ 25 ]. It was approved by the Cantonal Ethics Committee of Zurich (BASEC nr.…”

Subacute changes in brain functional network connectivity after nocturnal sodium oxybate intake are associated with anterior cingulate GABA/glutamate balance

“…To allow for habituation to the sleep laboratory setting, each experimental night was preceded by an adaptation night. Apart from the here presented post-sleep fMRI RSN results, GHB effects on sleep neurophysiology [31], kynurenine pathway metabolites [33], and post-awakening brain metabolite signals and vigilance [34] were also assessed in the experiment and published elsewhere.…”

Effects of general versus subarachnoid anaesthesia on circadian melatonin rhythm and postoperative delirium in elderly patients undergoing hip fracture surgery: A prospective cohort clinical trial

“…Each p-value is then multiplied by the number of tests and divided by its rank [36,37]. Although the Benjamini-Hochberg procedure may provide less stringent control of Type I errors compared to familywise error rate controlling procedures, it was applied to the multiple analysis of cortisol data in another study, in which the sampling protocol was similar to that used in the present study, and the cortisol levels were dynamically measured at five equally spaced time points [38]. All analyses were performed using SPSS software, version 25.0 (SPSS Inc., USA) or Prism 8 software (GraphPad, USA).…”