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

D A Dornbierer, M Boxler, C D Voegel, B Stucky, A E Steuer, T M Binz, M R Baumgartner, D M Baur, B B Quednow, T Kraemer, E Seifritz, H P Landolt, O G Bosch, D A Dornbierer, M Boxler, C D Voegel, B Stucky, A E Steuer, T M Binz, M R Baumgartner, D M Baur, B B Quednow, T Kraemer, E Seifritz, H P Landolt, O G Bosch

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.

Keywords: BDNF; GHB; Gamma-hydroxybutyrate; TRYCATS; cortisol; kynurenine pathway; neuroinflammation; neuropsychiatric disorders.

© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Session design. Abbreviations: BDNF, brain-derived neurotrophic factor; CAR, cortisol-awakening response; GHB, gamma-hydroxybutyrate; TRYCATs, tryptophan catabolites.
Figure 2.
Figure 2.
TRYCATs serum concentrations at 3 h post-awakening/7.5 h post–GHB challenge with placebo vs GHB. *P < .05, **P < .01, ***P < .001 (Benjamini-Hochberg correction). Abbreviations: 3HK, hydroxykynurenine; GHB, gamma-hydroxybutyrate; KYNA, kynurenic acid; TRYCATs, tryptophan catabolites.
Figure 3.
Figure 3.
Cortisol-awakening response at 3 h post-awakening/7.5 h post–GHB challenge with placebo vs GHB. *P < .05, **P < .01 (Benjamini-Hochberg correction). Abbreviations: GHB, gamma-hydroxybutyrate.
Figure 4.
Figure 4.
BDNF serum levels at 3 h post-awakening/7.5 h post–GHB challenge with placebo vs GHB. Abbreviations: BDNF, brain-derived neurotrophic factor; GHB, gamma-hydroxybutyrate; NS, not signficant.

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