Effects of Etifoxine and Alprazolam on Pregnenolone, Cortisol, and 18-kDa Translocator Protein in Healthy Men: A Placebo-Controlled Study.

Authors

Marco Riebel, Lisa-Marie Brunner, Doris Melchner, Anett Dörfelt, Jens Volkmar Schwarzbach, Rainer Rupprecht, Caroline Nothdurfter

Published in

Pharmacopsychiatry. Aug 21, 2026. Epub Aug 21, 2026.

Abstract

INTRODUCTION:: The non-benzodiazepine anxiolytic etifoxine is hypothesized to act as a neurosteroidogenic agent via the 18-kDa translocator protein. In a placebo controlled design, we compared its steroidogenic effects with those of alprazolam.
METHODS:: In a double-blind within-subject design, healthy male participants (N=29) received etifoxine (150 mg/d), alprazolam (1.5 mg/d), and placebo in randomised order for 5 days. Pregnenolone expression and cortisol expression were assessed at the end of each treatment in the morning, and at four time points in the afternoon. Thrombocyte 18-kDa translocator protein expression was measured in the morning.
RESULTS:: Analysis of morning samples revealed higher 18-kDa translocator protein expression (χ ²=7.41 and p=0.025) after etifoxine intake compared to alprazolam intake (p=0.025). Both alprazolam and etifoxine were associated with lower pregnenolone levels (p<0.005). The 18-kDa translocator protein did not mediate the medication effects on pregnenolone (average causal mediation effects for etifoxine vs. placebo contrast: p=0.276). Afternoon measurements showed that alprazolam reduced cortisol (χ ²=66.76, p<0.001), and that both alprazolam and etifoxine reduced pregnenolone levels (χ ²=31.75, p<0.001). State anxiety was only marginally lowered by medication (p=0.092), and no biological markers-cortisol, pregnenolone, or 18-kDa translocator protein-predicted anxiety ratings (all p > 0.40).
CONCLUSIONS:: We confirmed the effects of benzodiazepines on cortisol and pregnenolone levels in healthy male participants. Etifoxine administration was associated with a decrease in peripheral plasma pregnenolone. Taken together, however, plasma pregnenolone levels do not seem to reflect etifoxine binding to 18-kDa translocator protein and central anxiolytic mechanisms in humans.

PMID:
42628937
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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