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

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.