Fundam Clin Pharmacol. 2026 May;40(3):e70092. doi: 10.1111/fcp.70092.
ABSTRACT
Psychotropic medicines are known to impair cognitive function acutely, but the specific effects of individual substances remain underexplored. This study investigates the effects of dexamphetamine and zolpidem on cognitive performance to quantify the potential risk of intake and their pharmacokinetic and pharmacodynamic relationship. This randomized, double-blind, placebo-controlled trial (EudraCT 2021-005381 – 17) included 60 healthy men aged 26 ± 5 (mean ± SD) years. Participants received a single oral dose of 30-mg dexamphetamine, 5-mg zolpidem, or placebo (n = 20 per group). Cognitive performance was assessed at baseline and 3 and 8 h after dosing using the computerized Psytest system. Dexamphetamine and zolpidem improved sustained attention, with significant reduction of omissions at 8 h. Reaction time improved in both groups, but zolpidem impaired phasic alertness. Working memory remained unchanged. Plasma concentration of dexamphetamine and zolpidem was 70.8 ± 10.4 ng/mL and 39.0 ± 20.7 ng/mL at 3 h and 45.9 ± 7.9 ng/mL and 8.7 ± 6.6 ng/mL at 8 h, respectively. No correlation between drug plasma concentration and cognitive performance measures was demonstrable. Dexamphetamine caused the strongest subjective effects and highest liking ratings, whereas zolpidem elicited greater subjective dislike. Tolerability was best with placebo, followed by zolpidem and dexamphetamine. Single therapeutic doses of dexamphetamine and zolpidem modestly affected cognitive function 3 h after intake, with no relationship between cognitive performance and the study medicines’ plasma concentration. Both medicines improve cognition after 8 h but differed in subjective emotional effects. Nevertheless, generalizability is limited by the inclusion of healthy men only. Trial Registration: EudraCT: Nr: 2021-005381-17.
PMID:42087266 | DOI:10.1111/fcp.70092
