A small crossover trial found faster and less variable responses after lisdexamfetamine, while guanfacine increased response variability. The single-dose schedule and timing of testing limit what this comparison can say about longer-term treatment with either medicine.
El Masri and colleagues tested 22 children and adolescents with ADHD after lisdexamfetamine, extended-release guanfacine and placebo in a randomized, double-blind crossover design with weekly washouts. Tasks assessed attention, inhibition and time discrimination. A typically developing comparison group was tested once without medication.
The investigators combined reaction-time measures across tasks and assessed the coefficient of variation, which expresses variability relative to average response time. This variability index and mean speed describe different aspects of performance; one should not substitute for the other.
Lisdexamfetamine improved composite mean reaction time and response-time variability compared with placebo and guanfacine. Guanfacine worsened variability relative to placebo. These reported pairwise comparisons used false-discovery-rate correction.
The main analyses for time-discrimination errors and continuous-performance-task omission errors did not reach significance, despite moderate to large estimated effects. Those findings remain uncertain rather than confirmed additional benefits. The study does not support describing every tested cognitive function as improved.
Neurocognitive testing occurred about three hours after medication. The authors noted that this schedule preceded guanfacine’s expected peak and might favor lisdexamfetamine. They also emphasized that a single-dose guanfacine challenge differs from treatment over the longer period needed to evaluate its behavioral effects.
The sample was small and selected, and acute laboratory performance does not establish comparative long-term effectiveness, school outcomes or tolerability. A null finding can reflect limited precision, but that possibility does not convert it into a positive result. These are cognitive-task responses after prescribed study doses, not validated blood-concentration or individual driving-impairment measures.
Read our analysis of plasma dexamphetamine levels and cognitive scores.
Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD. doi:10.3389/fpsyt.2025.1676472.