Abstract
<title>Abstract</title> <p> <bold>Background:</bold> Lisdexamfetamine is a long-acting amphetamine-based prodrug widely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Its gradual conversion into dextroamphetamine provides a predictable pharmacokinetic profile, but its sympathomimetic activity may affect cardiovascular parameters, particularly heart rate, blood pressure, and electrocardiographic findings. This systematic review aimed to synthesize the available evidence on the cardiovascular effects and safety of lisdexamfetamine in individuals with ADHD and healthy volunteers. <bold>Methods:</bold> This systematic review was conducted according to PRISMA 2020 recommendations and prospectively registered in PROSPERO. Searches were performed in PubMed/MEDLINE, Embase, Cochrane Library, Google Scholar, and SciELO for studies published between January 2000 and March 2026. Eligible studies included clinical trials, open-label extension studies, observational studies, pharmacokinetic/pharmacodynamic studies, case reports, and systematic reviews reporting cardiovascular outcomes or safety data related to lisdexamfetamine. Study selection was performed in Rayyan, and risk of bias was assessed using tools appropriate to each study design, including RoB 2, the Newcastle–Ottawa Scale, and AMSTAR 2. <bold>Results:</bold> A total of 727 records were identified, of which 99 duplicates were removed. After screening 628 titles and abstracts, 70 full-text reports were assessed for eligibility, and 20 studies were included in the final synthesis. Across pediatric, adult, and healthy volunteer populations, lisdexamfetamine was consistently associated with small mean increases in heart rate, generally ranging from 4 to 7 beats per minute, and modest increases in systolic and diastolic blood pressure, usually between 1 and 4 mmHg. Available studies did not show consistent evidence of clinically meaningful QTc prolongation or a significant increase in serious cardiovascular adverse events. However, most clinical studies excluded individuals with relevant cardiovascular disease or uncontrolled hypertension, limiting the generalizability of these findings to higher-risk populations. <bold>Conclusions:</bold> Lisdexamfetamine appears to have an overall favorable cardiovascular safety profile in selected and clinically monitored populations. Its main cardiovascular effects are modest increases in heart rate and blood pressure, consistent with its sympathomimetic mechanism. Nevertheless, individualized cardiovascular assessment and regular monitoring remain necessary, especially during long-term treatment and in patients with pre-existing cardiovascular risk factors. </p>