Abstract Body (Do not enter title and authors here): Background:
Centrally acting stimulants are widely prescribed for attention-deficit/hyperactivity disorder (ADHD), narcolepsy, and related neuropsychiatric conditions, but concerns persist regarding their cardiovascular safety. These agents, including amphetamines, methylphenidate, modafinil, and lisdexamfetamine, elevate sympathetic tone and may precipitate cardiac arrhythmias, including atrial fibrillation (AF) and ventricular tachyarrhythmias. Yet, published data remain inconsistent and fragmented across varying designs. We conducted a comprehensive systematic review and meta-analysis to clarify the arrhythmic risk associated with commonly prescribed stimulants.
Hypothesis:
We hypothesized that prescription stimulants are associated with increased risk of incident or recurrent cardiac arrhythmias, with variable risk based on stimulant class.
Methods:
PubMed, MEDLINE (Ovid), APA PsycINFO (Ovid), Cochrane Library, and Web of Science were searched through May, 2025. Eligible studies included randomized trials, cohort studies, and case-control designs comparing stimulant use to either no stimulant or an alternative, reporting adjusted effect estimates for arrhythmia. Two reviewers screened all records (κ = 0.78), extracted data, and assessed the risk of bias using the ROBINS-I tool. Adjusted odds, rates, and hazard ratios were converted to log-HRs and pooled using random-effects models. Between-study heterogeneity was quantified using I^2 and τ^2 ; publication bias was assessed by funnel plot.
Results:
Fourteen studies (N = 3,660,068) met the inclusion criteria. Overall stimulant use was associated with an 83% increased risk of arrhythmia (HR 1.83; 95% CI 1.34–2.50; I^2=97.6%). Amphetamines showed the highest risk (HR 2.67; 95% CI 1.41–5.06; I^2=97.6%), followed by methylphenidate (HR 1.65; 95% CI 1.24–2.21; I^2=87.8%). Sudden cardiac death or ventricular fibrillation (N=882,629) did not reach statistical significance (HR 1.45; 95% CI 0.90–2.32; I^2=68.4%). Funnel plots appeared symmetric, and meta-regression showed no substantial influence of sample size on effect estimates.
Conclusion:
All major stimulant subclasses were significantly associated with increased arrhythmia risk, with the highest risk observed in amphetamines. These findings emphasize the potential cardiovascular consequences of stimulant therapy and reinforce the need for ongoing cardiac monitoring. Further research is warranted to delineate the safety profiles of individual stimulant medications.