Abstract
Introduction Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that can persist from childhood into adulthood. Stimulant medications such as methylphenidate and amphetamine derivatives are the mainstay of treatment, yet their potential immunomodulatory effects remain unclear. While most upper respiratory tract infections (URTIs) are benign and self-limiting, some may result in healthcare visits and lost productivity. Proposed mechanisms linking stimulant use to infection risk include sympathetic nervous system activation, hypothalamic-pituitary-adrenal axis modulation, stimulant-induced insomnia, and reduced salivary flow - all of which may impair mucosal immunity. This study aimed to evaluate whether stimulant medication use in ADHD is associated with increased risk of URTIs using a large real-world dataset. Methods We performed a retrospective cohort study using the TriNetX research network, which aggregates de-identified electronic health records from 149 healthcare organizations worldwide (>170 million patients). ADHD patients were identified by International Classification of Diseases, 10th Revision (ICD-10) codes F90.0-F90.2. Two cohorts were defined: ADHD patients without stimulant prescriptions (control; n = 1,798,001) and ADHD patients prescribed stimulants (medication cohort; n = 1,099,756; amphetamine, dextroamphetamine, lisdexamfetamine, methylphenidate, modafinil, or dexmethylphenidate). We did not include antidepressants and antipsychotics in the cohorts or in their comparison. The outcome was a diagnosis of URTI (ICD-10 J00-J06). Risk estimates, Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazards modeling were performed within TriNetX, with significance set at p < 0.05. Results A total of 2,897,757 ADHD patients were included (mean age 21.2 ± 15 years; 42.1% female). URTI incidence was higher in the medication cohort (31.2%, n = 343,385) than in controls (28.5%, n = 512,849). Stimulant exposure was associated with increased URTI risk: risk difference 0.027 (95% confidence interval (CI): 0.026-0.028; p < 0.001), risk ratio 1.095 (95% CI: 1.091-1.099), and odds ratio 1.138 (95% CI: 1.132-1.144). Kaplan-Meier analysis demonstrated significantly lower URTI-free survival in medicated patients (log-rank χ² = 2285.0; p < 0.001). The hazard ratio for URTI in the medicated cohort was 1.111 (95% CI: 1.106-1.116; p < 0.001). Median survival without URTI was 3757 days in controls versus 3176 days in the medicated group. Discussion Stimulant-treated ADHD patients exhibited an 11% higher relative risk of URTI compared with unmedicated patients. Some possible mechanisms may include immune suppression via catecholamine-mediated shifts in cytokine profiles, sleep disruption leading to impaired host defenses, and medication-induced xerostomia, reducing mucosal protection. Our findings align with prior clinical and epidemiologic studies reporting higher infection rates in ADHD populations, although prior results have been mixed. Conclusion In this large multi-institutional analysis, stimulant use in ADHD was moderately associated with increased URTI risk. These findings warrant consideration in risk-benefit discussions for ADHD treatment, particularly for patients with frequent infections or compromised immunity. Future prospective studies should explore dose-response effects, adherence, and biologic mediators to clarify causality and guide preventive strategies.