Methylphenidate (MPH) and its active enantiomer, dexmethylphenidate, are widely prescribed as first-line therapies for attention deficit hyperactivity disorder (ADHD), yet their increasing non-medical use highlights significant clinical and toxicological challenges. MPH blocks dopamine (DAT) and norepinephrine (NET) transporters, thereby elevating synaptic catecholamine levels. While this underpins therapeutic efficacy, prolonged or abusive exposure has been associated with mitochondrial impairment, disrupted bioenergetics, and excessive reactive oxygen species (ROS) production, which collectively contribute to neuronal stress and long-term neurotoxicity. Growing evidence suggests that the gut-brain axis may critically influence MPH outcomes: diet-induced shifts in microbiome composition appear to regulate oxidative stress, neuroinflammation, and drug metabolism, opening potential avenues for dietary or probiotic interventions. From a forensic perspective, the detection and monitoring of MPH misuse require advanced methodologies, including enantioselective LC-MS/MS and analysis of alternative matrices such as hair or oral fluids, which enable retrospective exposure assessment and improves abuse surveillance. Despite its established therapeutic profile, MPH remains a compound with a narrow balance between clinical benefit and toxicological risk. Future directions should prioritize longitudinal human studies, biomarker identification for abuse monitoring, and the development of mitochondria-targeted therapies to minimize adverse outcomes and enhance safety in long-term treatment.

The Perspective presents the strategy of double chiral switches of drugs, illustrating the scenario of consecutive double chiral switches of methylphenidate. The two chirality centers of methylphenidate hydrochloride give rise to four stereoisomers grouped into two racemates, two enantiomer pairs: [(αR,2S)/(αS,2R)] (racemate a) and [(αR,2R)/(αS,2S)] (racemate b). A detailed analysis of the development, drug-regulatory approvals and the corresponding patents and trademarks of methylphenidate drugs indicated the following double chiral switches: (±)-[(αR,2R)/(αS,2S)]-methylphenidate HCl + (±)-[(αR,2S)/(αS,2R)]-methylphenidate HCl (Centedrin)→(±)-[(αR,2R)/(αS,2S)]-methylphenidate HCl (Ritalin)→(+)-(αR,2R)-methylphenidate HCl (Focalin). The analysis showed that the Food and Drug Administration approval of Ritalin in 1955 represented the first chiral switch of the mixture of two racemates to the single racemate b. In 2001, Ritalin underwent a second chiral switch to the single-enantiomer Focalin. Ritalin and Focalin developed into successful Attention-Deficit/Hyperactivity Disorder (ADHD) drugs. Notably, the single-enantiomer drug Focalin has not driven away the racemate Ritalin from ADHD markets. The notations of the active ingredients of Ritalin (methylphenidate hydrochloride) and of Focalin (dexmethylphenidate hydrochloride) are stereochemically flawed and the designations of the stereodescriptors of relative configurations erythro and threo are obsolete. The Perspective calls for correct notations of methylphenidate drugs and for future applications of the double chiral-switches strategy.

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.

Dexmethylphenidate is an isomer of methylphenidate. No information is available on the clinical use of dexmethylphenidate during breastfeeding; however, the manufacturer estimates that a fully breastfed infant would receive a relative dose of 0.2 to 0.7% of the maternal weight adjusted dose. In dosages prescribed for medical indications, limited evidence indicates that methylphenidate levels in milk are very low and not detectable in infant serum. The effects of dexmethylphenidate in milk on the neurological development of the infant have not been well studied If dexmethylphenidate is required by the mother, it is not a reason to discontinue breastfeeding.[1] It is possible that large dosages of methylphenidate might interfere with milk production, especially in women whose lactation is not well established.