Reinventing amlodipine.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, and pharmacological treatments have limited mechanistic specificity. Most nonstimulants target noradrenergic tone but show modest efficacy. l-Type calcium channels (LTCCs) modulate neuronal excitability, catecholaminergic transmission, cortical plasticity, and neuroinflammation, processes central to ADHD pathophysiology. This review evaluates the evidence for repurposing the LTCC blocker amlodipine as a novel ADHD therapeutic. We propose a mechanistic framework where amlodipine acts within attention/arousal circuits to stabilize dopaminergic and noradrenergic tone, restore D2-autoreceptor feedback, enhance plasticity, and reduce neuroinflammation. This systems-level model provides explanatory links between drug action and ADHD pathophysiology, highlighting therapeutic avenues not addressed by current treatments. Contrary to historical assumptions, recent evidence confirms that amlodipine penetrates the blood-brain barrier. Convergent preclinical findings show phenotype rescue in zebrafish and rat models of ADHD, accompanied by normalization of ADHD-relevant metabolic pathways. Complementary biobank analyses suggest reduced traits associated with ADHD among genetically at-risk individuals taking amlodipine. Given enantiomeric pharmacology, S-amlodipine, with higher LTCC affinity and fewer off-target liabilities than R-amlodipine, emerges as a preferred candidate. Together, these findings warrant a reappraisal of LTCC modulation in ADHD. By providing mechanistic explanations of how amlodipine engages ADHD-relevant circuits, this review clarifies its therapeutic potential and reshapes our understanding of the drug itself, with implications for repurposing, enantiomer-specific development, and broader clinical translation. We outline next steps, including comparative S- versus R-amlodipine studies, mechanistic dissection of LTCC subtypes in attentional networks, and controlled clinical testing to evaluate amlodipine's viability as a nonstimulant therapeutic. SIGNIFICANCE STATEMENT: Genetic, preclinical, and translational evidence implicates dysregulated l-type calcium channel signaling in attention-deficit/hyperactivity disorder, providing a mechanistic rationale for evaluating amlodipine as a therapeutic candidate. S-amlodipine is the rational development form, as it mediates the principal l-type calcium channel activity, whereas R-amlodipine may contribute to nonbeneficial brain or tolerability effects. This review defines a clear translational path focused on S-amlodipine, warranting prospective, dose-optimized clinical trials to determine efficacy on attentional and executive dysfunction with acceptable safety.