Validation of L-Type Calcium Channel Blocker Amlodipine As a Novel ADHD Treatment Through Cross-Species Analysis, Drug-Target Mendelian Randomization, and Clinical Evidence from Medical Records

ADHD is a chronic neurodevelopmental disorder which significantly affects life outcomes. First-line treatments carry the risk of adverse side effects and present a high abuse potential, coupled with a 25% rate of non-response, necessitating novel treatments. Here, we validate amlodipine as an ADHD treatment using model rats and zebrafish and human genetic data. Amlodipine reduced hyperactivity in the Open Field Test in SHR rats and reduced both hyperactivity and impulsivity in the 5-Choice Serial Reaction Time Task in adgrl3.1-/- zebrafish. We show that amlodipine also passes the blood brain barrier and reduces telencephalic activation. Mendelian Randomization analysis using human genetic data revealed significant associations between ADHD and genetic variations in the subunits of L-type calcium channels (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3), and the combined genes targeted by amlodipine. Finally, we show that amlodipine mitigates key ADHD symptoms in a cohort of people with a high ADHD genetic liability. Given its well-tolerated profile, its efficacy in mitigating both hyperactivity and impulsivity across different species, coupled with genetic evidence from human data, the potential utility of amlodipine as a novel treatment for human ADHD is compelling.### Competing Interest StatementK.K., H.TH., H.S.S., D.H., and B.G. are employees of 3Z Pharma. H.A.B., J.L.C., and M.F.S are employees of biotx.ai GmbH.### Funding Statement3Z is supported by Icelandic Technology Development Fund grant no. 2220781-601. The research work at biotx.ai GmbH was supported by the Investitionsbank des Landes Brandenburg (ILB), the European Regional Development Fund (ERDF), and the European Social Fund+ (ESF+). The research has been conducted using the UK Biobank Resource under Application no. 36226.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The research has been conducted using the UK Biobank Resource and has been approved by the UK Biobank under Application no. 36226I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors