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

Haraldur Porsteinsson; Hannes A. Baukmann; Hildur S. Sveinsdottir; Dagmar P. Halldorsdottir; Bartosz Grzymala; Courtney Hillman; Jude Rolfe-Tarrant; Matthew O. Parker; Justin L. Cope; Charles N. J. Ravarani; Marco F. Schmidt; Karl A. E. Karlsson

doi:10.1038/s41386-025-02062-x

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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

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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

Haraldur Porsteinsson, Hannes A. Baukmann, Hildur S. Sveinsdottir, Dagmar P. Halldorsdottir, Bartosz Grzymala, Courtney Hillman, Jude Rolfe-Tarrant, Matthew O. Parker, Justin L. Cope, Charles N. J. Ravarani, …

Neuropsychopharmacology

14/02/2025

DOI: https://doi.org/10.1038/s41386-025-02062-x

PMID: 39953207

Abstract

Neurosciences

Neurosciences & Neurology

Pharmacology & Pharmacy

Psychiatry

ADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity in adgrl3.1-/- zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (alpha 1-C; CACNA1C, beta 1; CACNB1, alpha 2 delta 3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.

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Title: 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
Creators: Haraldur Porsteinsson (Author) - 3Z,Menntavegur 1, Reykjavik, Iceland
Hannes A. Baukmann (Author) - Biotx Ai GmbH, Muhlenberg 11, Potsdam, Germany
Hildur S. Sveinsdottir (Author) - 3Z,Menntavegur 1, Reykjavik, Iceland
Dagmar P. Halldorsdottir (Author) - 3Z,Menntavegur 1, Reykjavik, Iceland
Bartosz Grzymala (Author) - 3Z,Menntavegur 1, Reykjavik, Iceland
Courtney Hillman (Author) - University of Surrey, School of Biosciences
Jude Rolfe-Tarrant (Author) - University of Surrey
Matthew O. Parker (Author) - University of Surrey, School of Biosciences
Justin L. Cope (Author) - Biotx Ai GmbH, Muhlenberg 11, Potsdam, Germany
Charles N. J. Ravarani (Author) - Biotx Ai GmbH, Muhlenberg 11, Potsdam, Germany
Marco F. Schmidt (Author) - Biotx Ai GmbH, Muhlenberg 11, Potsdam, Germany
Karl A. E. Karlsson (Corresponding Author) - Reykjavík University
Publication Details: Neuropsychopharmacology
Publisher: Springer Nature
Number of pages: 11
Publication Date: 14/02/2025
Date accepted for publication: 28/01/2025
Grant note: 3Z is supported by Icelandic Technology Development Fund grant no. 2220781-601. The research work at biotx.ai GmbH is supported by the Investitionsbank des Landes Brandenburg (ILB), the European Regional Development Fund (ERDF), and the European Social Fund+ (ESF+).
Identifiers: 99971466502346; WOS:001420953800001
Copyright: © The Author(s) 2025. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Academic Unit: School of Biosciences; Biosciences
Language: English
Resource Type: Journal article
Data Access Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

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

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