A new study published in Neuropsychopharmacology provides preliminary evidence that amlodipine, a widely used medication for high blood pressure, may help manage symptoms of attention-deficit/hyperactivity disorder (ADHD). In a series of experiments using animal models and human genetic data, researchers found that amlodipine reduced hyperactivity and impulsivity—key features of ADHD—while also demonstrating potential advantages over current stimulant medications. The findings suggest that this well-tolerated drug could serve as a foundation for a new type of non-stimulant treatment for the condition.
ADHD is a common neurodevelopmental condition that typically emerges in childhood and can persist into adulthood. It is characterized by persistent symptoms of inattention, hyperactivity, and impulsivity that interfere with daily life, academic achievement, work performance, and social relationships. ADHD affects an estimated 2 to 5 percent of the global population and is associated with a higher risk of other mental health problems, including mood and anxiety disorders, substance use, and even suicide.
Current treatments for ADHD typically involve stimulant medications such as methylphenidate or amphetamines. These drugs can be effective for many people, but they are also associated with several drawbacks. Side effects like insomnia, appetite loss, headaches, and increased blood pressure are common. There is also a potential for misuse, especially in adolescents and young adults. Importantly, about 25 percent of individuals with ADHD do not experience adequate symptom relief from any available medication. These limitations have driven researchers to explore new therapeutic options that are both effective and better tolerated.
Researchers at 3Z Pharmaceuticals in Iceland sought to identify a non-stimulant medication that could offer an alternative for individuals who do not respond well to existing treatments. They focused on amlodipine, a widely used drug for treating high blood pressure, because it targets L-type calcium channels—proteins in the brain that help regulate electrical activity in neurons and are increasingly recognized as playing a role in neuropsychiatric disorders.
The researchers hypothesized that modulating these calcium channels could help alleviate the symptoms of ADHD. Their goal was to determine whether amlodipine, which already has a strong safety record, could be repurposed as a novel treatment for the disorder. Their strategy was to integrate findings across multiple experimental systems—including behavioral testing in rats and zebrafish, pharmacological and brain imaging studies, and human genetic analyses.
“At 3Z, we developed a high-throughput behavioral screening platform for drug discovery, using genetically engineered zebrafish models,” explained corresponding author Karl Ægir Karlsson, the CEO of 3Z and a professor of neuroscience at Reykjavik University. “The platform is built to detect therapeutic effects across a wide range of neuropsychiatric disorders with a behavioral phenotype. ADHD was a natural fit: it’s highly prevalent, current medications have significant limitations — including adverse effects and a large non-responder group — and there’s a clear need for novel therapeutics.”
“Crucially, we also engineered a robust zebrafish model of ADHD that exhibits core behavioral symptoms like hyperactivity and impulsivity. These symptoms are reversed by existing ADHD medications, giving us a solid positive control and validating the model’s predictive power. With this in place, we were positioned to conduct an unbiased drug repurposing screen to identify compounds with improved efficacy or safety profiles.”
In the first part of the study, researchers tested five drug candidates in rats bred to exhibit ADHD-like hyperactivity. Among the options, only amlodipine consistently reduced hyperactive behaviors, particularly in female rats. These effects were observed after 30 days of treatment and were confirmed through objective measures such as distance traveled and time spent moving. Other compounds tested did not show significant effects.
To extend their findings to another species, Karlsson and his colleagues examined how amlodipine affected behavior in zebrafish with a genetic mutation linked to impulsivity and hyperactivity. Zebrafish are a useful model for studying brain function, as they share a large proportion of their genes with humans. In this experiment, the researchers used a behavioral task designed to measure impulsive actions. They found that amlodipine significantly reduced premature responses in the zebrafish, indicating improved impulse control. The results were comparable to those produced by methylphenidate.
The researchers then explored whether amlodipine could enter the brain and influence neural activity. They confirmed that the drug crosses the blood-brain barrier in both zebrafish and rats. In zebrafish, exposure to amlodipine reduced activation of a brain region involved in regulating attention and behavior, as indicated by a drop in the expression of a protein called c-Fos. These results suggest that the behavioral effects of amlodipine are likely due to its direct action on the brain, not just its effects on blood pressure.
“The magnitude and consistency of amlodipine’s behavioral effects in our ADHD model were unexpected, given the widespread assumption that the drug does not significantly cross the blood-brain barrier (BBB),” Karlsson told PsyPost. “This posed a challenge in interpreting our data: the effects were too robust to plausibly arise from peripheral mechanisms alone.”
“Applying Occam’s Razor, the most straightforward explanation was that amlodipine does in fact reach the brain. We confirmed this directly using unbound brain-to-plasma partition coefficient assays across multiple species, including zebrafish, mice, and rats. These assays demonstrated that amlodipine does cross the BBB, at levels consistent with central nervous system (CNS) activity.”
To understand how these findings might apply to humans, the researchers conducted genetic analyses using large datasets. One analysis used a technique called Mendelian randomization to explore whether genetic variations that affect calcium channels are linked to ADHD. The results showed a significant association between ADHD and several subunits of L-type calcium channels—the same ones targeted by amlodipine. This supports the idea that these channels may play a role in ADHD symptoms and could be a meaningful treatment target.
A second genetic analysis looked at data from the UK Biobank, a large-scale health database with genetic and health information from over 500,000 participants. Individuals with a higher genetic risk for ADHD were more likely to report mood swings and risk-taking behavior. However, among those taking amlodipine, these tendencies were less common, suggesting that the drug may help manage some core features of ADHD even outside of a clinical diagnosis.
“We identified amlodipine, a commonly prescribed calcium channel blocker for hypertension, as a candidate for repurposing in ADHD,” Karlsson said. “Our findings suggest that it targets a previously underappreciated mechanism in the brain relevant to attention and impulse control. This is significant because it shows how existing medications, already well-characterized in terms of safety and pharmacology, can be redirected to address unmet needs in psychiatric disorders — potentially reducing the time and cost of drug development.”
The researchers emphasize that while these findings are promising, amlodipine is not yet approved for ADHD treatment and further testing in clinical trials is necessary. Still, the drug’s long-standing safety record and widespread availability make it an appealing candidate for repurposing. Amlodipine is already approved by the Food and Drug Administration, is inexpensive, and has a low risk of drug interactions.
One strength of the study was its multi-pronged approach, which combined laboratory experiments with large-scale human genetic data. By showing consistent effects across species and methods, the researchers were able to build a compelling case for further investigation. The study also introduced a new way of using genetic tools to assess drug effects across multiple biological targets, an approach that could help accelerate drug discovery for other brain disorders.
However, the research is not without limitations. The animal studies, while informative, do not fully capture the complexity of human ADHD, which involves a wide range of behavioral and cognitive symptoms. Additionally, the genetic analyses relied on self-reported symptoms and indirect measures of ADHD traits rather than formal diagnoses. Future clinical studies will be needed to determine whether the benefits of amlodipine extend to diagnosed individuals and how the drug compares to existing treatments in real-world settings.
“While amlodipine shows promise in preclinical models, it is not currently suitable for use in ADHD in its marketed form,” Karlsson noted. “Further optimization through chemical modification is necessary to enhance CNS selectivity and ensure a favorable therapeutic index in the context of ADHD.”
The researchers are now preparing to launch a Phase II clinical trial to formally evaluate the safety and effectiveness of amlodipine for ADHD in humans. If successful, this effort could pave the way for a new class of non-stimulant treatments, offering hope to individuals who do not respond to or cannot tolerate current medications.
“While the spotlight is on amlodipine and ADHD, this work also represents a proof-of-concept for a broader drug repurposing pipeline for CNS disorders,” Karlsson said. “Our approach combines unbiased screening in disease-relevant zebrafish models with human genetic validation to prioritize and de-risk candidates before clinical development. This dual strategy can accelerate the discovery of novel CNS therapeutics by leveraging known molecules in new ways — a particularly attractive proposition in an area where traditional drug development has often struggled.”
The study, “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,” was authored by Haraldur Þorsteinsson, Hannes A. Baukmann, Hildur S. Sveinsdóttir, Dagmar Þ. Halldórsdóttir, Bartosz Grzymala, Courtney Hillman, Jude Rolfe-Tarrant, Matthew O. Parker, Justin L. Cope, Charles N. J. Ravarani, Marco F. Schmidt, and Karl Karlsson.
