Prescription stimulants such as Ritalin and Adderall are widely used to treat attention deficit hyperactivity disorder (ADHD), including in children. In the U.S., about 3.5 million children ages 3 to 17 are taking an ADHD medication, a number that has increased as more children are diagnosed with the neurodevelopmental disorder.
Stimulant drugs have long been thought to treat ADHD by acting on areas of the brain that control attention, but a new study by researchers at Washington University School of Medicine in St. Louis challenges that thinking. Led by Benjamin Kay, MD, PhD, assistant professor of neurology, and Nico U. Dosenbach, MD, PhD, the David M. & Tracy S. Holtzman Professor of Neurology, it shows for the first time that these drugs act primarily on the brain’s reward and alertness centers, rather than its attentional circuitry.
The findings, published on December 24 at Cellsuggest that prescription stimulants enhance performance by making people with ADHD more alert and interested in tasks, rather than directly improving their ability to focus. The researchers also found that the stimulant drugs produced patterns of brain activity that mimicked the effect of good sleep, reversing the effects of sleep deprivation on brain activity.
“I prescribe a lot of stimulants as a pediatric neurologist, and I’m always taught that they facilitate attentional systems to give people more voluntary control over what they pay attention to,” said Kay, who treats patients at St. Louis Children’s Hospital. “But we’ve shown that’s not the case. Instead, the improvement we see in attention is a secondary effect of the child being more alert and finding a task more rewarding, which naturally helps them pay more attention to it.”
Kay said the findings point to the importance of addressing insufficient sleep in addition to considering stimulant medications for children being evaluated for ADHD.
Unexpected brain activity
To understand how stimulant drugs affect the brain, the research team looked at resting-state functional magnetic resonance imaging or fMRI data — a type of neuroimaging that indicates a person’s brain activity when not engaged in a specific task — from 5,795 children ages 8 to 11 who participated in the Adolescent Cognitive Brain Development (ABCD) Study. The ABCD study is a long-term, multicenter study tracking the neurodevelopment of more than 11,000 children from across the US, including a site based at WashU Medicine.
The researchers analyzed fMRI scans and compared brain connectivity patterns between children who received prescription stimulants and children who did not on the day of the scan. Compared to children who did not take stimulants, children who received stimulants on the day of the scan showed increased activity in areas of the brain associated with arousal or alertness and areas that predict how rewarding an activity will be. Their scans did not show significantly increased activity in areas classically associated with attention.
The researchers validated their observation in an experiment in five healthy adults without ADHD who were not normally taking stimulant medication. Participants were scanned using resting-state fMRI before and after receiving a dose of a stimulant drug, allowing precise measurement of changes in brain connectivity. The researchers again found that arousal and reward centers in the brain, not attention centers, were activated by the drugs.
Essentially, we discovered that stimulants pre-reward our brains and allow us to continue working on things we normally don’t care about – like our least favorite subject at school, for example.’
Nico U. Dosenbach, MD, PhD, the David M. & Tracy S. Holtzman Professor of Neurology
In other words, the study’s findings suggest that rather than “lighting up” a child with ADHD’s attention centers, the stimulant drugs work by helping to make activities that the child normally has trouble focusing on feel relatively more rewarding, he noted. This extra motivation helps children continue with challenging activities as well as tedious tasks.
“These results also provide a possible explanation for how stimulants treat hyperactivity, which previously seemed paradoxical,” Dosenbach added. “Anything that kids can’t focus on—those tasks that make them anxious—are tasks that don’t reward them. In a stimulant, they can sit better because they’re not getting up to find something better to do.”
Stimulants, ADHD and sleep
Compared to ADHD children who did not receive a stimulant, ADHD children who received a stimulant had better grades in school (as reported by their parents) and performed better on cognitive tests given as part of the ABCD study. Children with more severe ADHD showed the greatest gains in cognitive outcomes associated with taking prescription stimulants.
Despite their significant effects on brain activity, the researchers found that stimulant drugs were not associated with cognitive benefits in all children who took them. Children who slept less than the recommended nine or more hours a night and took a stimulant got better grades in school than children who did not get enough sleep and did not take a stimulant. However, stimulants did not translate into improved performance for neurotypical children who got enough sleep. (It is not clear why these children were taking stimulant medication.) That is, stimulants were associated with improved cognitive performance only for participants with ADHD or those who did not get enough sleep.
“We saw that if a participant didn’t get enough sleep, but took a stimulant, the brain signature of insufficient sleep was erased, as were the associated behavioral and cognitive declines,” Dosenbach said.
The authors noted that this boost in performance despite sleep deprivation may come at a long-term cost.
“Not getting enough sleep is always bad for you, and it’s especially bad for kids,” Kay said. He noted that children who are overtired may show classic ADHD symptoms, such as difficulty paying attention in class or dropping grades, leading to a misdiagnosis in some cases when the real culprit is sleep deprivation. The stimulant drug may then appear to help by mimicking some of the effects of a good night’s sleep, while still leaving the child vulnerable to the long-term effects of sleep deprivation. Kay urged clinicians to consider sleep deprivation as a factor in ADHD diagnoses and explore strategies or treatments to enhance children’s sleep.
Dosenbach and Kay’s results point to the need for future studies on the potential long-term effects of stimulants on brain function. The researchers noted that these drugs could have a restorative effect by activating the brain’s waste-clearing system during wakefulness, but they are just as likely to cause permanent damage if used to make up for chronic sleep deficits.
Kay BP, Wheelock MD, Siegel JS, Raut R, Chauvin RJ, Metoki A, Rajesh A, Eck A, Pollaro J, Wang A, Suljic V, Adeyemo B, Baden NJ, Scheidter KM, Monk JS, Whiting FI, Ramirez-Perez RT Shiremen, TervoaC Hermosillo RJM, Nelson SM, Hendrickson TJ, Madison T, Moore LA, Miranda-DomÃnguez O, Randolph A, Feczko E, Roland JL, Nicol GE, Laumann TO, Marek S, Gordon EM, Raichle ME, Barch DM, and FairDAch Stimulant drugs affect arousal and reward, not attentional networks. Cell. 24 December 2025. DOI: 10.1016/j.cell.2025.11.039
This work was supported by NIH grants NS140256 (EMG, NUFD), EB029343 (MW), MH121518 (SM), MH129493 (DMB), NS123345 (BPK), NS098482 (BPK), DA04121482 (DAF), DA04121404 (DAF) MH115357 (DAF), MH096773 (DAF and NUFD), MH122066 (EMG, DAF and NUFD), MH121276 (EMG, DAF and NUFD), MH124567 (EMG, DAF and NUFD), and NSAF211 (NUFD) from the National Spastic Dysphonia Association (EMG); from the Mallinckrodt Institute of Radiology pilot funding (EMG). by the Andrew Mellon Predoctoral Fellowship from the Dietrich School of Arts & Sciences, University of Pittsburgh (BTC); and by the Extreme Science and Engineering Discovery Environment (XSEDE) Bridges at the Pittsburgh Supercomputing Center through grant TG-IBN200009 (BTC).
Calculations were performed using the University of Washington’s Research Computing and Informatics Facility (RCIF). RCIF has received funding from NIH S10 program grants: 1S10OD025200-01A1 and 1S10OD030477-01.
This article reflects the view of the authors and may not reflect the views or opinions of the NIH or ABCD consortium investigators.
Source:
Journal Reference:
