ADHD drugs don’t work the way we thought

For decades, stimulant medications have been thought to work by directly influencing brain regions responsible for attention. New research from Washington University School of Medicine in St. Louis calls that explanation into question. The study was led by Benjamin Kay, MD, PhD, an assistant professor of neurology, and Nico U. Dosenbach, MD, PhD, the David M. & Tracy S. Holtzman Professor of Neurology. Their findings suggest that these medications primarily affect brain systems involved in reward and wakefulness rather than the networks traditionally linked to attention.

Published Dec. 24 in Cell, the study indicates that stimulants may improve performance by making people with ADHD feel more alert and more interested in what they are doing. Instead of directly sharpening focus, the drugs appear to increase engagement with tasks. The researchers also observed brain activity patterns that resembled the effects of a good night’s sleep, counteracting the typical brain changes associated with sleep deprivation.

“I prescribe a lot of stimulants as a child neurologist, and I’ve always been taught that they facilitate attention 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. Rather, the improvement we observe in attention is a secondary effect of a child being more alert and finding a task more rewarding, which naturally helps them pay more attention to it.”

Kay said the results emphasize the need to consider sleep quality alongside medication when children are being evaluated for ADHD.

Brain imaging reveals unexpected patterns

To examine how stimulants affect the brain, the researchers analyzed resting state functional MRI, or fMRI, data from 5,795 children ages 8 to 11 who took part in the Adolescent Brain Cognitive Development (ABCD) Study. Resting state fMRI measures brain activity when a person is not performing a specific task. The ABCD study is a long term, multisite project following the brain development of more than 11,000 children across the U.S., including a site at WashU Medicine.

The team compared brain connectivity in children who took prescription stimulants on the day of their scan with those who did not. Children who had taken stimulants showed stronger activity in brain regions associated with arousal and wakefulness, as well as areas involved in predicting how rewarding an activity might be. In contrast, the scans did not show notable increases in regions classically tied to attention.

Adult experiment confirms the findings

The researchers tested their results in a smaller study involving five healthy adults without ADHD who did not normally take stimulant medications. Each participant underwent resting state fMRI scans before and after taking a stimulant dose. This allowed the team to precisely track changes in brain connectivity. Once again, the medications activated reward and arousal networks rather than attention networks.

“Essentially, we found that stimulants pre-reward our brains and allow us to keep working at things that wouldn’t normally hold our interest — like our least favorite class in school, for example,” Dosenbach said. He explained that instead of directly activating attention centers, stimulants make tasks that are usually difficult to focus on feel more rewarding. That increased sense of reward can help children stick with both challenging and repetitive activities.

“These results also provide a potential explanation for how stimulants treat hyperactivity, which previously seemed paradoxical,” Dosenbach added. “Whatever kids can’t focus on — those tasks that make them fidgety — are tasks that they find unrewarding. On a stimulant, they can sit still better because they’re not getting up to find something better to do.”

ADHD treatment, sleep, and performance

Within the ABCD study, children with ADHD who were taking stimulant medications had higher school grades, according to parent reports, and performed better on cognitive tests than children with ADHD who were not taking stimulants. The largest improvements were seen in children with more severe ADHD symptoms.

However, the benefits were not observed in every child. Among participants who slept less than the recommended nine or more hours per night, those who took stimulants earned better grades than sleep deprived children who did not take the medication. In contrast, stimulants were not linked to improved performance in neurotypical children who were getting enough sleep. (It is not clear why these kids were taking stimulant medications.) Overall, the link between stimulants and improved cognitive performance appeared only in children with ADHD or in those who were not getting sufficient sleep.

“We saw that if a participant didn’t sleep enough, but they took a stimulant, the brain signature of insufficient sleep was erased, as were the associated behavioral and cognitive decrements,” Dosenbach said.

Potential risks of masking sleep deprivation

The researchers cautioned that better performance despite poor sleep may come with long term consequences.

“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 can show symptoms that resemble ADHD, including difficulty paying attention in class or declining grades. In some cases, this could lead to a misdiagnosis when sleep deprivation is the underlying issue. Stimulant medications may appear to help by imitating some effects of adequate sleep, while still leaving children exposed to the long term harms of chronic sleep loss. Kay urged clinicians to consider sleep deprivation during ADHD evaluations and to explore ways to improve sleep.

Questions that remain

Dosenbach and Kay said their findings highlight the need for further research into the long term effects of stimulant use on the brain. They noted that stimulants might have a restorative role by activating the brain’s waste clearing system during wakefulness. At the same time, the medications could potentially cause lasting harm if they are used to compensate for ongoing 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 N, Krimmel SR, Shinohara RT, Tervo-Clemmens B, Hermosillo RJM, Nelson SM, Hendrickson TJ, Madison T, Moore LA, Miranda-Domínguez O, Randolph A, Feczko E, Roland JL, Nicol GE, Laumann TO, Marek S, Gordon EM, Raichle ME, Barch DM, Fair DA, and Dosenbach NUF. Stimulant medications affect arousal and reward, not attention networks. Cell. Dec. 24, 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), DA041148 (DAF), DA04112 (DAF), MH115357 (DAF), MH096773 (DAF and NUFD), MH122066 (EMG, DAF, and NUFD), MH121276 (EMG, DAF, and NUFD), MH124567 (EMG, DAF, and NUFD), and NS129521 (EMG, DAF, and NUFD); by the National Spasmodic Dysphonia Association (EMG); by 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 allocation TG-IBN200009 (BTC).

Computations were performed using the facilities of the Washington University Research Computing and Informatics Facility (RCIF). The 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 opinions or views of the NIH or ABCD consortium investigators.