New Research on How Ritalin Works in Humans

By Holly VanScoy, Ph.D.

(May 11, 2001) -- It's pretty common knowledge that Ritalin -- a prescription drug with the chemical name methylphenidate -- is widely prescribed for attention deficit hyperactivity disorder (ADHD) in the United States. In fact, it's one of the most widely used drugs for any condition. Lawrence H. Diller, M.D., a psychiatrist and author of the 1998 book Running on Ritalin, pointed out that it's now prescribed to some four million children in the United States annually.

What parents, physicians or anyone else in the American medical establishment hadn't known was just how Ritalin worked its apparent magic of calming overactive children and helping them focus their attention more productively.

Research published in the January 15, 2001 issue of the Journal of Neuroscience by the U.S. Department of Energy's Brookhaven National Laboratory, however, is being hailed as a big step forward in understanding the drug's method of action in human beings.

Nearly Half a Century of Uncertainty

According to Peter R. Breggin, M.D., director of the International Center for the Study of Psychiatry and Psychology in Bethesda, Md., stimulant drugs, including methylphenidate and amphetamine, were first approved for the control of problem behaviors in children in the mid-1950s.

By the mid-1990s, ADHD was the most commonly diagnosed mental health condition of childhood. And the rate at which Ritalin was being prescribed had begun to soar.

But although it has been widely and steadily used for decades for a range of behaviors such as distractibility, short attention span, hyperactivity, impulsivity and emotional lability, even the experts prescribing Ritalin weren't sure how the drug achieved its results. After many years of mislabeling its effects as "paradoxical," many in the mental health community admitted the drug's method of action in the human brain was completely baffling.

It's only now -- after more than 40 years of uncertainty -- that the answer has emerged. According to Nora Volkow, M.D., lead researcher and associate laboratory director at Brookhaven, Ritalin works by stimulating the brain chemical dopamine.

Studies in Mice Provide Clues

The Brookhaven scientists' findings came about two years after researchers at Duke University Medical Center reported that Ritalin and similar stimulant drugs seemed to boost the levels of both dopamine and serotonin in laboratory mice.

Dopamine is believed to be carry messages from one part of the brain to another. Serotonin, by contrast, is a brain chemical associated with a sense of well-being.

Previous studies of mice had hinted at a possible connection between Ritalin and dopamine -- at least in furry laboratory animals -- but the link between Ritalin and serotonin was a new finding, according to Paul Gainetdinov, M.D., one of the Duke researchers. "Hyperactivity may develop when the relationship between dopamine and serotonin is off-balance in the brain," he hypothesized in the January 1999 issue of the journal Science.

Stimulates Attention and Motivational Circuits

The Brookhaven researchers didn't pursue Ritalin's effect on serotonin connection, but they did focus intently on the influence of Ritalin on the dopamine levels of their human subjects. The study evaluated Ritalin use in 11 healthy adult males using a special computer-assisted imaging technology that highlighted the response of each subject's brain chemistry.

Although previous research had shown the drug given intravenously (IV) increased dopamine levels in the brain, this research was the first to assess the effects on the brain when the Ritalin was administered by mouth -- the way most young patients take their medication each day. Subjects were also given the amount of Ritalin comparable to that prescribed for most U.S. youngsters.

"For the first time, we saw that Ritalin given at the doses commonly used to treat children with ADHD significantly increases levels of dopamine," said Volkow. "It appears to amplify dopamine release. One can therefore speculate that the amplification of weak dopamine signals in individuals with ADHD by Ritalin enhances task-specific signaling, improves attention, and decreases distractibility -- the three most common symptoms of the disorder."

As Alan I. Leshner, Ph.D., Director of the National Institute on Drug Abuse Research, noted, "This research begins to explain how Ritalin works. And in doing so, the research helps us better understand the biology of ADHD. This can help doctors appropriately diagnose and treat children with the disorder. And it could eventually provide practitioners with a clearer framework for prescribing the medication."

More Research Ahead

The research team was quick to point out that their recent results still leave many questions unanswered. For example, none of the subjects of the study were children, and none had ADHD symptoms. Also, they were all males and otherwise healthy.

Volkow and Leshner said that their efforts to fully understand how Ritalin works in the brains of hyperactive children still has a way to go. The next logical step in analyzing the drug's effects, they said, is to study how Ritalin affects individuals who have been given a task. They hope to learn more about how Ritalin stimulates greater attention to detail, and how it reduces levels of physical activity in the young children for whom it is most often prescribed.

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Reviewed: 01/2006