Is Methylphenidate's (Ritalin) Mode of Action Similar to Cocaine?

For forty years, psychiatrists have been prescribing methylphenidate (Ritalin) to children with attention-deficit hyperactivity disorder (ADHD) without knowing just what makes the medication work. An estimated 4 to 6 million children take methylphenidate daily as a treatment for ADHD, one of the mostly widely diagnosed psychiatric disorders of childhood.

According to an article published in the Journal of the American Medical Association's "Medical News and Perspectives" section, researcher Nora Volkow, M.D., psychiatrist and imaging expert at Brookhaven National Laboratory in Upton, New York, and colleagues have used advanced imaging techniques such as postitron emission tomography (PET) to better understand how methylphenidate acts on the brain.

Chemically, methylphenidate is similar to cocaine and other stimulants. The stimulant decreases activity and increases the ability to concentrate in people with ADHD, while people without ADHD tend to find its effects unpleasant.

Cocaine works on the brain's dopamine system, which has been identified as a "major player" in compulsive behavior, such as drug-taking and overeating. Research has demonstrated that cocaine works by blocking about 50 percent of the brain's dopamine transporters, leading to a surfeit of dopamine in the synapse and a subjective effect of intense pleasure.

Given methylphenidate's chemical similarities to cocaine, Volkow and colleagues sought to examine the effect of the stimulant on the dopamine system. They believed that it might work like cocaine but, since it rarely produces a high and has not been reported to be addictive, less potently than cocaine, blocking fewer dopamine transporters.

Volkow and her colleagues used PET to scan the brains of 11 healthy men who took various doses of oral methylphenidate. Tire results surprised the researchers: instead of being a less potent transport inhibitor than cocaine, methylphenidate was more potent. They found that a typical methylphenidate dose given to children (0.5 mg/kg) blocked 70 percent of dopamine transporters in the adult subjects. It was, in fact, a stronger stimulant than cocaine.

Why, then, doesn't methylphenidate use in children produce the kind of strong signals that would yield a "high" and lead to addiction?

The researchers hypothesized that methylphenidate might have slower mechanism of action than cocaine, giving the dopamine system a chance to interpret transporter congestion as a signal that too much dopamine is being produced. The result might be less dopamine in the synapse, which would suppress the reward signal. However, a second PET study proved this hypothesis wrong. Subjects who took methylphenidate displayed high levels of extracellular dopamine -- just like people using cocaine.

The answer was discovered after Volkow and colleagues combined their research with the work of another research team. In 1999, Darin Dougherty and colleagues from Massachusetts General Hospital in Boston reported that people with ADHD have many more dopamine transporters than people without the disorder. Because the transporters remove dopamine from the synapse, children with ADHD never get a pleasurable "reward" signal from circuit receptors.

Furthermore, the weak dopamine signals produced by children with the condition mean that usually interesting activities provide fewer rewards; i.e., the attention circuitry is "underfed."

At the same time these children experience another, related effect: random, distracting neuron firing, or, as Volkow describes it, "more noise and less signal." This background "hum" interferes with concentration, making children with ADHD more distractible. Methylphenidate alters the balance, by increasing the signal and reducing the noise. The stimulant blocks dopamine transporters and increases attention signaling.

While cocaine is reported to do the same, the drugs do differ in an important way: Methylphenidate takes about an hour to raise dopamine levels, while inhaled or injected cocaine acts in seconds. The speed of the reaction appears to be a significant factor in the addiction process.

Volkow and her colleagues are planning to continue their research on methyiphenidate's effects on the dopamine pathway. They plan to map dopamine levels in volunteers who have ADHD when they are at rest or while concentrating. Other research efforts will seek molecular tools to screen children for dopamine transporter levels; children with high levels could be identified early and targeted for behavioral solutions before methylphenidate is prescribed.

Volkow notes that it is possible that social interactions can increase dopamine receptors but adds that it is unclear whether better interplay also affects transporter levels.

The long-term effects of taking methylphenidate for years are unknown. However, some studies have indicated higher levels of drug addiction in children with ADHD who took methylphenidate. Volkow says that because people with low levels of dopamine receptors are at a greater risk for drug addiction, researchers need to understand if methylphenidate can alter the whole dynamic of the dopamine pathway.

Vastag B: Pay attention: Ritalin acts much like cocaine. Journal of the American Medical Association 2001; 286:905-906.