PAY ATTENTION: RITALIN ACTS MUCH LIKE COCAINE

WashingtonAdvanced imaging research has answered a 40-year-old question
about methylphenidate (Ritalin), which is taken daily by 4 million to 6
million children in the United States: how does it work? The answer may
unsettle many parents, because the drug acts much like cocaine, albeit
cocaine dripped through molasses (J Neurosci. 2001;21:RC121).

Taken orally in pill form, methylphenidate rarely produces a high and has
not been reported to be addictive. However, injected as a liquid it sends a
jolt that "addicts like very much," said Nora Volkow, MD, psychiatrist and
imaging expert at Brookhaven National Laboratory, Upton, NY. "They say it's
like cocaine."

Representative distribution volume PET images of the radiotracer
[11C]raclopride from one of the study participants show that radiotracer
binding is reduced at the level of the striatum (bottom left) after oral
administration of 60 mg of methylphenidate. Reduced radiotracer binding
indicates decreased availability of open dopamine receptors after
methylphenidate-induced increases in extracellular dopamine. Cocaine
produces a similar effect in those who take it. (Photo credit: Courtesy of
Brookhaven National Laboratory)

Acknowledged as leaders in the field of brain imaging of drug effects,
Volkow and colleagues have spent several years tracing the effects on the
brain of drugs of addiction, using positron emission tomography (PET) and
other advanced techniques. Among their long list of findings, they've
identified the brain's dopamine system as a major player in compulsive
behavior, including drug taking and overeating.

A PRAGMATIC PARADOX

Building on that base, Volkow, associate laboratory director for life
sciences at Brookhaven, hit the trail of a legal stimulant. Although they
have used it to treat attention-deficit/hyperactivity disorder (ADHD) for
40 years, psychiatrists and pharmacologists have never known how or why it
worked. Chemically similar to cocaine and other stimulants, methylphenidate
presents a pragmatic paradox: it decreases activity and increases the
ability to concentrate in people with ADHD, but in studies, about half of
those without ADHD find it unpleasant, like drinking too much coffee.

"I've almost been obsessed about trying to understand [methylphenidate]
with imaging," said Volkow at a recent media conference. "As a
psychiatrist, sometimes I feel embarrassed [about the lack of knowledge]
because this is, by far, the drug we prescribe most frequently to children."

So the team went to work with PET scans to examine the dopamine system,
which stimulates reward and motivation circuits during pleasurable
experienceseating, having sex, learning. To pick one of many pleasures,
tasting chocolate ice cream will trigger cells in the basal ganglia to
release dopamine molecules. These float across the synapse to neurons in a
reward circuit. Receptors on these cells sop up the dopamine, activating
signals that translate to "this experience is worth paying attention to."
Too much signal and the experience feels unpleasant, overstimulating. Too
little, and the experience elicits a yawn; no pleasure, only boredom and
distraction.

Volkow wanted to know how methylphenidate affects this signal. But instead
of focusing on dopamine receptors, she tracked another part of the system.
After the pleasure signal is sent on its way, dopamine molecules recycle
back to the neurons that produced them. There, transportersalso called
autoreceptorsact as vacuum cleaners, scouring the synapse for another
go-around.

Earlier research had shown that cocaine blocks about 50% of these
transporters, leading to a surfeit of dopamine in the synapse and a hit of
pleasure. Because of methylphenidate's chemical similarities to cocaine,
pharmacologists thought that it might work in the same way, only less
potently, blocking fewer transporters. Animal studies with high doses of
methylphenidate indicated that this could be the case.

STARTLING RESULTS

Using a radiotracer, [11C]raclopride, that labels dopamine transporters,
the team scanned 11 healthy men who took various doses of oral
methylphenidate. The results were shocking.

"We were surprised as hell," said Volkow. "We didn't expect this." Instead
of being a less potent transport inhibitor than cocaine, methylphenidate
was more potent. A typical dose given to children, 0.5 mg/kg, blocked 70%
of dopamine transporters. "The data clearly show that the notion that
Ritalin is a weak stimulant is completely incorrect," Volkow said.

More pondering led the team to consider two theories. Methylphenidate could
be blocking the recycling of dopamine exactly as cocaine does, leading to
strong signals that would yield a high and lead to addiction. But this did
not jibe with four decades of clinical experience.

So they considered another possibility. Perhaps methylphenidate seeps into
the brain slowly, and as one by one the drug molecules block the
transporters, dopamine cells shift gears. Like a union foreman yelling to
an assembly line to slow down, the cell interprets the transporter
congestion as a signal that too much dopamine is being produced. The neuron
cranks down production, sending less dopamine into the synapse, suppressing
the reward signal.

The two theories opposed each other. But Volkow was unfazed. "We had to let
the data speak for itself," she said.

That meant measuring the amount of dopamine floating in the synapses.
Fortunately, the investigators had at hand another radioactive label that
binds only to open dopamine receptors. A weak PET signal would mean low
numbers of open receptors, which in turn would mean that large amounts of
dopamine occupied the synapse.

After combining data from the volunteers, the team got its second surprise.
Those who took methylphenidate displayed high levels of extracellular
dopaminejust like people using cocaine. But if methylphenidate works like
cocaine, why aren't millions of US children getting high and becoming addicted?

CAPTURING THE ANSWER

The answer came after Volkow combined her results with those from another
research team. In 1999, Darin Dougherty, MD, and colleagues at
Massachusetts General Hospital and Harvard University Medical School
reported that people with ADHD have many more dopamine transporters than
those without the condition (Lancet. 1999;354:2132-2133). This surplus
increases the collective cleaning power of each cell; as dopamine fires
into the synapse it is quickly sucked back, before it can home in on reward
circuit receptors. "There isn't enough time for it to produce a signal,"
said Volkow.

It finally started to make sense. Children with ADHD produce weak dopamine
signals, meaning that usually interesting activities provide fewer rewards.
In effect, their attention circuitry is underfed. At the same time, they
experience a related effect: random, distracting neuron firing. Or, as
Volkow put it, more noise and less signal. This background hum interferes
with concentration, making the child more distractible.

Methylphenidate flips the relationship, upping the signal and reducing the
noise. After someone swallows methylphenidate, it enters the bloodstream
and eventually finds the brain, where it blocks dopamine transporters and
increases attention signaling. Again, cocaine acts the same way. But the
two drugs differ in a significant way: methylphenidate takes about an hour
to raise dopamine levels, whereas inhaled or injected cocaine hits the
brain in seconds. "It is the speed at which you increase dopamine that
appears to be a key element of the addiction process," said Volkow.

While the team is unclear on why this speed factor is so important, future
research will focus on it. They also plan to map dopamine levels in
volunteers who have ADHD when they are at rest or while concentrating.
Other research will search for molecular tools to screen children for
dopamine transporter levels; those with high levels could be identified
early and encouraged with behavioral solutions before methylphenidate is
prescribed. "We know that social interactions can increase dopamine
receptors," said Volkow, but whether better interplay also affects
transporter levels is unknown.

The long-term dopamine effects of taking methylphenidate for years, as many
do, are another unknown. The only two large epidemiological studies
conflict. One reports more drug addiction in children with ADHD who took
methylphenidate compared with children with ADHD who took no drug (J Learn
Disabil. 1998;31:533-544); the other shows the opposite result (Pediatrics.
1999;104:e20).

Because people with low levels of dopamine receptors are at risk for drug
addiction, Volkow said that researchers need to understand if
methylphenidate can alter the whole dynamic of the dopamine pathway. "Could
chronic use of Ritalin make you more vulnerable to decreased dopamine brain
activity as cocaine does? It's a key question nobody has answered."