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Pay Attention: Ritalin Acts Much Like Cocaine
Brian Vastag
WASHINGTON -- Advanced 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 Neuro-sci. 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 liqu id 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."
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 experiences -
eating, 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, over-stimulating. 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, transporters - also called autoreceptors -
act as vacuum cleaners, scouring the synapse for another go-around.
(see charts)
Courtesy of Brookhaven National Laboratory
Re presentative 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.
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 extra-cellular dopamine
- just 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: e2O).
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."
JAMA, August 22/29, 2001 – Vol. 286, No. 8 © 2001 American Medical
Association. All Rights Reserved.