Ritalin Acts Like 'Cocaine Dripped Through Molasses'
Source: Journal of the American Medical Association
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 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."
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,
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,
transporters also called autoreceptors act 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 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: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."
http://www.mapinc.org/drugnews/v01.n1542.a02.html
Mike Lee, MA
P435A Duff Roblin Building
(204) 474-6627 (office)
Dept of Psychology
University of Manitoba
Winnipeg, MB Canada
[EMAIL PROTECTED], http://home.cc.umanitoba.ca/~mdlee, http://home.cc.umanitoba.ca/~mdlee/Teaching.html
Owner: Talk-Psychology Mailing List for Students of Introductory Psychology
"Our situation on this Earth seems strange. Every one of us appears here involuntarily,
and uninvited, for a short stay without knowing why. To me it is enough to wonder at the secrets."
-- Albert Einstein
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--Henry David Thoreau
