Pay Attention: Ritalin Acts Much Like Cocaine

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> http://www.drakeinstitute.com/home.phtml/add/2002-10-03-232946/1

>

> 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 #8722; 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 #8722; also

> called autoreceptors #8722; act as vacuum cleaners, scouring the synapse

for

> another go-around.

>

>

>

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.

>

>

>

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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 #8722; 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. .

>

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>