Pay Attention: Ritalin Acts Much Like Cocaine

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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 #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.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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. .