Published online 17 March 2009 | Nature | doi:10.1038/news.2009.170

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Cognitive enhancement drug may also cause addiction

Modafinil's effect on the brain suggests it could be addictive for some.

A drug used to treat narcolepsy — and often taken to increase alertness and improve cognitive performance — may have the potential to become addictive, a small pilot study has shown.

Brain-imaging studies performed on ten men before and after taking the drug, called modafinil (Provigil), showed that it boosts levels of a chemical called dopamine, which influences the brain's reward system1. Drugs of abuse, from tobacco to heroin, also impact dopamine levels, particularly in an area of the brain called the nucleus accumbens. In the new study, published on 17 March by the Journal of the American Medical Association, modafinil also increased dopamine in that region.

The effect of cognitive-enhancement drugs on the brain is not well known.Getty

It is an indirect measure of the propensity to trigger addiction, and patients rarely become dependent upon modafinil, notes Martha Farah, director of the Center for Cognitive Neuroscience at the University of Pennsylvania in Philadelphia, who was not involved with the study. "However, we know that drug dependence is a result of drugs' effects on the brain's reward system," she says, "and so finding that modafinil affects this system is also relevant and should prompt us to look more carefully at the risks of dependence for this drug."

Use and abuse

Meanwhile, the results should not prompt those who take modafinil for medical conditions to discontinue the drug, says study author Nora Volkow, director of the National Institute on Drug Abuse in Bethesda, Maryland. Physicians, however, should be aware that addiction is a possibility and can tell their patients to watch for signs of dependency, she says.

The US Food and Drug Administration has approved modafinil to treat narcolepsy and some other sleep disorders, and doctors will sometimes prescribe the drug off label to treat attention-deficit disorder and schizophrenia. In recent years, the drug has joined the ranks of methylphenidate (Ritalin) and amphetamines — drugs which are misused , often by students, to improve cognitive function. A recent survey by Nature found that of those who use drugs to improve focus, 44% have tried modafinil.

Addiction is a familiar consequence of taking stimulants such as amphetamines or cocaine and has been found among those who take methylphenidate as well, although generally only when abnormally high doses of the drug are taken, or when the drug is administered by injection rather than orally. But researchers thought modafinil acted via a different mechanism — one that did not affect the dopamine system.

"People were saying, 'With Provigil, we don't have to worry'," says Volkow. "Unfortunately, that is not the case. As of now, all of the medications that are being used with the expectation of improving cognitive performance have the potential to produce addiction."

Addictive qualities

Modafinil was thought to promote wakefulness by increasing responses to brain hormones called orexins. But animal studies showed that rodents that lack dopamine receptors are unresponsive to the drug, and in 2006, researchers found that modafinil affects dopamine levels in the brains of rhesus macaques2.

The animals in these studies were often given high doses of the drug by injection, whereas humans would take the drug orally and at lower doses. So Volkow, along with Joanna Fowler of Brookhaven National Laboratory in Upton, New York, and their colleagues, decided the effects needed to be analyzed directly in humans.

Volkow and her team administered labelled compounds that bound to free dopamine receptors and dopamine transporters to ten paid volunteers before and after the volunteers took modafinil. By imaging these compounds, the team was able to estimate how many receptors and transporters in the brain were bound to dopamine after taking the drug. They found that modafinil blocked dopamine transporters in the brain, resulting in an increase in dopamine concentration.

The study was performed in only ten subjects, but that is not unusual for labour-intensive brain-imaging studies, notes Michael Minzenberg, who studies neurochemical systems at the University of California, Davis Health System Imaging Research Center. Pilot studies such as this may not capture the full variation in how individuals within a population will respond to the drug, he says, but the impact on the dopamine system is clear.

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Still, that dopamine connection may not tell the full story, says Bertha Madras, professor of psychobiology at Harvard Medical School in Southborough, Massachusetts. For example, some drugs increase dopamine levels but have other properties that make them aversive rather than addictive. "The full spectrum of the pharmacology of the drug is what drives the abuse potential," she says. 

  • References

    1. Volkow, N. D. et al. JAMA 301, 1148-1154 (2009).
    2. Madras, B. K. et al. J. Pharmacol. Exp. Therapeutics 319, 561-569 (2006).
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