TUESDAY, March 17, 2009 -- Modafinil, a narcolepsy drug used illicitly by an increasing number of people to enhance mental performance, could be addictive, according to a small study of 10 people who underwent high-tech brain scans.
Modafinil is also prescribed to shift workers to help them stay awake and to people with fatigue due to sleep apnea, multiple sclerosis, or other conditions. It is sometimes used "off-label" to treat attention deficit hyperactivity disorder (ADHD), although the Food and Drug Administration declined to approve the drug for ADHD due to concerns about potentially life-threatening skin reactions.
Nora D. Volkow, MD, of the National Institute on Drug Abuse in Bethesda, Md., and her colleagues found that the drug, sold as Provigil, boosted the amount of dopamine in the brain. Dopamine is a "feel-good" chemical that drives the brain's reward system. Drugs of abuse, such as cocaine, cause euphoria by sharply increasing levels of dopamine; the faster the increase, the more powerful the high.
While the effect of modafinil was much weaker than that of cocaine, or in fact of other stimulant drugs used to treat ADHD such as methylphenidate (Ritalin), it did affect the dopamine system, according to the study in the Journal of the American Medical Association. And it upped dopamine levels in a part of the brain called the nucleus accumbens, a key element of the brain circuitry involved in feeling pleasure.
In addition, the therapeutic dose of modafinil is 200 mg, about 10 times the therapeutic dose of methylphenidate (20 mg), suggesting both drugs may have a similar effect on dopamine in the brain at therapeutic doses, according to the report. Modafinil had initially been thought to act on brain chemicals other than dopamine. So it was thought to be safer than stimulants used to treat ADHD, which are known to have the potential for abuse.
"All drugs of abuse have some type of effects on the dopamine system and so this type of finding would be consistent with a potential for abuse," said Michael Minzenberg, MD, of the University of California at Davis, who studies brain neurochemistry but wasn’t involved in the current study. However, he added, this study in and of itself can’t prove or disprove that modafinil is indeed prone to abuse or addiction.
Next page: What the study found
A number of animal studies have suggested that the drug indeed affected the dopamine system, including a 2006 investigation in monkeys. In the current study, Dr. Volkow and her team have confirmed that modafinil affects dopamine in humans, too.
She and her colleagues performed positron emission tomography scans of 10 healthy men after giving them a placebo, 200 mg, or 400 mg of modafinil. People with narcolepsy typically receive a 200 mg dose of modafinil, while the 400 mg dose is given to people with ADHD. Along with the drug or placebo, the men were given a radioactive substance that binds to dopamine receptors in the brain, which allowed the researchers to measure changes in levels of dopamine outside brain cells. In a second experiment, the men were given cocaine along with modafinil or placebo, to see how modafinil affected the ability of brain cells to use dopamine.
At both doses, the researchers found, modafinil increased dopamine levels in the brain. It also bound to many of the same sites targeted by cocaine. "The mechanisms of action seem to be very similar to those of cocaine," Dr. Volkow says.
The possibility that modafinil could be abused "does not invalidate the therapeutic value of this medication, which is very important," she says. However, she said, it shows that anyone taking the drug should do so with a prescription and under a doctor’s care, with appropriate follow-up.
Next page: Brand-name drug is expensive
People who have no medical need for this medication should think twice about taking it to enhance their mental performance, Dr. Volkow says. While not everyone who uses it will become addicted, she explains, some people may be vulnerable. Right now the relatively high cost of Provigil has limited its recreational use, she says, but when the drug comes off patent in 2012 and cheaper generic versions become available, any abuse and addiction potential is likely to be revealed. Provigil costs about $10 for a 200 mg dose, although the price can vary.
"There are individuals that will become addicted when they become exposed to stimulants," Dr. Volkow says. "Time will tell whether the same is true for modafinil."
Jeffry Vaught, PhD, notes that when the drug was approved over a decade ago, its label warned that it had the potential to be abused and suggested doctors monitor patients carefully if they have a history of drug abuse. "It's been that way since the beginning," says Vaught, the chief scientific officer and executive vice president at Cephalon, Inc., which makes Provigil.
The company has been checking for signs that the drug is being abused, says Vaught, but "we've just not picked up any signals that there's any abuse liability that would cause us concern."
He notes that the drug is currently being studied as a treatment for methamphetamine and cocaine addiction and "generally you do that with a substance that's considerably less to non abuseable." It's also being studied as a treatment for bipolar disorder.
Vaught says the company does not condone the use of the drug for enhancing mental performance. "I would also state from a scientific perspective that there's limited to no data to suggest there's any cognitive benefit in normal individuals," he says.