Modafinil: The Ultimate Wake-up Pill?

A Narcolepsy Drug Helps Keep Fatigue at Bay for Others, Too

In 1998, the Food and Drug Administration approved the prescription drug modafinil for the treatment of excessive daytime sleepiness in narcoleptics. But this medication has become a star of sorts in the sleep world, gaining popularity and garnering interest beyond narcoleptic circles. It has been put to off-label use as a wake-up pill by those without the sleep condition and its success has paved the way to research that some say could change the future of shuteye.


The interest in sleep is not surprising in a country that does not get enough. Although the average person needs about eight hours of sleep, adults get only an average of seven hours during the workweek, and 36 percent log less than 6.5 hours' sleep on weeknights. One-quarter of adults have even taken sleep medication in the past year.

Before modafinil, the heavy-hitter stimulants of choice for those combating the urge to snooze have been amphetamines such as Dexedrine. But aside from their addictive properties, they caused a range of side effects from agitation, irritability and nausea to increased heart rate, tics and impotence. When the drug wears off, it can lead to a rebound effect that causes extreme fatigue or depression.

Modafinil mostly bypasses the downsides of staying up. "Unlike most wake-promoting drugs, it has very few side effects," says Tom Scammell, M.D., a sleep expert and an assistant professor in neurology at the Beth Israel Deaconess Medical Center in Boston. The most common side effects in patients in clinical trials include headaches (1 percent), nausea (1 percent), depression (1 percent) and nervousness (1 percent).

A June 2000 study published in Psychopharmacologia studied the drug's effects on people's abilities to accomplish demanding tasks despite a lack of sleep. At the United States Army Aeromedical Research Laboratory in Fort Rucker, Alabama, six pilots were kept awake continuously for two forty-hour periods. They were given modafinil in one session and a placebo in the other. The pilots were then evaluated in helicopter simulator flights, resting electroencephalograms (EEGs), and mood questionnaires. The drug lessened the effects of sleep deprivation in four of six flight maneuvers tested compared to the placebo. It also reduced slow-wave EEG activity (when one begins to fall asleep, EEG begins to slow) and decreased self-reported problems with mood and alertness.


Modafinil: The Ultimate Wake-up Pill? (<i>cont'd</i>)

The military has a high-stake interest in this new drug. Wartime missions often require sleep deprivation of pilots. Vietnam War aircrews were the first to widely use amphetamines. More recently, the Air Force gave Dexedrine to most flight crews during the Persian Gulf War. More than 60 percent of those who used it said it had been "essential" to accomplishing their mission.

Beyond the military, there is huge mainstream potential for a drug that would keep people awake and alert without significant side effects. Shift workers and those looking to take on another job or expand their hours of productivity could benefit.


"It can keep you more alert, but whether it can keep you at full mental performance remains to be seen," says Scammell. "Can a surgeon still operate with the same precision?"

Although modafinil has inspired much research, relatively little is actually known about how it works. "The fundamental mechanism remains obscure," says Scammell.

Brain cells, also known as neurons, rely on neurotransmitters like dopamine, to communicate with each other. One neuron releases a neurotransmitter, which relays a message to the next one. The brain's neurons serve many distinct functions. Some are involved in making you fall asleep, while others wake you up. One thing that scientists have learned in recent years is that the systems that put you to sleep probably do so by shutting off the ones that promote wakefulness and vice versa.

Dopamine plays an important role in one of the wake-promoting pathways in the brain. One of the primary ways amphetamines keep people awake is by blocking protein structures known as transporters from reabsorbing the neurotransmitters back into the cells that released them.

One of the ways in which modafinil works could be similar, affecting the neurotransmitter dopamine, Scammell says. One study, conducted by him and his colleagues, found the drug activated rat brain neurons that normally respond to dopamine. A different study by Stanford researchers reported that rats that lacked a reuptake transporter for dopamine did not respond to modafinil.

Because modafinil seems like such a great fix to a sleepy problem, Scammell says he worries that people with real medical reasons for their sleepiness, such as sleep apnea, will take the medication instead of getting a proper evaluation by their doctors. And ultimately, there's nothing like the real thing. "As best as I'm aware, if you're really sleep-deprived, it doesn't matter how many stimulants you give somebody," he says. "There's no substitute for sleep."