It's Wake-Up Time

Kiss your pillow good-bye. A new breed of drugs promises to do for drowsiness what Prozac did for depression.

By Richard Martin

In January 2003, US Air Force majors William Umbach and Harry Schmidt faced court-martial after a friendly fire incident in Afghanistan that killed four Canadian soldiers and wounded eight others. During a pretrial hearing, Umbach's lawyer spilled one of the Pentagon's dirty little secrets - the pilots had been on speed when they dropped the fatal bomb. Their judgment was impaired, he claimed, because superiors pressured them to prepare for the mission by taking Dexedrine, a practice he described as common. The charges were dropped, but not before the revelation sparked public outrage: Why were our boys flying $30 million jets on uppers?

That the pilots were using chemicals to remain alert shouldn't have surprised anyone: Officers have always sought ways to keep the troops awake. Chinese sentries along the Great Wall took the herb ma huang (active ingredient: ephedrine). Incan warriors chewed coca leaves in Andean passes. And the Air Force itself has used "go pills" since World War II. Today, a program funded by Darpa is studying natural alertness mechanisms like that of the white crowned sparrow, which can stay awake for up to two weeks during migration. The goal is to produce a GI who can go without sleep for seven days.

Joel Benjamin

Right now, the US Army Aeromedical Research Laboratory is testing an antisleep agent called modafinil. Developed by the French firm Lafon to fight narcolepsy and sold by Pennsylvania drugmaker Cephalon under the name Provigil, the compound can keep users up for two or three days at a stretch, with negligible side effects and little risk of addiction. Modafinil was approved by the FDA in 1998 and has been used to treat excessive sleepiness in patients with Parkinson's, Alzheimer's, and multiple sclerosis; it's also been shown to help cocaine addicts kick the habit. The French Foreign Legion used the drug in Gulf War I, and although the Pentagon won't comment, several news outlets reported that coalition troops were taking it during the drive to Baghdad earlier this year.

But modafinil isn't just for soldiers and sick people anymore. This year, Cephalon submitted to the FDA a supplemental application that would give physicians a free hand to prescribe Provigil for lesser sleep problems, such as shift-work drowsiness. Even without that approval, the drug is attracting a wider market: Truckers, students, and others pulling all-nighters account for a growing portion of Provigil's $200 million in annual sales.

In the mainstream media, the discovery of a chemical key to a 24/7 society sparked the predictable hand-wringing. But Provigil has little appeal as a recreational drug. Unlike amphetamines, which stimulate the entire central nervous system, modafinil doesn't jazz up users - it simply shuts off their sleep jones. There's none of the euphoria produced by cocaine or the bliss from ecstasy. It just helps people stay awake. And eventually, staying awake just gets boring.

In fact, the medical establishment is excited about Provigil precisely because it's the first effective stimulant with no significant potential for abuse. What's more, the same research that led to stay-awake drugs will revolutionize treatment of a sleep disorder at the opposite end of the spectrum: insomnia. During the past decade, scientists have realized that the urges for sleep and wakefulness aren't subject to a single control like the throttle of a boat. Rather, they're interrelated yet independent drives controlled by distinct mechanisms in the brain - think of the accelerator and brake in a car. Scientifically, modafinil's beauty is in its precision. Although its exact mechanism of action is not fully understood, it affects only the urge to stay awake.

That same basic breakthrough behind modafinil is already being used by several companies - Cephalon, Neurocrine Biosciences, and an innovator in the field, Hypnion - to develop compounds similar to but more effective than Provigil. Within a decade, some say, continuous alertness could be available over the counter. And since the technique of targeting a specific receptor will likely lead to better sleeping pills, a restful night could be sold in drugstores as well; chronic insomnia, a condition that affects 20 to 40 percent of Americans, could be a thing of the past.

"It's time for a revolution," says Dale Edgar, cofounder of Hypnion. He should know - he's the scientist whose research on sleep helped lay the groundwork for modafinil. "The drugs will do for sleep disorders what Prozac did for depression."

In a technology park in Worcester, Massachusetts, down hallways bathed in muted red light, live the best-rested rodents in the world. As researchers in surgical gear tiptoe past their cages, dozens of mice and rats doze contentedly; others scurry around their Plexiglas enclosures. Affixed to each of them are miniature radio transmitters.

These animals are the test subjects for Hypnion's new sleep-wake drugs. Company scientists monitor the results with a drug-testing system called Score 2000 that receives the radio signals and tracks reactions remotely over a network. In an adjoining lab, data streaks across terminals: vital signs, movement, feeding habits, and, most important, sleep patterns. Edgar developed the system with a colleague at Stanford using a grant from the Air Force and the Department of Defense, which was looking into applications of medical sensing for troops in the field.

Hypnion is so deep in stealth mode that some people in sleep science don't even know it exists. Edgar, however, has already made his mark: In the mid-'90s, under contract for Cephalon, he used an earlier version of Score to help perfect modafinil and make the Pennsylvania firm one of the hottest in the biotech world.

Now Edgar and his team are developing a line of anti-drowsiness pharmaceuticals that they hope will put Hypnion in the same league. While modafinil represents a breakthrough, he says, "the first drug in its class is rarely the best." As a private company in preclinical development, Hypnion won't say much about what it has in the pipeline, but just as Prozac has largely been superseded by Zoloft and Paxil, Edgar believes Provigil will be replaced by better wakefulness drugs.