Get ready for 24-hour living

• 18 February 2006
• From New Scientist Print Edition. Subscribe and get 4 free issues.
• Graham Lawton

A good night's sleep

SO MUCH to do, so little time. Between ahectic work schedule and a thriving social life, Yves (not his realname), a 31- year-old software developer from Seattle, often doesn'thave time for a full night's sleep. So he swallows something to makesure he doesn't need one. "If I take a dose just before I go to bed, Ican wake up after 4 or 5 hours and feel refreshed," he says. "The alarmgoes off and I'm like, let's go!"

Yves is talkingabout modafinil, a stimulant that since its launch seven years ago hasacquired a near-mythical reputation for wiring you awake without thejitters, euphoria and eventual crash that come after caffeine oramphetamines. Yves has been popping modafinil on and off for the pastthree years and says it is "tremendously useful". "I find I can be veryproductive at work," he says. "I'm more organised and more motivated.And it means I can go out partying on a Friday night and still goskiing early on Saturday morning."

Modafinil isjust the first of a wave of new lifestyle drugs that promise to do forsleep what the contraceptive pill did for sex - unshackle it fromnature. Since time immemorial, humans have structured their livesaround sleep. In the near future, we will, for the first time, be ableto significantly structure the way we sleep to suit our lifestyles.

"Themore we understand about the body's 24-hour clock the more we will beable to override it," says Russell Foster, a circadian biologist atImperial College London. "In 10 to 20 years we'll be able topharmacologically turn sleep off. Mimicking sleep will take longer, butI can see it happening." Foster envisages a world where it's possible,or even routine, for people to be active for 22 hours a day and sleepfor two. It is not a world that everyone likes the sound of. "I thinkthat would be the most hideous thing to happen to society," says NeilStanley, head of sleep research at the Human PsychopharmacologyResearch Unit in the University of Surrey, UK. But most sleepresearchers agree that it is inevitable.

If thatsounds unlikely, think about what is already here. Modafinil has madeit possible to have 48 hours of continuous wakefulness with few, ifany, ill effects. New classes of sleeping pills are on the horizon thatpromise to deliver sleep that is deeper and more refreshing than thereal thing. Further down the line are even more radical interventions -wakefulness promoters that can safely abolish sleep for several days ata stretch, and sleeping pills that deliver what feels like 8 hours ofsleep in half the time. Nor is it all about drugs: one research teameven talks about developing a wearable electrical device that can wakeyour brain up at the flick of a switch.

To somedegree, we are already adept at controlling sleep. Most people infull-time work deprive themselves of sleep during the week,deliberately or otherwise, and catch up at the weekend. We oftenaugment our sleep-suppressing powers with caffeine, nicotine or illegalstimulants such as cocaine and amphetamines. We are also highlydependent on substances that help us sleep. According to someestimates, 75 per cent of adults suffer at least one symptom of a sleepproblem a few nights a week or more. In 1998, a team from the HenryFord Health Sciences Research Institute in Detroit, Michigan, publisheda study revealing that 13 per cent of adult Americans had used alcoholto help them get to sleep in the previous year, and 18 per cent hadused sleeping pills (Sleep, vol 21, p 178).

Despitethe enormous resources that we pour into getting good sleep andwakefulness when we want them, most of the drugs at our disposal arecrude instruments at best. The vast majority of sleeping pills - knownin the business as hypnotics - are simply "knockout drops" that put youin a state almost like sleep but without its full restorativeproperties. "Hypnotic-induced sleep is better than no sleep, but itisn't natural sleep," says Stanley. With their addictive nature, thedrugs we use to keep us awake, such as coffee and amphetamines, areeven worse. In combination with our clock-watching lifestyles, thesesleep and wake aids are driving ever more people into what Foster callsthe "stimulant-sedative loop" where they need nightly help getting tosleep and daily help staying awake.

Modafinil haschanged the rules of the game. The drug is what's known as a eugeroic,meaning "good arousal" in Greek. It delivers natural-feeling alertnessand wakefulness without the powerful physical and mental jolt thatearlier stimulants delivered. "There are no amphetamine-like feelings,"says Yves. And as Yves' way of taking it shows, being on modafinildoesn't stop you from falling asleep if you want to.

Infact, its effects are so subtle that many users say they don't noticeanything at all - until they need to. "I wouldn't say it makes me feelmore alert or less sleepy. It's just that thoughts of tiredness don'toccur to me," says Yves. "If there's a job at hand that I should bedoing, I'm focused, but if I'm watching a movie or something, there isno effect."

People who take modafinil for medicalreasons usually take just enough of the drug in the morning to see themthrough the day, but it also seems to be able to deliver sustainedwakefulness - for a couple of days at least. "The military has testedsequential dosing," says Jeffrey Vaught, president of R&D atCephalon, modafinil's Pennsylvania-based manufacturer. "It works for 48hours or so, but eventually you need to sleep."

Perhapsthe most remarkable thing about modafinil is that users don't seem tohave to pay back any "sleep debt". Normally, if you stayed awake for 48hours straight you would have to sleep for about 16 hours to catch up.Modafinil somehow allows you to catch up with only 8 hours or so. Wellbefore Cephalon took an interest in the drug, French researchersdiscovered this effect in cats back in the early 1990s (Brain Research, vol 591, p 319), and it has since been found to apply to humans too.

Sohow does modafinil work? "No one really knows," admits Vaught. He saysthat Cephalon thinks it understands the drug, but is keeping thedetails under wraps. What is clear is that, like other stimulant drugs,modafinil prevents nerve cells from reabsorbing the excitatoryneurotransmitter dopamine once they release it into the brain. Thedifference is that it somehow does so without producing the addictivehighs and painful crashes associated with most stimulants. A number ofindependent studies suggest that this might be because it alsointerferes with the reuptake of another neurotransmitter, noradrenalin.

Howeverit works, modafinil is proving hugely successful. Since it hit themarket in 1998, sales have been climbing steadily - from $25 million in1999 to around $575 million in 2005. Cephalon insists that the drug isfor treating "medical" sleepiness caused by diseases such as narcolepsyand sleep apnoea.

Even so, it's clear thatmodafinil is becoming a lifestyle drug for people like Yves who wantoff-the-peg wakefulness. "At first I got it from a friend, and then Igot diagnosed as a narcoleptic online," says Yves.

Allthe indications are that modafinil is extremely safe. The drug can haveside effects, most commonly headaches, but up to now there have been nosevere reactions, says Vaught. In fact, it is hard to find anyone witha bad word to say about modafinil, except that there may be unseenproblems down the line as the drug becomes more widely used. "I thinkit's unlikely that there can be an arousal drug with no consequences,"says Foster. In the long run, it is possible that casual users mighthave to keep upping their dose to get the same effect. Stanley hassimilar worries. "Is it a potential drug of abuse?" he asks. "Will itget street value? We'll see."

Cephalon does notseem to be worried. Modafinil's success has spurred it to develop asuccessor, armodafinil. The company is also developing other eugeroics- one experimental drug called CEP-16795 switches off the H3 histaminereceptor, which appears to be one of the molecular switches thatcontrols the sleep-wake cycle. However, Vaught claims that the originalwill be a tough act to follow. "Modafinil is very effective and verysafe," he says. "How do you beat it?"

There areideas as to how. Last year, Sam Deadwyler of Wake Forest University inWinston-Salem, North Carolina, reported the results of an experimentwith a drug called CX717. The findings suggest that modafinil won'thave the field to itself forever.

Deadwyler kept11 rhesus monkeys awake for 36 hours, throughout which they performedshort-term memory and general alertness tests (Public Library of Sciences Biology,vol 3, p 299). At that level of sleep deprivation, a monkey'sperformance would normally drop to the point where it could barelyfunction at all, but Deadwyler found that CX717 had remarkablerestorative powers. Monkeys on the drug were doing better after 36hours of continual wakefulness than undrugged monkeys after normalsleep. When Deadwyler imaged their brains with functional magneticresonance imaging, (fMRI), he found that the drug maintained normalactivity even in severely sleep-deprived individuals. The results buildon those of an earlier, small-scale trial on 16 men that found CX717could largely reverse the cognitive decline that comes with 24 hours ofsleep deprivation (New Scientist, 14 May 2005, p 6).

Soldiers get high

CX717belongs to a class of drugs called ampakines, which subtly ramp upbrain activity by enhancing the action of its main excitatoryneurotransmitter, glutamate. Cortex Pharmaceuticals of Irvine,California, which developed CX717, originally saw the drug as acognitive booster for people with Alzheimer's, but it is its potentialto counter the effects of sleep deprivation that is attracting the mostattention.

Later this year, the Defense AdvancedResearch Projects Agency (DARPA), based in Arlington, Virginia, willput CX717 through its paces as a wakefulness promoter for combat. In anexperiment designed to mimic the harsh demands of special ops,investigators will push 48 volunteers to the limit - four consecutivenights of hard work with only 4 hours of recovery sleep in between."They'll go from being tired to exhausted to crashing," says RogerStoll, Cortex's chief executive. For some of them, however, the ordealwill be softened by regular doses of CX717. DARPA hopes the drug willcounteract the sleep deprivation.

The trial shouldhelp answer some outstanding questions about CX717's potential. "Wedon't know yet if it eliminates feelings of sleepiness," says Stoll."The early signs are that people function better, their brain is alittle more hyped. But we haven't tested sleepiness directly." As withmodafinil, the evidence suggests that people struggle to tell ifthey're on the drug or not, and that hasn't turned out to be much of aproblem for modafinil.

Whatever the outcome of theDARPA trial, CX717 won't be the last word on eugeroics. Stoll saysCortex has similar but more powerful molecules up its sleeve. Thoughtthey are being developed mainly as memory enhancers, some may turn outto be powerful wakefulness promoters too. Industry giantsGlaxoSmithKline and Eli Lilly have ampakine programmes of their own,and at least one other company, Arena Pharmaceuticals of San Diego,California, has declared an interest in wakefulness promoters, thoughit hasn't released any details of its research.

Whenand if those drugs come through, the US military is sure to beinterested. DARPA is one of the most active players in the drive toconquer sleep, setting up and funding much of the basic research onwakefulness. The army and air force have research programmes too.

It'seasy to see why DARPA is interested. "We make the assumption thatsoldiers are going to be sleep-deprived," says DARPA neuroscientist AmyKruse, who runs the agency's sleep-deprivation research programme. "Wewant to know what we can do to bring them back up to the level theywould be at if they had a good night's sleep."

WhenDARPA talks about sleep deprivation, it really means it. Soldiers onspecial ops sometimes have to be awake, alert and active for 72 hoursat a stretch with only minimal rest. That's like starting work onMonday morning and not stopping until Thursday. "Three days, that'swhen they really start hurting," says Kruse.

Themilitary has a long history of using caffeine and amphetamines to getits people through. It has now added modafinil to the list, and isclearly interested in CX717. And Kruse says she is confident that thereis lots of room for further improvement.

Lastyear, a DARPA-funded team led by Giulio Tononi at the University ofWisconsin Madison discovered a strain of fruit flies that gets by onjust a third the normal amount of sleep. The "minisleep" mutant carriesa change to a single gene, encoding a protein involved in potassiumtransport across cell membranes. Intriguingly, defects in potassiumchannels are associated with reduced sleep in humans, particularly inthe autoimmune disease Morvan's syndrome, one symptom of which ischronic sleeplessness. What that suggests, says Kruse, is that newdrugs designed to latch onto potassium channels in the brain couldradically alter the need for sleep. There are also likely to be othermolecular targets in the brain just waiting to be exploited, she says.

DARPAis meanwhile pursuing other strategies to conquer sleep deprivation. AtYaakov Stern's lab at Columbia University in New York, DARPA-fundedneuroscientists have used fMRI to image the brains of sleep-deprivedpeople, to find out which regions are affected when you are very tired.Then they used a transcranial magnetic stimulation (TMS) machine -routinely used to switch localised brain regions on and off - to switchoff those areas and see if that reversed the effects.

"Thisis all proof of concept," says Stern. "It's hard to imagine a sleepdeprived pilot using TMS," not least because the machines are too bulkyto fit in a cockpit. "The next step is to apply TMS before or duringsleep deprivation to see if it blunts the effect. That has more of ashot at a lasting effect." Stern says his team is also looking into anew technique called DC brain polarisation, which has similarbrain-boosting effects to TMS but uses DC current instead of magnetism.The beauty of this "poor man's TMS" is that the equipment issignificantly smaller and cheaper - it could even be incorporated intoheadgear that gives you a jolt of wakefulness at the flick of a switch.And then there's always neurofeedback - training people to activate thebrain regions that get hit by sleep deprivation, effectively willingthemselves awake.

The military isn't justinterested in wakefulness. It also has a keen interest in the otherside of the coin. John Caldwell works at the US Air Force ResearchLaboratory in San Antonio, Texas. He has spent most of his careertesting the effects of stimulants, including modafinil, on pilots. "I'mthe guy who puts sleep-deprived pilots in a plane, gives them drugs andsays, did it work?" he says. He has also done a handful of studies onsleep aids - testing the best way to help night pilots sleep wellduring the day, for example. In recent months Caldwell has become awarethat there is a quiet revolution going on in sleep medicine. "There's anew idea out there," he says. "Drugs that change sleep architecture."

Sleepresearchers have known for over 50 years that sleep isn't merely alengthy period of unconsciousness, but consists of several differentbrain states (see Diagram). How those states are put together to build a full night's sleep is called sleep architecture.

Catching the slow waves

Inthe past, says Caldwell, sleeping pills were designed not to mess withsleep architecture, although they generally do, suppressing the deepestand most restorative "slow-wave" sleep in favour of shallower stage 2sleep. Now, though, modifying sleep architecture is seen as the wayforward. There are two new drugs in the offing that significantlyincrease the amount of slow-wave sleep. One of them, gaboxadol, made byMerck, is in phase III clinical trials and could be on the market nextyear. To Caldwell these drugs hold out the promise of a power nap parexcellence. "Maybe you can make a short period of sleep morerestorative by filling it with up with slow-wave sleep," he says.

Muchlike modafinil, gaboxadol and the other slow-wave sleep promoter -Arena Pharmaceuticals' APD125, currently in phase II - are the start ofsomething bigger. For more than 35 years, sleeping pills have been aone-trick pony. If you wanted to send someone to the land of nod, therewas only one way of doing so - targeting the neurotransmitter GABA,which is the brain's all-purpose dimmer switch. Old-fashioned hypnoticssuch as barbiturates and benzodiazepines work by making neurons moresensitive to the soporific effects of GABA. It's also why alcohol makesyou sleepy. Even the newer, cleaner sleeping pills, such as the marketleader Ambien, work through the GABA system.

Manipulatingthe GABA system is a sure-fire way of putting people to sleep, but ithas its problems. One is that the brain adapts to the drugs, whichmeans that most cannot be taken for more than a few days without losingtheir potency. The effects often linger well into the morning, makingpeople feel groggy and hung over. Many are also addictive.

What'smore, sleep quality has rarely been considered. "In the past we wouldtake a hypnotic and say, does it put you to sleep?," says Stanley."That's a pretty inexact way of dealing with it. In that respect,alcohol is a good hypnotic." Now, however, there is a recognition thatthere is much more to sleep than the GABA system. Last year the firstnon-GABA sleeping pill came onto the market - the first new class ofhypnotic for 35 years. Rozerem, made by Japanese firm Takeda, mimicsthe effects of the sleep-promoting hormone melatonin. Nor is it theonly one. There are at least three other new classes of hypnotic thatdon't go anywhere near the GABA system. And though gaboxadol worksthrough GABA, it hits a type of receptor that has never been targetedby drugs before.

According to Stanley, there iseven more scope for improvement. "It is possible that pharmaceuticalswill allow you a condensed dose of sleep," he says, "and we are notthat far away from having drugs that put you to sleep for a certainlength of time." He predicts you could soon have tablet combining ahypnotic with an antidote or wakefulness promoter designed to give youa precise number of hours' sleep. "A 4, 5 or 6-hour pill."

Weseem to be moving inescapably towards a society where sleep andwakefulness are available if not on demand then at least on request.It's not surprising, then, that many sleep researchers have naggingworries about the long-term impact of millions of us using drugs tooverride the natural sleep-wake cycle.

Stanleybelieves that drugs like modafinil and CX717 will tempt people tooverdose on wakefulness at the expense of sleep. "Being awake is seento be attractive," he says. "It's not cool to be asleep." Foster hassimilar worries. "It seems like that technology will help us cope with24/7, but is coping really living?" he asks. Others point out thatthere are likely to be hidden health costs to overriding our naturalsleep-wake cycles. "Pharmaceuticals cannot substitute for normalsleep," says Vaught.

Still, even the doubtersadmit that to all intents and purposes we are already too far down theroad of the 24-hour society to turn back. For millions of people, goodsleep and productive wakefulness are already elusive, night work ornightlife a reality, and the "stimulant-sedative" loop all toofamiliar. As Vaught puts it, "We're already there." So why not make itas clean and safe as possible?