May 6, 2006
Modavigil "means I can go out partying on a Friday night and still go skiing early on Saturday morning."
A new drug tailors sleep to individual lifestyles but at what cost, asks Graham Lawton.
SO MUCH to do, so little time. Between a hectic work schedule and a thriving social life, Yves (not his real name), a 31-year-old software developer from Seattle, often doesn't have time for a full night's sleep. So he swallows something to make sure he doesn't need one. "If I take a dose just before I go to bed, I can wake up after four or five hours and feel refreshed," he says. "The alarm goes off and I'm like, let's go!"
Yves is talking about modafinil (marketed as Modavigil in Australia), a stimulant that since its launch seven years ago has acquired a near-mythical reputation for wiring you awake without the jitters, euphoria and eventual crash that come after caffeine or amphetamines. Yves has been popping modafinil on and off for the past three years and says it is "tremendously useful". "I find I can be very productive 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 go skiing early on Saturday morning."
Modafinil is just the first of a wave of new lifestyle drugs that promise to do for sleep what the contraceptive pill did for sex - unshackle it from nature. Since time immemorial, humans have structured their lives around sleep. In the near future, we will, for the first time, be able to significantly structure the way we sleep to suit our lifestyles.
"The more we understand about the body's 24-hour clock the more we will be able to override it," says Professor Russell Foster, a circadian biologist at Imperial College London. "In 10 to 20 years we'll be able to pharmacologically turn sleep off. Mimicking sleep will take longer, but I can see it happening." Professor Foster envisages a world in which it's possible, or even routine, for people to be active for 22 hours a day and sleep for two.
It is not a world that everyone likes the sound of. "I think that would be the most hideous thing to happen to society," says Dr Neil Stanley, head of sleep research at the Human Psychopharmacology Research Unit in the University of Surrey, in Britain.
But most sleep researchers agree it is inevitable.
If that sounds unlikely, think about what is already here. Modafinil has made it possible to have 48 hours of continuous wakefulness with few, if any, ill effects. New classes of sleeping pills are on the horizon that promise to deliver sleep that is deeper and more refreshing than the real thing. Further down the line are even more radical interventions - wakefulness promoters that can safely abolish sleep for several days at a stretch, and sleeping pills that deliver what feels like eight hours of sleep in half the time. Nor is it all about drugs: one research team even talks about developing a wearable electrical device that can wake your brain up at the flick of a switch.
To some degree we are already adept at controlling sleep. Most people in full-time work deprive themselves of sleep during the week, deliberately or otherwise, and catch up at the weekend. We often augment our sleep-suppressing powers with caffeine, nicotine or illegal stimulants such as cocaine and amphetamines. We are also highly dependent on substances that help us sleep. According to some estimates, 75 per cent of adults suffer at least one symptom of a sleep problem a few nights a week or more. In 1998, a team from the Henry Ford Health Sciences Research Institute in Detroit, Michigan, published a study revealing that 13 per cent of adult Americans had used alcohol to help them get to sleep in the previous year, and 18 per cent had used sleeping pills.
Despite the enormous resources that we pour into getting good sleep and wakefulness when we want them, most of the drugs at our disposal are crude instruments at best. The vast majority of sleeping pills - known in the business as hypnotics - are simply "knockout drops" that put you in a state almost like sleep but without its full restorative properties. "Hypnotic-induced sleep is better than no sleep, but it isn't natural sleep," says Dr Stanley. With their addictive nature, the drugs we use to keep us awake, such as coffee and amphetamines, are even worse. In combination with our clock-watching lifestyles, these sleep and wake aids are driving ever more people into what Professor Foster calls the "stimulant-sedative loop" where they need nightly help getting to sleep and daily help staying awake.
Modafinil has changed the rules of the game. The drug is what's known as a eugeroic, meaning "good arousal" in Greek. It delivers natural-feeling alertness and wakefulness without the powerful physical and mental jolt that earlier stimulants delivered. "There are no amphetamine-like feelings," says Yves. And as Yves' way of taking it shows, being on modafinil doesn't stop you from falling asleep if you want to.
Its effects are so subtle that many users say they don't notice anything at all - until they need to. "I wouldn't say it makes me feel more alert or less sleepy. It's just that thoughts of tiredness don't occur to me," says Yves. "If there's a job at hand that I should be doing, I'm focused, but if I'm watching a movie or something, there is no effect."
People who take modafinil for medical reasons usually take just enough of the drug in the morning to see them through the day, but it also seems to be able to deliver sustained wakefulness - for a couple of days at least. "The military has tested sequential dosing," says Jeffrey Vaught, president of research and development at Cephalon, modafinil's Pennsylvania-based manufacturer. "It works for 48 hours or so, but eventually you need to sleep."
Perhaps the most remarkable thing about modafinil is that users don't seem to have to pay back any "sleep debt". Normally, if you stayed awake for 48 hours straight, you would have to sleep for about 16 hours to catch up. Modafinil somehow allows you to catch up with only eight hours or so. Well before Cephalon took an interest in the drug, French researchers in the early 1990s discovered this effect in cats, and it has since been found to apply to humans too.
How does modafinil work? "No one really knows," admits Mr Vaught. He says that Cephalon thinks it understands the drug, but is keeping the details under wraps. What is clear is that, like other stimulant drugs, modafinil prevents nerve cells from reabsorbing the excitatory neurotransmitter dopamine once they release it into the brain. The difference is that it somehow does so without producing the addictive highs and painful crashes associated with most stimulants. Several independent studies suggest that this might be because it also interferes with the re-uptake of another neurotransmitter, noradrenalin.
However it works, modafinil is proving hugely successful. Since it hit the market in 1998, sales have been climbing steadily - from $US25 million ($A33.5 million) in 1999 to about $US575 million in 2005. Cephalon insists that the drug is for treating "medical" sleepiness caused by diseases such as narcolepsy and sleep apnoea.
Even so, it's clear that modafinil is becoming a lifestyle drug for people such as Yves who want off-the-peg wakefulness. "At first I got it from a friend, and then I got diagnosed as a narcoleptic online," says Yves.
All the indications are that modafinil is extremely safe. The drug can have side effects, most commonly headaches, but up to now there have been no severe reactions, says Mr Vaught. It is hard to find anyone with a bad word to say about modafinil, except that there may be unseen problems down the line as the drug becomes more widely used. "I think it's unlikely that there can be an arousal drug with no consequences," says Professor Foster. In the long run, it is possible that casual users may have to keep upping their dose to get the same effect. Neil Stanley has similar worries. "Is it a potential drug of abuse?" he asks. "Will it get street value? We'll see."
Cephalon does not seem to be worried. Modafinil's success has spurred it to develop a successor, armodafinil. The company is also developing other eugeroics - one experimental drug called CEP-16795 switches off the H3 histamine receptor, which appears to be one of the molecular switches that controls the sleep-wake cycle. However, Mr Vaught claims that the original will be a tough act to follow. "Modafinil is very effective and very safe," he says.
"How do you beat it?"
There are ideas as to how. Last year, Samuel Deadwyler, of Wake Forest University in Winston-Salem, North Carolina, reported the results of an experiment with a drug called CX717. The findings suggest that modafinil won't have the field to itself forever.
Mr Deadwyler kept 11 rhesus monkeys awake for 36 hours, throughout which they performed short-term memory and general alertness tests. At that level of sleep deprivation, a monkey's performance would normally drop to the point where it could barely function at all, but Mr Deadwyler found that CX717 had remarkable restorative powers. Monkeys on the drug were doing better after 36 hours of continual wakefulness than undrugged monkeys after normal sleep. When Mr Deadwyler imaged their brains with functional magnetic resonance imaging, (fMRI), he found that the drug maintained normal activity even in severely sleep-deprived individuals. The results build on those of an earlier, small-scale trial on 16 men that found CX717 could largely reverse the cognitive decline that comes with 24 hours of sleep deprivation.
CX717 belongs to a class of drugs called ampakines, which subtly ramp up brain activity by enhancing the action of its main excitatory neurotransmitter, glutamate. Cortex Pharmaceuticals, of Irvine, California, which developed CX717, originally saw the drug as a cognitive booster for people with Alzheimer's, but it is its potential to counter the effects of sleep deprivation that is attracting the most attention.
Later this year, the Defense Advanced Research Projects Agency (DARPA), based in Arlington, Virginia, will put CX717 through its paces as a wakefulness promoter for combat. In an experiment designed to mimic the harsh demands of special operations, investigators will push 48 volunteers to the limit - four consecutive nights of hard work with only four hours of recovery sleep in between.
"They'll go from being tired to exhausted to crashing," says Roger Stoll, Cortex's chief executive. For some of them, however, the ordeal will be softened by regular doses of CX717. DARPA hopes the drug will counteract the sleep deprivation.
The trial should help answer some outstanding questions about CX717's potential. "We don't know yet if it eliminates feelings of sleepiness,"says Mr Stoll. "The early signs are that people function better, their brain is a little more hyped. But we haven't tested sleepiness directly." As with modafinil, the evidence suggests that people struggle to tell if they're on the drug or not, and that hasn't turned out to be much of a problem for modafinil.
Whatever the outcome of the DARPA trial, CX717 won't be the last word on eugeroics. Mr Stoll says Cortex has similar but more powerful molecules up its sleeve. Although they are being developed mainly as memory enhancers, some may turn out to be powerful wakefulness promoters, too. Industry giants GlaxoSmithKline and Eli Lilly have ampakine programs of their own, and at least one other company, Arena Pharmaceuticals, of San Diego, California, has declared an interest in wakefulness promoters, although it hasn't released any details of its research.
When and if those drugs come through, the US military is sure to be interested. DARPA is one of the most active players in the drive to conquer sleep, setting up and funding much of the basic research on wakefulness.
The army and air force have research programs, too.
It's easy to see why DARPA is interested. "We make the assumption that soldiers are going to be sleep-deprived," says DARPA neuroscientist Dr Amy Kruse, who runs the agency's sleep-deprivation research program. "We want to know what we can do to bring them back up to the level they would be at if they had a good night's sleep."
When DARPA talks about sleep deprivation, it really means it. Soldiers on special operations sometimes have to be awake, alert and active for 72 hours with only minimal rest. That's like starting work on Monday morning and not stopping until Thursday. "Three days, that's when they really start hurting," says Dr Kruse.
The military has a long history of using caffeine and amphetamines to get its people through. It has now added modafinil to the list, and is clearly interested in CX717. Dr Kruse says she is confident that there is lots of room for further improvement.
Last year, a DARPA-funded team led by Giulio Tononi, at the University of Wisconsin-Madison, discovered a strain of fruit flies that gets by on just a third the normal amount of sleep. The "minisleep" mutant carries a change to a single gene, encoding a protein involved in potassium transport across cell membranes. Intriguingly, defects in potassium channels are associated with reduced sleep in humans, particularly in auto-immune disease Morvan's syndrome, one symptom of which is chronic sleeplessness. What that suggests, says Dr Kruse, is that new drugs designed to latch onto potassium channels in the brain could radically alter the need for sleep. There are also likely to be other molecular targets in the brain just waiting to be exploited, she says.
Meanwhile, DARPA is pursuing other strategies to conquer sleep deprivation. At Dr Yaakov Stern's lab at Columbia University in New York, DARPA-funded neuroscientists have used fMRI to image the brains of sleep-deprived people, 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 switch off those areas and see if that reversed the effects.
"This is all proof of concept," says Dr Stern. "It's hard to imagine a sleep deprived pilot using TMS," not least because the machines are too bulky to fit in a cockpit. "The next step is to apply TMS before or during sleep deprivation to see if it blunts the effect. That has more of a shot at a lasting effect." Dr Stern says his team is also looking into a new technique called DC brain polarisation, which has similar brain-boosting effects to TMS but uses DC current instead of magnetism. The beauty of this "poor man's TMS" is that the equipment is significantly smaller and cheaper - it could even be incorporated into headgear that gives you a jolt of wakefulness at the flick of a switch. And then there's always neurofeedback - training people to activate the brain regions that get hit by sleep deprivation, effectively willing themselves awake.
The military isn't just interested in wakefulness. It also has a keen interest in the other side of the coin. John Caldwell works at the US Air Force Research Laboratory in San Antonio, Texas. He has spent most of his career testing the effects of stimulants, including modafinil, on pilots. "I'm the guy who puts sleep-deprived pilots in a plane, gives them drugs and says, did it work?" he says. He has also done a handful of studies on sleep aids - testing the best way to help night pilots sleep well during the day, for example. In recent months Mr Caldwell has become aware that there is a quiet revolution going on in sleep medicine. "There's a new idea out there," he says. "Drugs that change sleep architecture."
Sleep researchers have known for more than 50 years that sleep isn't merely a lengthy period of unconsciousness, but consists of several different brain state. How those states are put together to build a full night's sleep is called sleep architecture.
In the past, says Mr Caldwell, sleeping pills were designed not to mess with sleep architecture, although they generally do, suppressing the deepest and most restorative "slow-wave" sleep in favour of shallower sleep. Now, though, modifying sleep architecture is seen as the way forward. There are two new drugs in the offing that significantly increase the amount of slow-wave sleep. One of them, gaboxadol, made by Merck, is in phase III clinical trials and could be on the market next year. To Mr Caldwell these drugs hold out the promise of a power nap par excellence. "Maybe you can make a short period of sleep more restorative by filling it with up with slow-wave sleep," he says.
Much like modafinil, gaboxadol and the other slow-wave sleep promoter - Arena Pharmaceuticals' APD125, currently in phase II - are the start of something bigger. For more than 35 years, sleeping pills have been a one-trick pony. If you wanted to send someone to the land of nod, there was only one way of doing so - targeting the neurotransmitter GABA, which is the brain's all-purpose dimmer switch. Old-fashioned hypnotics such as barbiturates and benzodiazepines work by making neurons more sensitive to the soporific effects of GABA. It's also why alcohol makes you sleepy. Even the newer, cleaner sleeping pills, such as the market leader Ambien, work through the GABA system.
Manipulating the GABA system is a sure-fire way of putting people to sleep, but it has its problems. One is that the brain adapts to the drugs, which means that most cannot be taken for more than a few days without losing their potency. The effects often linger well into the morning, making people feel groggy and hungover.
Many are also addictive.
What's more, sleep quality has rarely been considered. "In the past we would take a hypnotic and say, does it put you to sleep?," says the University of Surrey's Dr 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 that there is much more to sleep than the GABA system. Last year the first non-GABA sleeping pill came onto the market - the first new class of hypnotic for 35 years. Rozerem, made by Japanese company Takeda, mimics the effects of the sleep-promoting hormone melatonin. Nor is it the only one. There are at least three other new classes of hypnotic that don't go anywhere near the GABA system. And though gaboxadol works through GABA, it hits a type of receptor that has never been targeted by drugs before.
According to Dr Stanley, there is even more scope for improvement.
"It is possible that pharmaceuticals will allow you a condensed dose of sleep," he says, "and we are not that far away from having drugs that put you to sleep for a certain length of time." He predicts you could soon have tablet combining a hypnotic with an antidote or wakefulness promoter designed to give you a precise number of hours' sleep. "A four-, five- or six-hour pill."
We seem to be moving inescapably towards a society where sleep and wakefulness are available if not on demand then at least on request. It's not surprising, then, that many sleep researchers have nagging worries about the long-term impact of millions of us using drugs to override the natural sleep-wake cycle.
Dr Stanley believes drugs such as modafinil and CX717 will tempt people to overdose on wakefulness at the expense of sleep. "Being awake is seen to be attractive," he says. "It's not cool to be asleep."
Imperial College's Professor Foster has similar worries. "It seems like that technology will help us cope with 24/7, but is coping really living?" he asks. Others point out that there are likely to be hidden health costs to overriding our natural sleep-wake cycles. "Pharmaceuticals cannot substitute for normal sleep," says Cephalon's Mr Vaught.
Still, even the doubters admit that to all intents and purposes we are already too far down the road of the 24-hour society to turn back. For millions of people, good sleep and productive wakefulness are already elusive, night work or nightlife a reality, and the "stimulant-sedative" loop all too familiar. As Mr Vaught puts it, "We're already there." So why not make it as clean and safe as possible?
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