What causes adenosine build up in the brain when awake?

What causes adenosine build up in the brain when awake?

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Adenosine is an important hormone in sleep regulation. It is postulated that when a person is awake, there is a build up of adenosine in the brain, which inhibits the neurons in the brain, and produces tiredness. (See answer for more information: What causes humans to be sleepy?)

However, I am wondering what specifically causes this adenosine build up. I understand ATP (adenosine tri-phosphate) is broken down to ADP in the brain to produce energy. I thought this ADP would then be used to re-generate ATP again etc, so I'm not sure how adenosine is built up in the brain over a day.

Basically I am unsure how Adenosine itself, as opposed to ATP or ADP, is produced during the waking state?

My theory is that during the high demand waking state there is insufficient energy to convert ADP back to ATP, and the excess ADP is broken down to adenosine somehow.

I would appreciate an explanation of how this build up occurs, and also an explanation of how this in turn how it induces sleepiness would be a plus.

Adenosine causes humans to become sleepy. But how ?

  • During day time we consume food which is broken down into glucose. This glucose is broken down by "Glycolysis" in cell's cytoplasm during which ATP is produced. This produced ATP is is then used by body as an energy supplier. ATP breaks down into ADP and then AMP with the release of energy which our body consumes for doing work.

(Fig 1- Structure of Adenosine to ATP)

Adenosine is produced continuously and starts to accumulate around and in Adenosine receptors such as A1, A2a, A2b and A3 (as shown in fig below).Adenosine inhibit signal propagation and energy production in at least A1. (Not all the receptors induce sleep when they receive Adenosine.) "A1 receptor" receives adenosine and induces sleep. A1 receptors are implicated in sleep promotion by inhibiting wake-promoting cholinergic neurons in the basal forebrain.

Continuous inhibition of A1 receptor by Adenosine slowly induces sleep by relaxing the brain and muscles but without substantially weakening their abilities!

How is Adenosine metabolized ?

During sleep the accumulated Adenosine is metabolized by Adenosine deaminase enzyme which catalyzes the irreversible deamination of 2'-deoxyadenosine and adenosine to deoxyinosine and inosine. With the reduction in the Adenosine content the body is excited from sleep slowly.

So in short summarize:

The accumulation of adenosine during waking periods is thus associated with the depletion of the ATP reserves stored as glycogen in the brain. The increased adenosine levels trigger non-REM sleep, during which the brain is less active, thus placing it in a recovery phase that is absolutely essential-among other things, to let it rebuild its stores of glycogen.

Because adenosine is continuously metabolized by the enzyme adenosine desaminase, the decline in adenosine production during sleep quickly causes a general decline in adenosine concentrations in the brain, eventually producing conditions more favourable to awakening.


What causes adenosine build up in the brain when awake? - Biology


Stanford researchers suggest how sleep re-charges the brain

STANFORD -- Why do we sleep? The answer seems obvious - to restore ourselves at the end of a long day. However, scientists have surprisingly little information about exactly what is restored during sleep. According to Stanford biologist Craig Heller, "the function of sleep is one of the major unanswered questions in biology."

Heller and a former graduate student may have found the answer to that question, at the level of individual brain cells. They suggest that only during deep, restful sleep can human brain cells replenish the energy stores they deplete during a full day of thinking, sensing and reacting.

Heller, the Lorry I. Lokey / Business Wire Professor of Biological Sciences and associate dean of research at Stanford, and Joel Benington, now a Stanford research scientist, presented their hypothesis in a recent issue of the journal Progress in Neurobiology , in a theory paper based on their research and a review of the scientific literature on neurobiology and sleep. In the journal Brain Research , they present the details of the experimental evidence supporting their ideas, from research they carried out at the Stanford Center for Sleep and Circadian Neurobiology.

Sleep is such a fundamental need that scientists long have known it must be governed by some form of homeostatic control, a feedback mechanism like the controls that keep the body's blood pressure, temperature and other aspects of its internal environment within narrow ranges.

Benington and Heller's experiments have identified a possible controlling agent of this homeostatic feedback, a neurotransmitting chemical, adenosine, that seems to govern how deeply a laboratory rat - and presumably a person - will sleep after a period of wakefulness.

Adenosine is released by brain cells when the cells' demand for energy exceeds available supplies. Heller and Benington speculate that adenosine release is one step in the homeostatic feedback loop, signaling the cells to rest so that the essential element they need - energy - can be replenished. They speculate that the brain's only source of stored energy, glycogen, is depleted in different regions of the brain where energy demands are high during wakefulness, and is then replenished during sleep.

Understanding the biochemical nature of sleep may lead to treatments for some sleep disorders, or allow chronic insomniacs to get enough restful sleep. Heller notes that scientists ultimately may be able to intensify the depth of sleep so a full night's rest could be gained in, say, four hours. Alternatively, the need for sleep could be temporarily "put on hold" when a person needs to stay alert beyond normal physiological limits - for example, during shift work, recovery from jet-lag or combat.

The need for sleep is so intense, said Benington, "it is virtually impossible to keep a sleep-deprived animal or person awake for very long periods." Other researchers have shown that lack of sleep leads shift workers to fall asleep at the factory bench, and causes thousands of over-tired drivers to fall asleep on the road each year.

The intensity of sleep need led Heller and Benington to the hypothesis that whatever is restored during sleep must be important to the brain's normal functioning.

Although glycogen supplies less than 6 percent of all the fuel needs of brain cells (the rest comes from glucose delivered via the bloodstream), it is necessary because it can be called into use very quickly to meet the needs of highly active cells in localized regions of the brain. Glycogen acts like a spare battery that keeps an electrical appliance running during a temporary power outage. Because the brain does not burn fat, glycogen is the only source of spare energy for neurons.

During normal thinking and reacting, Benington and Heller speculate, the relatively small glycogen stores in the brain gradually are used up, at least in certain regions. At this point, it becomes increasingly difficult for the brain to accommodate demands for sudden increases in regional activity.

Glycogen supplies take time to replenish unless brain cells stop their constant business of sensing and reacting, it should be difficult to rebuild this energy store. Thus, Benington and Heller say, the individual experiences glycogen loss as a buildup of the need for a good night's sleep.

Glycogen loss also triggers the release of adenosine. Heller and Benington speculate that adenosine release increases when glycogen is depleted, and that adenosine acts as a messenger to the cells, promoting restful sleep.

Benington designed an experiment to test the hypothesis that adenosine is the messenger in the sleep homeostatic feedback mechanism. He showed that its concentration influences brain cells after the onset of sleep, and seems to determine how deeply we sleep.

A chemical similar to adenosine was injected into rats that had already fully replenished their sleep need. The rats returned to deep sleep, as measured by EEG (electroencephalographic) scans. The EEG readings closely mimicked the slow electrical waves typically seen in normal sleep after prolonged wakefulness.

The conclusion was that restorative sleep is promoted by the presence of adenosine or a similar chemical.

Previous findings on the effects of caffeine on sleep fit with Heller and Benington's adenosine hypothesis. Caffeine is known to block the adenosine receptor sites on the brain cells, preventing adenosine from acting on the cell. It masks the need for sleep, but because it does not eliminate that need, caffeine is not a substitute for restful sleep. An extra cup of coffee can combat the drowsiness that comes from sleep need, but it just can't substitute for a good night's sleep.

The clock, the homeostat and REM sleep

What about the circadian rhythm, the familiar biological clock that tells owls to stay awake all night and humans to stay awake all day?

"Circadian control is critical to sleep and wakefulness," Heller said. However,
the sleep-need homeostat works independently from the circadian clock. In fact, Heller and Benington say, the clock is needed to keep humans and other diurnal animals awake during the day - without it, we would fall asleep as soon as our biochemical need for sleep was strong enough.

They cite recent research by Stanford research scientist Dale Edgar that shows that the circadian clock works like an alarm, "ringing" to keep us awake in spite of an increasing need for sleep. Animals without strong day-night schedules, like cats and guinea pigs, sleep in short bursts throughout the day, whenever the sleep homeostat signals a need for rest and energy restoration. Owls and humans sleep when the internal clock stops ringing.

If Heller and Benington's hypothesis is correct, once a person's clock shuts off at night, the sleep-need feedback mechanism takes over to ensure that he sleeps long enough to restore his brain's glycogen stores.

Their research also provides some evidence that a related biochemical homeostat controls REM sleep, the restless rapid-eye-movement sleep that often coincides with dreams. The sleep cycle, the switch between REM and non-REM sleep, normally occurs several times a night in humans, and many more times during the sleep of other mammals. In another set of papers in Progress in Neurobiology and Brain Research, Heller and Benington propose that REM sleep is needed to perform a biochemical task so that the body can return to non-REM sleep.

Non-REM is the deep sleep associated with slow-wave readings on the EEG. Heller and Benington propose that this is the essential part of sleep, where the sleep debt accumulated during waking is restored. Non-REM sleep has biochemical costs: for example, brain cells are kept in this quiet state thanks to a slow leak of positive ions from the cell membrane. Benington and Heller propose that a cycle of REM sleep, when the brain is partly active, may be needed to pump positive ions back into the cells, so another cycle of non-REM sleep can begin.

What about the dreams in REM sleep? Does REM clear the memory banks or consolidate new memories? Does it help us work through deeply seated psychological problems?

If its function were purely psychological, REM sleep would likely show different patterns in different animals. But it seems to make up about 20% of total sleep time in a wide variety of animals. As Heller noted, "You can't tell me a rat is working out his Freudian problems during REM sleep".

Putting the theory to the test

While this is not the only attempt to explain the function of sleep, Heller said it is the most comprehensive and compelling so far.

For example, experimental evidence that sleep need increases when the brain is heated, such as during exercise, has led some researchers to argue that sleep serves as a temperature regulation and recovery process for the brain. This evidence also can be explained by Heller and Benington's hypothesis, since an increase in temperature boosts the brain's metabolic rate. That could cause the glycogen stores to be used more rapidly, eventually resulting in greater sleep need.

However, Benington stressed, a number of outstanding questions about glycogen metabolism in the brain must be answered before the hypothesis can be confirmed. Benington and Heller now are working with Raymond Swanson, a researcher at the Veterans Affairs Medical Center in San Francisco, to directly measure glycogen levels during wakefulness and sleep. They want to test two questions crucial to the hypothesis: Are brain glycogen stores substantially depleted during normal waking behavior? Are they restored only during sleep?

Meanwhile, Heller and Benington's hypothesis has attracted enough attention that they shortly will begin testing the effect on sleep of certain drugs that mimic the effect of adenosine. Such compounds already have been developed by several pharmaceutical companies but until now were intended for other purposes.

Currently, there are no suitable drugs for the treatment of chronic insomnia. People rapidly develop tolerance to existing sleeping medication, leading them to take higher doses and to mix medications. This can result in bad side effects and even worse insomnia when they try to reduce the medications.

Heller and Benington expect that by manipulating the brain's own signaling system for the control of sleep, it may be possible to develop safe, effective medications that will help people achieve a good night's sleep.

Editor's note: Benington and Heller's theory paper, "Restoration of brain energy metabolism as the function of sleep," was published in the journal Progress in Neurobiology , Vol. 45 (1995), pp. 347-360. Their research report, "Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation," was published in the journal Brain Research , Vol. 692 (1995), pp. 79-80.

How the Brain Reacts to Sleep Deprivation

Summary: Sleep deprivation increases the number of available A1 adenosine receptors, but restorative sleep helps normalize them again, a new study reports.

Source: Forschungszentrum Jülich.

In a new study, scientists from Forschungszentrum Jülich together with partners from the German Aerospace Center (DLR) have investigated the molecular changes with which the human brain reacts to exceptionally long wake phases. The test subjects stayed awake for 52 hours and then had their brains scanned at Jülich’s PET Centre. Subsequently, they were taken to DLR in Cologne, where – monitored by the scientists – they were able to catch up on their sleep for 14 hours.

Lack of sleep can severely affect our performance and health. Moreover, a lack of sleep causes changes in the brain which the researchers were able to measure in their experiment. “Our investigations have shown that sleep deprivation increases the number of available A1 adenosine receptors. Thanks to the subsequent sleep phase, they then normalized back to the initial level,” reports PD Dr. David Elmenhorst from Jülich’s Institute of Neuroscience and Medicine (INM-2).

The A1 adenosine receptors are built into the cell wall as a type of receiver. Their function is to forward the signal from adenosine, the docking chemical messenger, to the interior of the cell, where it decreases the cell’s activity. It is thought that not only the adenosine itself but also the A1 receptors are responsible for the urge to sleep, which becomes stronger the longer a person stays awake. Adenosine is an elementary product of the energy metabolism. Its concentration varies practically second by second. The number of free receptors, in contrast, changes much more slowly and thus seems better suited for a kind of “sleep memory”.

Resistant to sleep deprivation

The effect of caffeine is also associated with this type of receptor. The stimulant accumulates at complex protein molecules and blocks them. In this series of experiments, the test subjects had to do without coffee and other invigorating substances. During their 52-hour wake phase, they were subjected to several performance tests: pressing buttons to measure their reaction time and memorizing words to determine their memory performance. One striking feature was the individual differences in performance: some of the sleep-deprived participants displayed extreme lapses, sometimes lasting several seconds, while in others a performance drop was hardly measurable. Such a predisposition could be advantageous for jobs in which people regularly have to perform reliably in spite of lacking sleep.

Average adenosine receptor density after a 52-hour wake phase (top) and after 14 hours of sleep (bottom). image is credited to Forschungszentrum Jülich / Ralf-Uwe Limbach.

“Astonishingly, we did not measure a constant value of A1 receptor density in this seemingly resistant group of test subjects, but a large increase,” reports David Elmenhorst. The higher value does not correspond to an exceptionally high concentration of receptor molecules, however, since positron emission tomography (PET) records only a net value. Tracer molecules in the blood stream of the test subjects dock to free receptor molecules and can be observed in the PET scanner when they decay. In this manner, only those receptors are recorded that are not blocked and therefore available at the time of measurement. “Our theory is, therefore, that the test subjects with high A1 receptor density produce relatively little adenosine and thus inhibit the cell activity to a lesser degree,” says Elmenhorst. Consequently, the total number of free receptors is higher at the time of the PET measurement.

EEG scan. Credit: Forschungszentrum Jülich / Ralf-Uwe Limbach.

Relevant for treating depression

These findings are also of relevance for clinical medicine: sleep deprivation is a quick tool against depression, but only effective for a short time. “There are many efforts to increase the duration of the therapeutic effects of sleep deprivation in the treatment of depression. But the problem so far is that when people sleep again just once they often fall back into their depressed state,” says David Elmenhorst. A better understanding of the interrelations between mood and adenosine regulation could thus contribute to optimizing the design of wake therapies.

The role of adenosine in the regulation of sleep

This paper presents an overview of the current knowledge about the role of adenosine in the sleep-wake regulation with a focus on adenosine in the central nervous system, regulation of adenosine levels, adenosine receptors, and manipulations of the adenosine system by the use of pharmacological and molecular biological tools. The endogenous somnogen prostaglandin (PG) D(2) increases the extracellular level of adenosine under the subarachnoid space of the basal forebrain and promotes physiological sleep. Adenosine is neither stored nor released as a classical neurotransmitter and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The extracellular concentration of adenosine increases in the cortex and basal forebrain during prolonged wakefulness and decreases during the sleep recovery period. Therefore, adenosine is proposed to act as a homeostatic regulator of sleep and to be a link between the humoral and neural mechanisms of sleep-wake regulation. Both the adenosine A(1) receptor (A(1)R) and A(2A)R are involved in sleep induction. The A(2A)R plays a predominant role in the somnogenic effects of PGD(2). By use of gene-manipulated mice, the arousal effect of caffeine was shown to be dependent on the A(2A)R. On the other hand, inhibition of wake-promoting neurons via the A(1)R also mediates the sleep-inducing effects of adenosine, whereas activation of A(1)R in the lateral preoptic area induces wakefulness, suggesting that A(1)R regulates the sleep-wake cycle in a site-dependent manner. The potential therapeutic applications of agonists and antagonists of these receptors in sleep disorders are briefly discussed.

How Caffeine Works

Why do so many people consume so much caffeine? Why does caffeine wake you up? In short, it's all about two words: brain chemistry.

In the article How Sleep Works, the action of adenosine is discussed in detail. But while it sounds like advanced science, it's really pretty simple. As adenosine is created in the brain, it binds to adenosine receptors. This binding causes drowsiness by slowing down nerve cell activity. In the brain, this also causes blood vessels to dilate, most likely to let more oxygen into that organ during sleep.

To a nerve cell, caffeine looks like adenosine: Caffeine binds to the adenosine receptor. However, caffeine doesn't slow down the cell's activity like adenosine would. As a result, the cell can no longer identify adenosine because caffeine is taking up all the receptors that adenosine would normally bind to. Instead of slowing down because of the adenosine's effect, the nerve cells speed up. Caffeine also causes the brain's blood vessels to constrict, because it blocks adenosine's ability to open them up. This effect is why some headache medicines like Anacin contain caffeine -- constricting blood vessels in the brain can help stop a vascular headache.

Caffeine's effect on the brain causes increased neuron firing. The pituitary gland senses this activity and thinks some sort of emergency must be occurring, so it releases hormones that tell the adrenal glands to produce adrenaline (epinephrine). Adrenaline is the "fight or flight" hormone, and it has a number of effects on your body:

  • Your pupils dilate.
  • The airway opens up (this is why people suffering from severe asthma attacks are sometimes injected with epinephrine).
  • Your heart beats faster.
  • Blood vessels on the surface constrict to slow blood flow from cuts and increase blood flow to muscles.
  • Blood pressure rises.
  • Blood flow to the stomach slows.
  • The liver releases sugar into the bloodstream for extra energy.
  • Muscles tighten up, ready for action.

This explains why, after consuming a big cup of coffee, your hands get cold, your muscles grow tense, you feel excited and your heart beats faster.

Adenosine isn't the only neurotransmitter affected by caffeine. Read on to learn about how the drug affects dopamine, another important chemical in the body.

How Much Coffee Is Too Much Coffee?

Modern science has helped us understand how coffee helps the brain and the different ways it can influence us neurologically.

However, this does not take away the fact that there are adverse effects of excessive coffee drinking.

So the question of “how much coffee is too much” remains an important one.

The Food and Drug Administration (FDA) classifies caffeine as both a food additive and a drug. (15)

The FDA recommends that adults restrict their caffeine intake to at most 400 milligrams daily which is equivalent to about 5 cups of coffee.

This quantity can not result in any of the negative effects associated with caffeine.

The American Academy of Pediatrics (AAP) advises against the consumption of caffeine and other psychoactive drugs by children and adolescents.

However, caffeine is not only present in coffee.

It can also be found in a number of common foods and drinks, which is perhaps one of the reasons why it is easy to forget caffeine is actually a drug.

Beverages and foods like tea, chocolate, energy drinks, syrup, jelly beans, marshmallows and waffles all contain varying amounts of caffeine.

Most of these foods are marketed to children which has raised concerns regarding their potential impact on children. As such, these substances should only be consumed in moderation. (16)

Deep into Sleep

While researchers probe sleep's functions, sleep itself is becoming a lost art.

Charles Czeisler, chair, Devision of Sleep Medicine, shown in the General Clinical Research Center at Brigham and Women’s Hospital

Photograph by John Soares

Charles Czeisler, chair, Devision of Sleep Medicine, shown in the General Clinical Research Center at Brigham and Women’s Hospital

Photograph by John Soares


The National Sleep Foundation&rsquos 2005 survey found that 75 percent of American adults experience symptoms of a sleep problem at least a few.

One of Sigmund Freud&rsquos great complaints about his mistreatment in life was that although he won a literary award for his famous book The.

Not long ago, a psychiatrist in private practice telephoned associate professor of psychiatry Robert Stickgold, a cognitive neuroscientist specializing in sleep research. He asked whether Stickgold knew of any reason not to prescribe modafinil, a new wakefulness-promoting drug, to a Harvard undergraduate facing a lot of academic work in exam period.

The question resonated on several levels. Used as an aid to prolonged study, modafinil is tantamount to a “performance-enhancing” drug—one of those controversial, and often illegal, boosters used by some athletes. In contrast to wakefulness-producing stimulants like amphetamines, modafinil (medically indicated for narcolepsy and tiredness secondary to multiple sclerosis and depression) does not seem to impair judgment or produce jitters. “There’s no buzz, no crash, and it’s not clear that the body tries to make up the lost sleep,” reports Stickgold. “That said, all sleeping medications more or less derange your normal sleep patterns. They do not produce normal sleep.” Even so, the U.S. military is sinking millions of dollars into research on modafinil, trying to see if they can keep soldiers awake and on duty—in Iraq, for example—for 80 out of 88 hours: two 40-hour shifts separated by eight hours of sleep.

“No—no reason at all not to,” Stickgold told the psychiatrist. “Not unless you think sleep does something.”

When people make the unlikely claim that they get by on four hours of sleep per night, Stickgold often asks if they worry about what they are losing. “You get a blank look,” he says. “They think that sleep is wasted time.” But sleep is not merely “down time” between episodes of being alive. Within an evolutionary framework, the simple fact that we spend about a third of our lives asleep suggests that sleep is more than a necessary evil. Much transpires while we are asleep, and the question is no longer whether sleep does something, but exactly what it does. Lack of sleep may be related to obesity, diabetes, immune-system dysfunction, and many illnesses, as well as to safety issues such as car accidents and medical errors, plus impaired job performance and productivity in many other activities.

Although the modern era of sleep research started in the 1950s with the discovery of REM (Rapid Eye Movement) sleep, the field remained, well, somnolent until recently. Even 20 years ago, “The dominant paradigm in sleep research was that ‘Sleep cures sleepiness,’” says Stickgold. Since then, researchers have developed a far more complex picture of what happens while we snooze. The annual meetings in sleep medicine, which only this year became a recognized medical specialty, now draw 5,000 participants. Harvard has long been a leader in the area. The Medical School’s Division of Sleep Medicine, founded in 1997 and chaired by Baldino professor of sleep medicine Charles Czeisler, has 61 faculty affiliates. The division aims to foster collaborative research into sleep, sleep disorders, and circadian biology, to educate physicians and the lay public, to influence public policy, and to set new standards of clinical practice, aiming, as its website ( declares, to create “a model program in sleep and circadian biology.”

A Culture of “Sleep Bulimia”

Imagine going on a camping trip without flashlights or lanterns. As the sun sets at the end of the day, daylight gradually gives way to darkness, and once the campfire burns down, you will probably go to sleep. At sunrise, there’s a similar gradient in reverse from the beginning of time, human beings have been entrained to these cycles of light and dark.

Homo sapiens is not a nocturnal animal we don’t have good night vision and are not especially effective in darkness. Yet in an instant on the evolutionary time scale, Edison’s invention of the light bulb, and his opening of the first round-the-clock power plant on Pearl Street in Manhattan in 1882, shifted our time-and-light environment in the nocturnal direction. At the snap of a switch, a whole range of nighttime activity opened up, and today we live in a 24-hour world that is always available for work or play. Television and telephones never shut down the Internet allows you to shop, gamble, work, or flirt at 3 a.m. businesses stay open ever-longer hours tens of millions of travelers cross multiple time zones each year, worldwide and with the growth of global commerce and communication, Wall Street traders may need to rise early or stay up late to keep abreast of developments on Japan’s Nikkei exchange or at the Deutsche Bundesbank.

Consequently most of us now sleep less than people did a century ago, or even 50 years ago. The National Sleep Foundation’s 2005 poll showed adult Americans averaging 6.8 hours of sleep on weeknights—more than an hour less than they need, Czeisler says. Not only how much sleep, but when people sleep has changed. In the United States, six to eight million shift workers toil regularly at night, disrupting sleep patterns in ways that are not necessarily amenable to adaptation. Many people get only five hours per night during the week and then try to catch up by logging nine hours nightly on weekends. “You can make up for acute sleep deprivation,” says David P. White, McGinness professor of sleep medicine and director of the sleep disorders program at Brigham and Women’s Hospital. “But we don’t know what happens when people are chronically sleep-deprived over years.”

“We are living in the middle of history’s greatest experiment in sleep deprivation and we are all a part of that experiment,” says Stickgold. “It’s not inconceivable to me that we will discover that there are major social, economic, and health consequences to that experiment. Sleep deprivation doesn’t have any good side effects.”

All animals sleep. Fish that need to keep swimming to breathe sleep with half their brains while the other half keeps them moving. It is uncertain whether fruit flies actually sleep (“We can’t put electrodes in their brains,” says White), but they seem at least to rest, because for extended periods they do not move. When researchers stopped fruit flies from resting by swatting at them, the flies took even longer rest periods. When lab technicians added caffeine to the water that the flies drank, they stayed active longer—and also rested longer after the drug wore off, evidence that the caffeine had disrupted their resting patterns.

Sleeping well helps keep you alive longer. Among humans, death from all causes is lowest among adults who get seven to eight hours of sleep nightly, and significantly higher among those who sleep less than seven or more than nine hours. (“Those who sleep more than nine hours have something wrong with them that may be causing the heavy sleep, and leads to their demise,” White notes. “It is not the sleep itself that is harmful.”)

Sleep is essential to normal biological function. “The immune system doesn’t work well if we don’t sleep,” says White. “Most think sleep serves some neurological process to maintain homeostasis in the brain.” Rats totally deprived of sleep die in 17 to 20 days: their hair starts falling out, and they become hypermetabolic, burning lots of calories while just standing still.

There once was a fair amount of research on total sleep deprivation, like that which killed the rats. Doctors would keep humans awake for 48, 72, or even 96 hours, and watch their performance deteriorate while their mental states devolved into psychosis. For several reasons, such studies rarely happen any more (“Why study something that doesn’t exist?” asks White) and researchers now concentrate on sleep restriction studies.

In this context, it is important to distinguish between acute and chronic sleep deprivation. Someone who misses an entire night of sleep but then gets adequate sleep on the following three days “will recover most of his or her normal ability to function, ” Czeisler says. “But someone restricted to only five hours of nightly sleep for weeks builds up a cumulative sleep deficit. In the first place, their performance will be as impaired as if they had been up all night. Secondly, it will take two to three weeks of extra nightly sleep before they return to baseline performance. Chronic sleep deprivation’s impact takes much longer to build up, and it also takes much longer to recover.” The body is eager to restore the balance Harvard undergraduates, a high-achieving, sleep-deprived population, frequently go home for Christmas vacation and pretty much sleep for the first week. Stickgold notes that “When you live on four hours a night, you forget what it’s like to really be awake.”

Sleep researcher Eve van Cauter at the University of Chicago exposed sleep-deprived students (allowed only four hours per night for six nights) to flu vaccine their immune systems produced only half the normal number of antibodies in response to the viral challenge. Levels of cortisol (a hormone associated with stress) rose, and the sympathetic nervous system became active, raising heart rates and blood pressure. The subjects also showed insulin resistance, a pre-diabetic condition that affects glucose tolerance and produces weight gain. “[When] restricted to four hours [of sleep] a night, within a couple of weeks, you could make an 18-year-old look like a 60-year-old in terms of their ability to metabolize glucose,” Czeisler notes. “The sleep-deprived metabolic syndrome might increase carbohydrate cravings and the craving for junk food.”

Van Cauter also showed that sleep-deprived subjects had reduced levels of leptin, a molecule secreted by fat cells that acts in the brain to inhibit appetite. “During nights of sleep deprivation, you feel that your eating goes wacky,” says Stickgold. “Up at 2 a.m., working on a paper, a steak or pasta is not very attractive. You’ll grab the candy bar instead. It probably has to do with the glucose regulation going off. It could be that a good chunk of our epidemic of obesity is actually an epidemic of sleep deprivation.”

Furthermore, “Many children in our society don’t get adequate amounts of sleep,” Czeisler says. “Contrary to what one might expect, it’s common to see irritability and hyperactivity in sleep-deprived children. Is it really surprising that we treat them with wake-promoting drugs like Ritalin?” Schools and athletic programs press children to stay awake longer, and some children may be chronically sleep-deprived. Czeisler once took his daughter to a swim-team practice that ran from eight to nine o’clock at night, and told the coaches that this was too late an hour for children. “They looked at me like I was from another planet,” he recalls. “They said, ‘This is when we can get the pool.’”

Stickgold compares sleep deprivation to eating disorders. “Twenty years ago, bulimics probably thought they had the best of all worlds,” he says. “They could eat all they wanted and never gain weight. Now we know that they were and are doing major damage to their bodies and suffering major psychological damage. We live in a world of sleep bulimia, where we binge on weekends and purge during the week.”

The Fatigue Tax

Lack of sleep impairs performance on a wide variety of tasks. A single all-nighter can triple reaction time and vastly increase lapses of attention. Sleep researcher David Dinges at the University of Pennsylvania studied such lapses using a “psychomotor vigilance task” on pools of subjects who had slept four, six, or eight hours nightly for two weeks. The researchers measured subjects’ speed of reaction to a computer screen where, at random intervals within a defined 10-minute period, the display would begin counting up in milliseconds from 000 to one second. The task was first, to notice that the count had started, and second, to stop it as quickly as possible by hitting a key. It wasn’t so much that the sleep-deprived subjects were slower, but that they had far more total lapses, letting the entire second go by without responding. Those on four hours a night had more lapses than those sleeping six, who in turn had more lapses than subjects sleeping eight hours per night. “The number of lapses went up and up for the whole two weeks,” says David White, “and they hadn’t plateaued at the end of the two-week study!”

There’s fairly large individual variation in susceptibility to the cognitive effects of sleep deprivation: in one of Charles Czeisler’s studies, somewhere between a quarter and a third of the subjects who stayed awake all night contributed two-thirds of the lapses of attention. “Some are more resistant to the impact of a single night of sleep loss,” he says. “But they all fall apart after two nights without sleep.” In a sleep-deprived state, says White, “Most of us can perform at a fairly low level. And a lot can run around sleep-deprived without it being obvious. But truck drivers, neurosurgeons, nuclear-plant workers—after six or eight hours, they have to put a second crew on and give them a break.” Very few people are really immune to sleep deprivation: in Dinges’s study, only one of 48 subjects had the same performance after two weeks of four hours’ nightly sleep as on day one.

Students often wonder whether to pull an all-nighter before an exam. Will the extra studying time outweigh the exhaustion? Robert Stickgold, who has studied sleep’s role in cognition for the past 10 years, reports that it depends on the exam. “If you are just trying to remember simple facts—listing all the kings of England, say—cramming all night works, ” he explains. “That’s because it’s a different memory system, the declarative memory system. But if you expect to be hit with a question like ‘Relate the French Revolution to the Industrial Revolution,’ where you have to synthesize connections between facts, then missing that night of sleep can be disastrous. Your ability to do critical thinking takes a massive hit—just as with alcohol, you’re knocking out the frontal-cortex functions.

“It’s a version of ‘sleeping on a problem,’” Stickgold continues. “If you can’t recall a phone number, you don’t say, ‘Let me sleep on it.’ But if you can’t decide whether to take a better-paying job located halfway across the country—where you have all the information and just have to weigh it—you say, ‘Let me sleep on it.’ You don’t say, ‘Give me 24 hours.’ We realize that it’s not just time we understand at a gut level that the brain is doing this integration of information as we sleep, all by itself.”

Not only mental and emotional clarification, but the improvement of motor skills can occur while asleep. “Suppose you are trying to learn a passage in a Chopin piano étude, and you just can’t get it,” says Stickgold. “You walk away and the next day, the first try, you’ve got it perfectly. We see this with musicians, and with gymnasts. There’s something about learning motor-activity patterns, complex movements: they seem to get better by themselves, overnight.”

Stickgold’s colleague Matthew Walker, an instructor in psychiatry, studied a simple motor task: typing the sequence “41324” as rapidly and accurately as possible. After 12 minutes of training, subjects improved their speed by 50 to 60 percent, but then reached a plateau. Those who trained in the morning and came back for another trial the same evening showed no improvement. But those who trained in the evening and returned for a retest the following morning were 15 to 20 percent faster and 30 to 50 percent more accurate. “Twenty percent improvement—what’s that?” asks Stickgold, rhetorically. “Well, it’s taking a four-minute mile down to three minutes and 10 seconds, or raising a five-foot high jump to six feet.”

Bodily Rituals

So sleep is essential, but exactly why we go to sleep remains a mystery. Professor of psychiatry Robert McCarley, based at the VA Boston Healthcare System, has linked sleep to the brain neurochemical adenosine. Adenosine binds with phosphorus to create adenosine triphosphate (ATP), a substance that cells break down to generate energy. McCarley and colleagues inserted microcatheters into cat brains while keeping the cats awake for up to six hours—a long time for a cat. They found that rising adenosine levels in the basal forebrain put the cat to sleep then, in the sleeping cat, adenosine levels fall again. In both cats and humans, the basal forebrain includes cells important for wakefulness, and adenosine turns these cells off, triggering sleep.

Like cats, when we are awake and active, we burn ATP, which breaks down to adenosine. Over time, adenosine levels build up, causing pressure for sleep. During sleep, many of the body’s cells are less active and hence burn less ATP, so adenosine levels fall again, setting the stage for wakefulness.

A drug like caffeine, however, partially blocks adenosine receptors, so the brain doesn’t perceive the actual adenosine level, and we don’t get tired. In a world that values wakefulness and productivity over rest and recovery, caffeine has become, in dollar amounts, the second-largest commodity (after oil) traded in the world. Some consumers require ever-greater jolts—one 24-ounce Starbucks beverage packs a walloping 1,000-plus milligrams of caffeine. (A commonly used figure for one cup of coffee is 100 milligrams.)

The lab run by Putnam professor of neurology Clifford Saper has done related research, refining the location and functions of the “sleep switch,” a group of nerve cells in the hypothalamus that turns off the brain’s waking systems conversely, the waking systems can turn off the sleep switch. “When you have a switch where either side can turn off the other, it’s what electrical engineers call a ‘flip-flop,’” Saper explains. “It likes to be in one state or the other. So we fall asleep, or wake up, quite quickly. Otherwise we’d be half asleep or half awake all the time, with only brief periods of being fully awake or asleep. But we’re not—we are either awake or asleep.”

The adenosine cycle at least partly explains the homeostatic drive for sleep—the longer we are awake, the greater our fatigue, and pressure to sleep builds up progressively. But circadian rhythms also profoundly affect sleep and wakefulness. Circadian cycles (from circa, meaning “about,” and dies, a “day”) are internal periodic rhythms that control many things like body temperature, hormone levels, sleep and wakefulness, digestion, and excretion. “The circadian cycles go way back in evolutionary time,” Charles Czeisler says. “They are probably older than sleep.”

Since the 1970s, Czeisler has established himself as one of the world’s leading authorities on circadian cycles and the chronobiology of sleep and wakefulness. He has done groundbreaking work in the sleep laboratory at Brigham and Women’s Hospital, where a special wing on one floor is shielded not only from sunlight, but from all external time cues. There, researchers can do exotic things like simulate the 708-hour lunar day or conditions on the International Space Station, where the sun rises and sets every 90 minutes. (Czeisler leads a sleep and chronobiology team that, under the auspices of NASA, researches human factors involved in space travel.)

Exotic light environments like space challenge human biology, partly because people differ from other mammals, which take short catnaps and rat naps throughout the day and night. In contrast, we have one bout of consolidated (unbroken) sleep, and one of consolidated waking, per day (or, in siesta cultures, two of each). In addition, “There is a very narrow window [in the daily cycle] in which we are able to maintain consolidated sleep,” Czeisler says, “and the window gets narrower and narrower as we get older.”

The origins of humans’ consolidated sleep take us to the beginnings of terrestrial life, since even prokaryotes—one-celled organisms like bacteria, lacking a nucleus—have built-in 24-hour rhythms. It is not surprising that these biological clocks are so universal, as they reflect the entrainment of all living things to the primeval 24-hour cycles of light and darkness created by the rotation of Earth.

“The light and dark cycle is the most powerful synchronizer of the internal circadian clock that keeps us in sync with the 24-hour day,” Czeisler says. As late as 1978, when he published a paper demonstrating this effect, many still believed that “social interaction was the most important factor in synchronizing physiological cycles—that we had evolved beyond light,” he says. “But much of our subsequent research shows that our daily cycles are more like those of cockroaches than we want to believe. We are very sensitive to light.”

Light strongly affects the suprachiasmatic nucleus (SCN), a biological clock in the anterior region of the hypothalamus that directs circadian cycles. All cells have internal clocks—even cells in a tissue culture run on 24-hour cycles. “They all oscillate like violins and cellos, but the SCN is the conductor that synchronizes them all together, ” Czeisler explains.

While the homeostatic pressure to sleep starts growing the moment we awaken, the SCN calls a different tune. Late in the afternoon, its circadian signal for wakefulness kicks in. “The circadian system is set up in a beautiful way to override the homeostatic drive for sleep,” Czeisler says. The circadian pacemaker’s signal continues to increase into the night, offsetting the build-up of homeostatic pressure and allowing us to stay awake well into the evening and so achieve our human pattern of consolidated sleep and wakefulness. (There is often a dip in the late afternoon, when the homeostatic drive has been building for hours but the circadian signal hasn’t yet kicked in Czeisler calls this “a great time for a nap.”) The evolutionary benefit of consolidated sleep and wakefulness is a subject of speculation Czeisler says that long bouts of wakefulness may enable us to “take advantage of our greater intellectual capacity by focusing our energy and concentration. Frequent catnaps would interrupt that.”

The circadian pacemaker’s push for wakefulness peaks between about 8 and 10 p.m., which makes it very difficult for someone on a typical schedule to fall asleep then. “The period from two to three hours before one’s regular bedtime, we call a ‘wake maintenance zone,’ ” Czeisler says. But about an hour before bedtime, the pineal gland steps up its secretion of the hormone melatonin, which quiets the output from the SCN and hence paves the way for sleep.

Some years ago, melatonin supplements became popular as a natural sleeping pill, but as Czeisler’s research has proven, light is a more powerful influence on the biological clock than melatonin. Mangelsdorf professor of natural sciences J. Woodland Hastings has shown that even a split-second of light exposure can shift the circadian cycle of a single-celled organism by a full hour. Light interferes with sleep, at least partly because it inhibits melatonin secretion and thus resets the biological clock. For this reason, those seeking a sound sleep should probably keep their bedroom as dark as possible and by all means avoid midnight trips to brightly lit bathrooms or kitchens blue light, with its shorter wavelength—and its resemblance to the sunlit sky—has the most powerful resetting effect.

Light resets the pacemaker even in the case of some completely blind people, who generally lose circadian entrainment and suffer recurrent insomnia. “The eye has two functions, just as the ear does, with hearing and balance,” says Czeisler. “The eye has vision, and also circadian photoreception.” A subset of about 1,000 photosensitive retinal ganglion cells connects by a direct neural pathway to the SCN these cells are sometimes active even in those who are blind to light. Exposure to bright light will decrease melatonin levels in some blind persons, and this subset, unlike other blind people, generally do not suffer from insomnia and are biologically entrained to the 24-hour day.

Disastrous Exhaustion

The human species, or much of it, anyway, apparently is trying to become simultaneously nocturnal and diurnal. Society has been squeezing the window for restful sleep ever narrower. (Czeisler likes to quote colleague Thomas Roth of the Henry Ford Sleep Disorders Center in Detroit, on the minimal-sleep end of the spectrum. “The percentage of the population who need less than five hours of sleep per night, rounded to a whole number,” says Roth, “is zero.”)

Czeisler has conducted several studies of medical interns, an institutionally sleep-deprived population who provide a hugely disproportionate fraction of the nation’s healthcare services. Interns work famously long 80- and even 100-hour weeks every other shift is typically 30 hours in duration. “On this kind of schedule, virtually everyone is impaired,” he says. “Being awake more than 24 hours impairs performance as much as having a blood-alcohol level of 0.1 percent—which is legally drunk.”

In addition to both acute and chronic sleep deprivation, interns sleep and wake in patterns that misalign with circadian cycles—being asked, for example, to perform with full alertness at 4 a.m. A fourth factor is that the human brain is “cold” and essentially impaired during the first half-hour after awakening—even more impaired, says Czeisler, than after 70 hours of sleeplessness. “It’s a colossally bad idea to have an intern woken up by a nurse saying, ‘The patient is doing badly—what shall we do?’ ” he says. “They might order 10 times the appropriate dose of the wrong med.”

The intensity and growing technological advance of medical care only enhance the probability of errors under such conditions. Christopher Landrigan, assistant professor of pediatrics, led a study that compared interns working traditional schedules with those on an alternate schedule of fewer weekly hours and no extended (e.g., 30-hour) shifts in intensive-care units. The doctors on the tiring traditional schedule made 36 percent more serious medical errors, including 57 percent more nonintercepted serious errors, and made 5.6 times as many serious diagnostic errors.

Some Harvard-affiliated teaching hospitals, like Brigham and Women’s, where Czeisler works, are taking the lead in substantially reducing work hours for physicians and surgeons in training. Yet no rules limit the work hours of medical students (including those at Harvard Medical School), and at the national level, little has changed for interns and residents. Not long ago, the Accreditation Council of Graduate Medical Education, faced with the threat of federal regulation, enacted new rules limiting extended shifts to 30 hours (before the new rules, they averaged 32 hours), and capped work weeks at 80 hours (beforehand, the average was 72 hours)—with exceptions allowable up to 90 hours. “The new, self-imposed rules largely serve to reinforce the status quo,” Czeisler says. “They haven’t brought about fundamental change, and haven’t changed the length of a typical extended shift, which is still four times as long as a normal workday. And those marathon shifts occur every other shift, all year, several years in a row during residency training.”

The risks don’t end when the doctors leave work. Research fellow in medicine Laura Barger led another group in a nationwide survey of interns that showed them having more than double the risk of a motor-vehicle crash when driving home after an extended shift. (They aren’t alone: 60 percent of American adults drove while drowsy in the past year.)

The moral of much sleep research is startlingly simple. Your mother was right: You’ll get sick, become fat, and won’t work as well if you don’t get a good night’s sleep. So make time for rest and recovery. Stickgold likes to compare two hypothetical people, one sleeping eight hours, the other four. The latter person is awake 20 hours a day, compared to 16 hours for the first. “But if the person on four hours is just 20 percent less efficient while awake, then in 20 hours of waking he or she will get only 16 hours of work done, so it’s a wash,” he says. “Except that they are living on four hours of sleep a night. They’re not gaining anything, but are losing a huge amount: you’ll see it in their health, their social interactions, their ability to learn and think clearly. And I cannot believe they are not losing at least 20 percent in their efficiency.”

Yet instead of encouraging restorative rest, many of our institutions are heading in the opposite direction. This fall, for example, Harvard will begin keeping Lamont Library open 24 hours a day, in response to student demand, and Harvard Dining Services has for several years offered midnight snacks. “These are the wrong solutions,” says Stickgold. “This is like the Boston Police Department getting tired of drunk drivers killing people and setting up coffee urns outside of bars. At Harvard there is no limit on the amount of work students are assigned you can take four courses and have three professors say, ‘This is your most important course and it should take the bulk of your time.’ Students are dropping to four hours of sleep a night, and the University sees it has to do something about it. But the way you deal with students overloaded with work is not by having dorms serve snacks at midnight and keeping the library open all night. Instead, you can cut back by one-third the amount of work you assign, and do that in every course without serious detriment.”

Such are the prescriptions of sleep researchers, which differ radically from those of the society and the economy. The findings of the sleep labs filter only slowly into the mainstream, especially in areas like medical internships, where enormous financial pressures favor the status quo. Even at Harvard Medical School, in a four-year curriculum, only one semester hour is devoted to sleep medicine. For a sleep disorder like narcolepsy, the average time between symptom onset and diagnosis is seven years for sleep apnea, four years. “Physicians aren’t being trained to recognize sleep disorders,” Czeisler says.

When all else fails, there is always the option of common sense. Sleep is quite possibly the most important factor in health, and neither caffeine nor sleeping pills nor adrenaline can substitute for it. “As it looks more and more like some of these processes occur exclusively during sleep and can’t be reproduced while we are awake, the consequences of losing them look more and more terrifying,” says Stickgold. “And that’s the experiment we are all in the middle of, right now.”

Overworked brains release adenosine to slow cells, trigger sleep, UT Southwestern researchers find

When cells in a certain part of the brain become overworked, a compound in the brain kicks in, telling them to shut down. This causes people to become drowsy and fall asleep. Alter that natural process by adding coffee or tea, and the brain compound - called adenosine - is blocked, and people stay awake.

These findings, available online and in the April 21 issue of the journal Neuron , offer new clues regarding the function of the brain in the body's natural sleep process, as well as potential targets for future treatments for insomnia and other sleep problems. Prolonged increased neural activity in the brain's arousal centers triggers the release of adenosine, which in turn slows down neural activity in the arousal center areas. Because the arousal centers control activity throughout the entire brain, the process expands outward and causes neural activity to slow down everywhere in the brain.

"Insomnia and chronic sleep loss are very common problems," said Dr. Robert W. Greene, professor of psychiatry and senior author of the study. "In addition, all the major psychiatric disorders, including depression, schizophrenia and post-traumatic stress disorder have sleep disruption as a prominent symptom.

"If we can understand better some of the factors involved in what makes us normally fall asleep, we can start to understand what might be going wrong when we don't."

Showing that increased brain cell activity triggers drowsiness also explains how caffeine works in helping people fight sleep. "We knew that coffee kept us awake," Dr. Greene said. "Now we know why: Coffee and tea are blocking the link between the prolonged neural activity of waking and increased levels of adenosine in cells, which is why they prevent us from getting drowsy."

Past studies by Dr. Greene and his colleagues have shown that adenosine may act as a "fatigue factor." When adenosine levels increase in the arousal centers -- as happens with prolonged waking -- mammals tend to fall asleep. But what hasn't been known before is what triggers the release of adenosine to induce sleep.

"Neurons in the brain do things -- such as talk to each other, process information and coordinate body activities - which is called neural activity," said Dr. Greene, who holds the Sherry Knopf Crasilneck Distinguished Chair in Psychiatry, in Honor of Albert Knopf. "When they do this over a long period of time, more and more adenosine is released and feeds back onto the cells to quiet them down. It's like telling them: 'You guys have worked too hard take it easy, and refresh yourselves.'

"What we have shown in our study is that it's this prolonged neural activity of being awake that causes adenosine levels to go up, which in turn makes a person feel drowsy. It's the brain's way of achieving a proper balance between the neural activity of waking and the need for sleep. If something goes wrong with this adenosine system, you may end up with insomnia."

Other UT Southwestern researchers on the study were Dr. David Chapman, a postdoctoral researcher in psychiatry, and Dr. Dario Brambilla, a former postdoctoral researcher in psychiatry, now at the University of Milan Medical School in Italy.

The study was supported by the National Institute of Mental Health and the Department of Veteran Affairs.

This news release is available on our World Wide Web home page at http://www8. utsouthwestern. edu/ utsw/ cda/ dept37389/ files/ 218303. html

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Risks and Side Effects

In IV form, adenosine should only be prescribed and given by a health care provider. While it’s usually safe, adenosine injections can potentially cause side effects at high doses, including chest pain, headaches, heart pounding, low blood pressure, nausea, sweating, flushing, light-headedness, sleep problems, coughing and anxiety. (23)

Women who are pregnant or breastfeeding should not taking adenosine, since it’s not entirely clear if this is safe. People with gout and heart disease should also avoid using it since it can raise the level of uric acid in the blood and possibly reduce blood flow to the heart. Supplementing with adenosine may make symptoms of gout, such as tenderness and swelling, worse and complicate heart disease work by increasing chest pains and risk of a heart attack.

You should avoid taking it if you have any of these medications:

  • Dipyridamole (Persantine)
  • Carbamazepine (Tegretol)
  • Gout medications, including allopurinol (Zyloprim), colchicine and probenecid (Benemid)
  • Use adenosine with precaution if you’re also taking methylxanthines, including aminophylline, caffeine and theophylline

Final Thoughts

  • Adenosine is a natural chemical found inside all human cells and an essential component of energy metabolism. It plays a role in the production of ATP, AMP and adenosine compounds that have important roles in the central nervous, immune, cardiovascular, respiratory and digestive systems.
  • Actions of adenosine include relaxing vascular smooth muscle (vasodilation), increasing blood flow (circulation), modulating neurotransmitter release, protecting the brain from oxidative stress, regulating T cell proliferation and cytokine production, and helping regulate the sleep cycle/circadian rhythm.
  • Doctors use medicinal adenosine, either in IV form or supplement form that can be taken orally, to manage health conditions including irregular heartbeats, organ failure, high blood pressure, cystic fibrosis, nerve pain, viruses that affect the skin, bursitis and tendonitis.
  • Supplemental ATP is used to improve athletic performance, exercise recovery, strength, power and endurance. Studies have found mixed results regarding ATP’s effects, but certain studies have shown it can help prevent muscle wasting, improve sprints and support muscle adaptions in response to resistance training.

Read Next: All About CoQ10 Benefits, Foods, Supplements & More


The following doses have been studied in scientific research:

  • For a heart condition marked by episodes of rapid heart rate (paroxysmal supraventricular tachycardia): Healthcare providers give adenosine by IV. A dose of 6 mg is given over 1-2 seconds. If this is not effective within 1-2 minutes, 12 mg can be given and repeated once if necessary.
  • For involuntary weight loss in people who are very ill (cachexia or wasting syndrome): Healthcare providers give ATP by IV at a dose of up to 75 mcg/kg per minute over 30 hours. This dose is given every 2-4 weeks for up to 28 weeks.
  • For leg sores caused by weak blood circulation (venous leg ulcer): Healthcare providers give AMP as a shot. To start, the shot is given at a dosage of 25 mg once or twice weekly. Then 25 mg two to three times weekly can be given.

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