Sleep / Wake Disorders & Weight Loss (Part 2)
University of California, San Francisco researchers are reporting direct evidence that sleep in early life may play a crucial role in brain development.
Their study, the cover story in the April 26 issue of Neuron, indicates that sleep dramatically enhances changes in brain connections during a critical period of visual development in cats, says the lead author of the study, Marcos G. Frank, PhD, a postdoctoral fellow in the laboratory of senior author Michael P. Stryker, PhD.
The capacity for “change,” or growth and strengthening, of connections between nerve cells is the basis of development in the brain. The elaboration and refinement of neural circuitry continues to a lesser extent in the adult brain. The process of growth, known as plasticity, is believed to underlie the brain’s capacity to control behavior, including learning and memory. Plasticity occurs when neurons are stimulated by events, or information, from the environment.
In their study, the researchers examined the effect of sleep on brain plasticity after cats experienced an environmental challenge. They determined that animals allowed to sleep for six hours after the period of environmental stimulation developed twice the amount of brain change as those cats kept awake during that time. The animals that were allowed to sleep even had slightly more brain change than the animals whose environmental challenge continued during the additional six hours.
The findings provide strong evidence, says Stryker, UCSF professor and chair of the Department of Physiology and a member of the UCSF Keck Center for Integrative Neuroscience, that a function of sleep is to help consolidate the effects of waking experience on cortical plasticity, converting memory into more permanent and/or enhanced forms.
“This is the first direct evidence that sleep modifies the effect of environmental stimuli on the development of new brain connections,” says Frank.
While the study focused specifically on the impact of sleep on neuronal remodeling during the critical period for visual development in the cat, the researchers believe the finding has broader implications, not just for plasticity during development in other brain structures, but for plasticity in the adult brain.
If this is shown to be the case, sleep could prove an important part of the strategy for preparing for such challenges as exams. “The fact that sleep provoked slightly more plasticity than double the amount of exposure to experience [when cats remained awake in a lit room] suggests that if you reviewed your notes thoroughly until you were tired and then slept, you’d achieve as much plasticity, or ‘learning,’ in the brain as if you’d pulled an all-nighter repeating your review of the material,” says Stryker.
Significantly, the researchers determined that the amount of plasticity in the brain depended on the amount of sleep known as non-rapid eye movement, a deep, quiet, slumber marked by large, slow brain waves. This is the sleep that a person falls into when he or she first goes to sleep and which accounts for half of sleep in animals of this age. Non-REM sleep alternates with periods of rapid eye movement, or so-called “dream” sleep, a period marked by rapidly changing brain waves and rapid bursts of eye movement.
This discovery offers direction for examining the two major hypotheses for how sleep impacts plasticity. One theory is that patterned neuronal activity following a period of environmental stimulation is replayed during non-REM sleep, strengthening neuronal connection changes. The alternative theory, which could also work in conjunction with the first, is that powerful growth factors, such as neurotrophins, which are known to be necessary for cortical plasticity, are released during non-REM sleep.
“Right now we don’t know if these neurotrophins are released during sleep. We do know that other growth factors are released during sleep and we also known that these neurotrophins play a role in learning and making the synapses of the brain stronger and weaker,” says co-author Naoum P. Issa, PhD, a postdoctoral fellow in the Stryker lab.
In either case, the new evidence that sleep appears to play a significant role in brain development puts researchers an important step closer to solving a mystery that has persisted for decades. “Every animal sleeps – even flies may have a state like sleep. But despite great progress in our understanding of the regulation and neurobiology of sleep, as well as the consequences of sleep loss on human performance, why the brain needs sleep has remained a mystery,” says Frank.
“Speculation has ranged from evolutionary theories – we need sleep to prevent us from wandering out of our caves in the dark or sleep is just a way of keeping us inactive for period of time when goblins or saber tooth tigers are out – to theories having to do with the function of neural networks,” says Stryker.
Researchers have known that in early development birds and mammals, including humans, sleep as much as three times the amount as adult birds and mammals. And they have long suspected that neuronal connections are remodeled during sleep. Previous studies in humans have shown that sleep and sleep loss influence learning and memory – two processes thought to depend on neuronal plasticity. And studies have shown that animals and humans deprived of sleep do not perform well on memory tasks. Other studies in rodents, birds and humans have suggested that neuronal activity initiated while awake is reactivated and possibly consolidated during subsequent sleep.
Other studies have shown that sleep and sleep loss modify the expression of several genes and gene products that may be important for synaptic plasticity; that certain forms of long-term potentiation, a neural process associated with the laying down of learning and memory, can be elicited in sleep, suggesting synaptic connections are strengthened during sleep; and that sleep amounts are very high and undergo dramatic modifications during developmental periods of heightened synaptogenesis and synaptic plasticity.
But while these findings together provide strong, suggestive evidence that synaptic circuits are modified during sleep the current study provides the first direct evidence that sleep and sleep loss modify experience-dependent changes in synaptic plasticity.
“The significance of our study is that we examined a system in which we know a great deal about the neural inputs and the outputs – we know how information gets into the visual cortex from the two eyes, how it changes during normal development, and we know a lot about what goes on in the circuitry to cause plasticity in this system, and to cause the loss of response to the eye after monocular deprivation,” says Stryker.
“Among other things, now we can begin to examine to what extent the mechanisms inherent in sleep are distinct from those governing cortical plasticity during wakefulness. We should also gain general insights into plasticity.”
To tease out the impact of sleep on plasticity during early brain development, the researchers established a model in which they measured in cats the response of neurons of the visual cortex to an environmental challenge -vision blocked in one eye for six hours. The visual deprivation initiates a rapid remodeling of neural circuitry known as ocular dominance plasticity. The researchers then examined the impact of sleep on the long-term effects of those changes by using brain imaging and making electrical recordings from brain cells.
First, in one set of cats they took a measurement of the brain change, or plasticity, immediately following the period of visual deprivation. Then, in the other three sets of cats, they examined the relative effects of sleep or lack of sleep on the initial plasticity. This is where the provocative findings were made, says Frank. The UCSF team determined that animals allowed to sleep for six hours after the period of visual deprivation developed twice the amount of brain change as those cats kept awake in a dark room during those six hours. The animals allowed to sleep also had twice the amount of change as the cats evaluated immediately following the period of visual deprivation. Finally, the cats allowed to sleep even had slightly more brain change than those animals who were kept awake in a light room with continued visual stimulation through one eye and whose brains had therefore had had twice as much time to respond to the light stimulus with just one eye open.
Source: Science Daily
By Herschel Lessin, MD.
It is an all too common scenario: Mrs. Lewis brings in her daughter, Samantha, for her two-year-old checkup. Mrs. Lewis looks terrible; her eyes are red and she seems to be dragging around with little energy. Samantha, on the other hand, is as happy and active as she could be—a delightful little girl. I begin by discussing the usual things that I discuss at checkups: safety, diet, behavior….When I get to that last one, I hear the question that comes my way more than any other question about the behavior of young children: “Doctor, when will my child sleep through the night?”
It seems that Mrs. Lewis has not had an uninterrupted night’s sleep for the past two years and it definitely shows.
One of the most frequent problems that concern and aggravate parents is the battle of the bedtime. Many of us find ourselves unable to get the kids to bed at a reasonable time without an unending struggle. Persistent crying and frequent nighttime awakenings further frustrate us. Let’s take a look at how the problems start and some possible solutions.
The problem often begins in early infancy. Most parents of very young infants will feed them at night while rocking them to sleep. They will then quietly tip-toe to the baby’s crib and gently lay the child down, praying to all the powers that be that the baby will not wake up. This bedtime ritual is common and perfectly appropriate for the very young infant. I repeat, for the very young infant. Unfortunately, a great many parents mistakenly continue this same technique as their child grows older. It is not unusual for me to see a two-, three- or even a four-year-old put to bed in this fashion. The problem arises when there is a brief awakening in the middle of the night. We all wake up like this several times a night. However, when this child awakens briefly, she has not only no idea where she is or how she got there, she also has no idea how to fall asleep again without the same rigmarole needed to get her down into bed in the first place. The end result is the crying, inconsolable child who must be repeatedly rocked to sleep all night long. Children need to learn to associate being in the crib alone with going to sleep, as opposed to being fed or rocked to sleep. Somewhere between the ages of four and nine months, you must begin to teach your child how to fall asleep on his/her own.
Rituals Are Important
Any of you who are parents will realize how important the bedtime ritual is for kids. Woe be it to the parent who deviates from it in any way. A bedtime ritual, however, is quite important in helping kids know what to expect as bedtime approaches. Kids, believe it or not, like their lives to be orderly and are comforted by such rituals. However silly it may seem, it serves the important purpose of providing the child a smooth and predictable transition to bedtime. The ritual should end with the child in the crib or bed falling asleep on her own.
One must establish a reasonable bedtime and put your child to bed at the same time every night. Remember, bedtime is for parents, not children. You need time at night to act like an adult, without children present. It is in both your and your child’s best interest to get the kids to bed at a reasonable time.
How To Begin
The start of quiet time begins about 30 minutes before bedtime. This serves both to alert the older children that bedtime is imminent and to end the playing of “monster games” and other rough-housing. Such a time can be soothing for infants. Quiet time is reading or coloring or playing quietly. As the end of quiet time approaches, provide a countdown for the older child: “Ten minutes to bedtime,” “Five minutes to bedtime…” Once quiet time is over, the bedtime ritual should begin. Depending on age, this may involve anything from baths, stories, drinks, bathroom trips, and kisses, to searching the child’s room to make sure there are no monsters under the bed or in the closet. Whatever the ritual is, it should be repeated without deviation every night.
Going To Bed VS Going To Sleep
There is a distinction to be made here. There is a difference between bedtime and sleep time. Parents determine bedtime. Children determine sleep time. You can put a child to bed, but you can’t make him sleep. So don’t try. If the child wishes to sing quietly or look at books for seemingly endless periods of time, that is his choice, and there is really nothing wrong with that as long as the child remains in bed. Despite your wishful thinking, you cannot force a child to sleep.
Have your child in bed at the established time. Tell him good night and that you will see him in the morning. Turn off the light, leave the room, and close the door. Door closing is optional, but I happen to be a big fan of this practice. If your bedroom door is closed, the child should knock before entering. If the child’s door is closed, you should do the same. Closing a child’s door and allowing a child to close his own door affords him a sense of privacy and personal space that I find quite valuable.
What About The Crying?
Now comes the hard part. You’ve gone through your ritual, put the child down to bed, and left the room. Some very easy kids will just amuse themselves and go to sleep. If you have one of those, you are not likely to be reading this article. Most kids will test you to see if you mean it. The best way to test you is to cry. In my years of caring for children, I have noticed that there are two types of people in the world, those that can listen to a child cry, and those who cannot. There are techniques to use for both types of parents. For the select few who feel like they can handle listening to their child, who is older than the age of eight to nine months, cry, I suggest the “cold turkey” method of dealing with bedtime crying. In order to use the cold turkey method, one must really mean it. Parents must be prepared for long periods of crying the first few days. Many parents, however, are pleasantly surprised that the children give in remarkably easily and without a lot of fuss. This is especially true if time-out techniques have been used previously, you mean what you say, and you have been consistent in dealing with your kids’ behavior. But there is no question that some kids will test you to the limit.
Let Them Cry
Once the door is closed, do not go back in the room. Once you have left, you must ignore all crying, whining, and pleading that may emanate from the room, no matter how pathetic or distressed it may sound. Research studies have shown that parents who are willing to do this will, in most cases, have good results within one week. Be warned however, that these same studies have shown that crying time will markedly increase the first few days that you use this technique. Thereafter, crying time will diminish rapidly and dramatically. How long do you let the child cry? As long as it takes. The last thing you want to do is to say, “I can’t take this any more, I’m going back in there.” If you go back in after 45 minutes of crying, you have just taught your child that not only don’t you mean what you say, but that he has to cry for 45 minutes before you come back in.
How long do kids cry? Depending on the temperament of the child, as little as 10 minutes, or as long as two to three hours. Don’t get discouraged, as it will quickly taper off. This method is more useful for older kids and I would not recommend using this technique for children younger than eight to nine months of age. The older child has already established a solid basic sense of trust, and the extended crying will not be a problem. And no child has ever been physically hurt by crying alone. Indeed, most parents suffer more in the listening than the child does in the crying.
A Kinder, Gentler Approach
If you know that you fall in the latter group, and that you would simply be unable to listen to your child cry, then there is an alternative. It is a bit more complicated and it takes a lot longer to see results, but many people prefer it. It involves gradually increasing the crying time over a period of weeks, with the parent initially leaving the room and then returning to comfort the child and be there while he gets to sleep. You are not allowed to pick the child up or to feed him, and he must be put in the crib while awake. This method was popularized by Dr. Richard Ferber and is described in detail in his wonderful book, Solve Your Child’s Sleep Problems.
Once the child is put down to bed after the ritual is completed and you leave the room, you wait for the child to cry. The first time the child cries, you should immediately respond by coming back into the room and soothing the child by voice and touch. However, you cannot pick the child up nor feed her. You should stay with her until she falls asleep. At the next awakening, wait one minute before responding, at the third, wait three minutes, and so on. Each few nights you should increase the amount of time it takes for you to respond to both the initial bedtime and to each of the awakenings. You should never pick the child up or feed her. Eventually, when you are up to 15, 20, or 30 minutes or so, the child will simply fall asleep without you and then you are on your way. As I said, many people prefer this method, despite it taking longer. I guess it depends whether you like your discomfort all at once, or in little bits for a longer time.
A Good Night’s Sleep
As I said earlier, bedtime is for parents, not for children. It is important for you as well as your child to defuse the battle of the bedtime. It’s hard to be a good care giver when you are sleep deprived. The best way is to use these techniques at the beginning, before a problem arises. Put your young infant in the crib while awake and teach her how to fall asleep on her own. But even if you’re too late for that, don’t despair; these techniques work quite well even in older kids with years of experience of having figured out that you don’t mean what you say. The key to all of these behavioral techniques is consistency and calm. Once you prove that you mean what you say, either gradually or cold turkey, life with your children can improve dramatically.
Source: Healthology, Inc.
Frequently asked questions about sleep
- How much should a person sleep?
Nowadays the old standard suggested that every adult needed to sleep around eight hours every night has been discarted. Even when there are some time lapses recommended for each age range, researchers have determined that an individual should sleep as many hours as needed in order to feel refreshed and with enough energy to carry out daily activities. Each case is different, but have one thing in common, more or less of each one’s healthy limit, often results in sleepiness, crankiness or some sleeping disorder.
Statistics indicate that most healthy young adults should sleep between seven to nine hours, a lapse that tends to decrease as we get older (usually as a consequence of some sleeping disorder). Newborns, toddlers and children need to sleep more. Every person must evaluate itself to check if they are capable to fully perform their daily activities, being alert and with energy until bedtime and then decide how much sleep.
- Why do we sleep less as we get older?
As we age, it is normal to experience changes in our sleep patterns that affect the quantity and quality of it. Commonly elders are unable to enjoy a restful and deep sleep, as the body ages it’s normal to have less energy. In Addition, seniors tend to have less daily responsibilities and plenty of free time which it’s used to take naps, or can be sleepy too early, they wake up several times every night, or sleeps less hours than needed, which results in tiredness during the day and a lack of energy that may trigger some sleep disorder.
Medical investigations have found that sleep disorders tend to increase with age, but researches also suggest that, in many cases this conditions in seniors can be caused by a physical or psychiatric illness and its medications.
- Is it possible to live without any sleep?
Of course not. Although a person can spend up to 3 days in a row awake usually for psychological reasons after a traumatic situation like losing a relative or having an accident, eventually the sleep urge is stronger and will gradually return to its normal sleeping cycle.
As mentioned before, the afflicted with sleep disorders are unable to achieve a restful and deep sleep during the night, but at least they fall asleep for a couple of hours a day or more.
- Is it possible to sleep too much?
Under normal circumstances a healthy individual will never sleep more than needed. Our body will fall asleep only for the amount of hours needed to feel refreshed, recharge energy and recover from normal daily fatigue.
When sleeping too much it becomes a chronic situation is a symptom of suffering from a sleep disorder, depression or any other psychiatric condition. Also an excessive sleep can be related to a physical illness or with some side effect of a medication.
- It is possible to compensate the sleep deprivation by sleeping more the next night?
Physicians use the term “sleep debt” to the amount of hours people lose of their regular sleep time. If your debt is low, due to lose two or more hours for a couple of days, going back after that to your normal schedule, will probably don’t have any consequence. For sleep debts greater than that, is useless to try to recover the lost hours.
On a short term basis, sleep deprivation may result in tiredness, lack of focus, memory problems, etc. The cases in which this situation becomes permanent are often associated with different sleep disorders and also with obesity, insulin resistance, diabetes, cardiac problems, among other problems.
- How can you have a healthy sleep hygiene?
A healthy sleep hygiene include a series of habits that can help to improve the your sleep quality, such as:
- Be sure to have enough sleep, every night. Not less, not more.
- Establish a regular schedule for wake up and go to bed. It’s normal to sometimes delay bedtime due to social activities, but don’t do it for many days in a row.
- Avoid overexercise late at night before bedtime.
- Do not watch TV, or use any electronic device (computer, video games, cell phone, tablet) while in bed.
- Reduce or eliminate the intake of caffeine or excessive alcohol at night.
- It is possible to learn while sleeping?
There is no conclusive evidence that support the fact that we can learn while we are sleeping. Nevertheless, many studies indicate that the brain is very active during this period, but there is no much information about our capacities during this important part of our life.
Circadian rhythms are regular changes in mental and physical characteristics that occur in the course of a day (circadian is Latin for “around a day”). Most circadian rhythms are controlled by the body’s biological “clock.” This clock, called the suprachiasmatic nucleus or SCN, is actually a pair of pinhead-sized brain structures that together contain about 20,000 neurons. The SCN rests in a part of the brain called the hypothalamus, just above the point where the optic nerves cross. Light that reaches photo receptors in the retina (a tissue at the back of the eye) creates signals that travel along the optic nerve to the SCN.
Signals from the SCN travel to several brain regions, including the pineal gland, which responds to light-induced signals by switching off production of the hormone melatonin. The body’s level of melatonin normally increases after darkness falls, making people feel drowsy. The SCN also governs functions that are synchronized with the sleep/wake cycle, including body temperature, hormone secretion, urine production, and changes in blood pressure.
By depriving people of light and other external time cues, scientists have learned that most people’s biological clocks work on a 25-hour cycle rather than a 24-hour one. But because sunlight or other bright lights can reset the SCN, our biological cycles normally follow the 24-hour cycle of the sun, rather than our innate cycle. Circadian rhythms can be affected to some degree by almost any kind of external time cue, such as the beeping of your alarm clock, the clatter of a garbage truck, or the timing of your meals. Scientists call external time cues zeitgebers (German for “time givers”).
When travelers pass from one time zone to another, they suffer from disrupted circadian rhythms, an uncomfortable feeling known as jet lag. For instance, if you travel from California to New York, you “lose” 3 hours according to your body’s clock. You will feel tired when the alarm rings at 8 a.m. the next morning because, according to your body’s clock, it is still 5 a.m. It usually takes several days for your body’s cycles to adjust to the new time.
To reduce the effects of jet lag, some doctors try to manipulate the biological clock with a technique called light therapy. They expose people to special lights, many times brighter than ordinary household light, for several hours near the time the subjects want to wake up. This helps them reset their biological clocks and adjust to a new time zone.
Symptoms much like jet lag are common in people who work nights or who perform shift work. Because these people’s work schedules are at odds with powerful sleep-regulating cues like sunlight, they often become uncontrollably drowsy during work, and they may suffer insomnia or other problems when they try to sleep. Shift workers have an increased risk of heart problems, digestive disturbances, and emotional and mental problems, all of which may be related to their sleeping problems. The number and severity of workplace accidents also tend to increase during the night shift. Major industrial accidents attributed partly to errors made by fatigued night-shift workers include the Exxon Valdez oil spill and the Three Mile Island and Chernobyl nuclear power plant accidents. One study also found that medical interns working on the night shift are twice as likely as others to misinterpret hospital test records, which could endanger their patients. It may be possible to reduce shift-related fatigue by using bright lights in the workplace, minimizing shift changes, and taking scheduled naps.
Many people with total blindness experience life-long sleeping problems because their retinas are unable to detect light. These people have a kind of permanent jet lag and periodic insomnia because their circadian rhythms follow their innate cycle rather than a 24-hour one. Daily supplements of melatonin may improve night-time sleep for such patients. However, since the high doses of melatonin found in most supplements can build up in the body, long-term use of this substance may create new problems. Because the potential side effects of melatonin supplements are still largely unknown, most experts discourage melatonin use by the general public.
Richard J. Wurtman, Cecil H. Green Distinguished Professor and Director
Clinical Research Center, MIT, Cambridge, MA
Pineal glands of humans and other mammals secrete melatonin at night. Consequently, plasma levels of the hormone exhibit pronounced circadian rhythms (Lynch et al.), with nighttime levels rising tenfold or more above those observed during daylight hours (i.e., 100 to 200 pg/mL vs. 5 to 10 pg/mL). In humans (but not in nocturnally active laboratory rodents) this nighttime elevation is temporally associated with normal sleep and indeed may constitute the chief signal that controls the timing of the sleep rhythm. The other “homeostatic” factors that regulate sleep behavior — the processes that require individuals to obtain a characteristic number of sleep hours per 24-h period and to make up sleep deficits — do not appear to depend on melatonin.
Evidence that physiologic elevations in plasma melatonin levels, comparable to those that normally occur at night, can induce sleepiness and promote sleep was first obtained in 1994. Dollins et al. showed that giving healthy young volunteers a daytime, low oral dose of melatonin (0.3 mg) — which elevated their plasma melatonin levels to those usually occurring nocturnally — decreased sleep latency, measured as the number of minutes it took for them to fall asleep in a sleep laboratory. Higher doses were no more effective than the physiologic (0.3 mg) dose and, in some subsequent studies, were even less effective. Moreover, the sleep-promoting effect of melatonin was independent of changes in body temperature (which are observed after larger doses) and was not associated with subsequent performance decrements (as sometimes occur with benzodiazepine hypnotics).
In the Dollins et al. study melatonin was administered at 11:45 a.m., a time when plasma levels normally are very low. This was done so that any effect the melatonin might have on sleep onset would clearly be recognized as a direct action and not simply as the consequence of a change the melatonin might have produced in the timing of circadian rhythms. No treatment can produce, in 1 day or less, a 10- to 12-h shift in such rhythms. However, melatonin administration at the same time of day for several days can shift circadian rhythms, usually at the rate of 1 to 2-h per day (Lewy et al., Arendt et al.). But if melatonin is given at a time when its plasma levels are rising anyhow — for example at 11:00 p.m., when many people choose to go to sleep — it does not shift the phasing of circadian rhythms. Melatonin does effectively promote sleep if given at any time between about noon and bedtime.
Besides facilitating sleep onset in people wishing to fall asleep at times of day when their plasma levels of melatonin are normally low (i.e., in daytime), more recent studies have shown that melatonin can also sustain sleep in older people who suffer from insomnia associated with subnormal plasma melatonin levels (Wurtman et al., 2000).
Sleep quality characteristically undergoes clinically relevant deterioration in many older people, manifests sometimes as increased sleep latency but more commonly as frequent and long-lasting nocturnal awakenings. This deterioration is associated in many older people with a major decline in peak nocturnal melatonin levels, to 30 to 40 pg/mL or less (Waldhauser et al., 1988, Brzezinski et al.). This decline has been demonstrated in all but one (Zeitzer et al.) of the more than 20 studies that have been written on this subject. It should be noted that no adequate longitudinal data are available that trace individuals’ plasma melatonin cycles over the course of life, so we cannot tell whether or not those with the lowest nocturnal levels at age 70 or 80 also exhibited relatively low levels at age 20 or 30. The age-related decline in nocturnal melatonin levels may be related to the poorly understood replacement of pineal parenchymal tissue by calcification — a progressive pathologic process that can start as early as the first decade of life.
There is evidence that an age-related “melatonin deficiency state” is responsible for the insomnia of some older people and that this insomnia can be treated with low doses of melatonin, which restore the amplitude of the plasma melatonin rhythm to that seen in young adults. In an initial study (Wurtman et al., 1995), nine elderly insomniac subjects who received melatonin (0.3 mg) 30 min before bedtime demonstrated significant increases in sleep efficiency (the percent of the time in bed when the subjects actually slept, assessed polysomnographically) and significant decreases in nocturnal awakenings and sleep latency. In a more recent, larger study (Wurtman et al., 2000), two groups of older subjects, with and without insomnia (initially demonstrated actigraphically, and then confirmed by polysomnography), received a placebo or each of three melatonin doses (0.1, 0.3, or 3.0 mg) at random for 7-day periods, followed by 7-day washout periods. Once again, giving the hormone corrected the depressed sleep efficiencies of the insomniacs; moreover the physiologic dose (0.3 mg) was significantly more effective than either the higher or lower doses in producing this desired effect (Wurtman et al., 2000).
The hormone had no discernable effect on sleep among the noninsomniac subjects, even though they, like the insomniacs, had nighttime plasma melatonin levels well below those seen in normal young adults. Apparently the age-related decline in nocturnal plasma melatonin is not sufficient, in itself, to cause insomnia in all individuals: “homeostatic” mechanisms may be capable of sustaining sleep in some individuals. However, insomniac patients who manifest melatonin deficiency can be treated effectively by correcting the hormone deficiency. Similar observations on the anti-insomnia effects of a physiologic dose of melatonin in older people have also been described by numerous investigators (Garfinkel et al., Laudon et al., Haimov et al., Hughes et al.). Such doses apparently do not shift circadian rhythms if administered at the subject’s normal bedtime hour; moreover — unlike higher doses, they also have no effect on body temperature.
Thus melatonin can promote sleep onset and maintenance in two situations, i.e., among persons whose plasma melatonin levels are low simply because they want to sleep at a “physiologically inappropriate” time of day (e.g., shift-workers), and among older people whose pineal glands fail to secrete adequate quantities of the hormone at night. It also promotes sleep in certain pediatric neurologic diseases associated with insomnia, e.g., Angelman’s syndrome (Zhdanova et al., 1999). The exogenous hormone does not seem to affect sleep in those who have no difficulty sleeping, even though they may have nocturnal plasma melatonin levels as low as their insomniac counterparts.
The brain loci and the endogenous macromolecules on which the hormone acts to produce its sleep-promoting effects are not known. Melatonin “receptors” coupled to inhibition of cyclic AMP synthesis have been described (Liu et al., 1997) in brain regions thought to control circadian rhythms, but no data are available on its receptors in the brain areas most associated with sleep. It also remains to be shown that the chronic daily administration of oral melatonin, for many months or years, will continue to ameliorate insomnia. It might be predicted that low doses — which elevate the hormone within its normal nocturnal range — would continue to work, while higher doses, like those sometimes sold in health-food stores (e.g., 3 to 5 mg), would down-regulate receptors and ultimately stop working or even exacerbate insomnia. As described below, some evidence suggests that that this apparently does happen.
Unfortunately, the U.S. Food and Drug Administration (FDA) has not elected to regulate the use of melatonin as a drug; instead — unlike such other hormones as thyroxine and the estrogens — melatonin preparations providing any dosage can be sold by anyone, anywhere, without regulatory approval, and with no supporting clinical evidence of efficacy or safety, and no guarantee of purity, so long as their labels do not claim that they are to be used to treat a particular disease. Concern about the purity of such preparations is heightened by melatonin’s structural similarity to the indole amino acid tryptophan. The sale of an unregulated (by the FDA) batch of synthetic tryptophan in the United States in the 1980s led to many deaths from the “eosinophilia-myalgia syndrome,” caused by a previously unknown impurity generated during the synthetizing process. All melatonin preparations contain synthetic melatonin, since its concentrations in plants and even in animal pineals are too low to allow them to serve as a commercial source of even the low, physiologic doses needed to promote sleep. Might some synthetic melatonin preparations, also unregulated by the FDA, contain the impurity that caused EMS? Apparently, yes (Williamson et al.). In actuality, it is unlikely that they would cause this syndrome even if they do contain the impurity, because melatonin doses sold in health food stores, though enormous in relation to need, provide far less of the indole than the grams of tryptophan that people formerly took.
Probably the reason that few side effects of health food store melatonin preparations have been noted, besides nightmares, is that the hormone happens to be strikingly nontoxic. However, as might be expected, many people do describe morning-after sleepiness after taking supraphysiologic doses of melatonin–most likely related to the persistence of high blood hormone levels well into the morning hours. And others describe losing the ability to respond to melatonin’s sleep-promoting effects after a few days of treatment, perhaps signaling receptor down-regulation.
The United States stands alone among developed nations in its failure to regulate melatonin as a drug. If this circumstance continues, perhaps the best that can be hoped is that a safe, effective, and pure preparation will be developed for the European or Canadian or Japanese markets and then subsequently introduced into the United States.
Source: MedScape and © The McGraw-Hill Companies, Inc.
By Clark T. Sawin, MD, Deputy Medical Inspector.
Veterans Health Administration, Department of Veterans Affairs.
Professor of Medicine, Boston University School of Medicine.
Melatonin, a normal secretion of the pineal gland, has captured public attention recently because of its effects on mood, sleep, and jet-lag. It has also been suggested that melatonin stimulates the immune system, and has antioxidant, anticancer, and antiaging properties.
Because melatonin occurs naturally in plants and some foods, it can be sold as a food supplement without approval from the Food and Drug Administration (FDA). It can be synthesized easily and is now widely sold to millions of persons in the United States, with annual sales exceeding $200 million. Nevertheless, the FDA has not yet approved it for any indication except as an orphan drug for the rare blind patient with a clinical sleep disorder. Over-the-counter sales are banned in Great Britain and Germany. Some of the over-the-counter products may contain unidentified impurities.
Little evidence supports the widespread use of melatonin although it may have some benefit in a few specific conditions. Scientific and public health concerns over the dissonance between its wide use and evidence of benefit led to the convening of a workshop by the National Institutes of Health in 1996. The workshop’s general conclusions were that, while there have been no medical catastrophes caused by melatonin, there are few data on either long-term safety or efficacy, there can be occasional side-effects, and there is little evidence that it has any health long-term benefits although it may have some short-term benefit for insomniac patients or for travelers crossing several time-zones (see Clinical use below).
Melatonin is so named because it lightens frog skin by causing melanocyte (“mela”) pigment granules to move (“ton”) to the center of the cell; the result is that less incident light is absorbed by the skin surface and the skin appears lighter. Melatonin had originally been sought as an antagonist of melanocyte-stimulating hormone (MSH), which has the opposite effect, ie, it causes dispersal of the granules and therefore darkens frog skin. There is, however, no evidence that melatonin affects skin color in humans.
The search for the lightener of frog skin led to the pineal gland (named because of its resemblance to a pine cone), an evolutionarily ancient organ that, in mammals, has lost its direct neural connection to the brain. The pineal makes and secretes most of the body’s melatonin; it also contains other biogenic amines and peptides. In addition to the pineal gland, small amounts of melatonin are synthesized in the retina and gut; melatonin’s role at these sites is unclear.
Melatonin is a tryptophan derivative. In the pineal gland tryptophan is hydroxylated and decarboxylated to form serotonin (5-hydroxytryptamine); the serotonin is then converted to melatonin by acetylation and methylation. The rate-limiting enzyme is serotonin N-acetyltransferase. Both synthesis and secretion of melatonin from the pineal are dependent upon adrenergic stimuli that reach the gland via the cervical sympathetic ganglia; these stimuli activate beta-adrenergic receptors on the pinealocytes, which then act via a type II cyclic AMP protein kinase to stimulate melatonin production. Alpha-1-adrenergic stimuli may also stimulate melatonin secretion.
Control of Melatonin Secretion
The principal known environmental factor affecting melatonin secretion is light; melatonin itself has no effect upon its own secretion. Bright light inhibits melatonin secretion via the following steps:
- Light hits the retina and triggers impulses in the retino-hypothalamic tract, which connects the retina to the hypothalamic suprachiasmatic nucleus (SCN), an area involved in the regulation of body rhythms. The retinal photoreceptor responsible for melatonin inhibition is unknown; this photoreceptor is in neither the rods nor cones, previously thought to be the only photoreceptors in the retina.
- Neural impulses from the SCN descend to the cervical spinal cord and then to the superior cervical sympathetic ganglia; these impulses inhibit the beta-adrenergic sympathetic outflow from the ganglia to the pineal gland.
- The light-stimulated inhibition of beta-adrenergic outflow to the pineal gland leads to inhibition of the synthesis and secretion of melatonin.
Darkness has the opposite effect from light, resulting in an activation of adrenergic stimuli to the pineal gland; the consequence is a marked rise in melatonin secretion. This mechanism has been worked out largely in animals, although the effect of beta-adrenergic blockade supports its presence in humans; the beta-blocking drug atenolol inhibits darkness-induced melatonin secretion.[15, 16]
In normal young adults, serum melatonin concentrations are highest during the night (about 60 to 200 pg/mL [261 to 870 pmol/L]) and lowest during the day (about 10 to 20 pg/mL [44 to 87 pmol/L]).[17, 18] The night-time peak occurs later in persons who identify themselves as “evening” persons compared with “morning” persons. Most of the melatonin in serum is bound to protein with about one-fourth circulating in the free form. A brief exposure to light for only a few minutes during the night is sufficient to inhibit melatonin secretion.
There are conflicting data on whether nocturnal melatonin secretion diminishes with age.[20, 21] Urinary excretion of melatonin appears to be inversely correlated with age.
Actions of Melatonin
The physiologic actions of melatonin are mediated via specific receptors. The best data concern melatonin’s effects on reproduction and on biologic rhythms. These actions are likely mediated by melatonin 1a or 1b [Mel(1a) or Mel(1b)] receptors in the SCN, which in turn inhibit the activity of adenylate cyclase.[24, 25, 26, 27] Mel(1b), but not Mel(1a), receptors can also act via guanylyl cyclase, at least in vitro. There may be a further contribution to the reproductive effects of melatonin via Mel(1a) receptors in the pars tuberalis of the pituitary gland.[26, 29] There are allelic variations in the human Mel(1a) receptor but it is uncertain whether these are related to any disease state. Other melatonin receptors, such as Mel(1b) in the retina, Mel(1c) in the brain, and Mel(1a) receptors elsewhere in the body are of uncertain physiologic significance.
Melatonin secreted from the pineal gland appears to reach its sites of action in the SCN and pars tuberalis via the circulating blood stream rather than from within the central nervous system. Whether there are actions elsewhere in the body is unclear although there are reports of in vitro effects of melatonin to block the action of estrogen receptors or to promote osteoblast differentiation.
Melatonin has effects on reproductive function in rodents. Darkness or short photoperiods cause the gonads to shrink in rats and hamsters; this does not occur if the pineal is removed. The available data point to melatonin as the pineal effector of gonadal involution. Thus, darkness leads to a higher serum melatonin concentration. The melatonin then probably shrinks rodent gonads by acting on melatonin receptors in the SCN, which in turn probably causes a decrease in the secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus and therefore a decrease in gonadotropin secretion and gonadal function.
Whether melatonin has a physiologic role in the regulation of gonadal function in humans is murky. Evidence in favor of a physiologic relationship between melatonin and the human hypothalamic-pituitary-gonadal (HPG) axis includes the following:
- Hypogonadal men with GnRH deficiency have high nocturnal serum melatonin concentrations, while those with primary hypogonadism have decreased concentrations. Testosterone therapy normalizes melatonin secretion in both types of hypogonadism.
- Women with hypothalamic amenorrhea (and presumed GnRH deficiency) or with Kallman’s syndrome (and known GnRH deficiency) have high nocturnal serum melatonin concentrations;[36, 37] in those with hypothalamic amenorrhea, the high concentrations return to normal after estrogen treatment.
- Decreased melatonin secretion, as evidenced by decreased urinary excretion of melatonin, occurs in perimenopausal women somewhat before the expected rise in follicle-stimulating hormone (FSH) secretion.
These data suggest an inverse relationship between the secretion of GnRH and melatonin, although other investigators have found an increase in melatonin secretion in men with primary hypogonadism. In addition, exogenous melatonin can stimulate prolactin secretion in women,[40, 41] another possible locus of an effect on the HPG axis.
On the other hand, there is evidence against a role of melatonin in human (or primate) reproduction:
- There is no proven relationship between the onset of puberty and melatonin secretion in humans[42, 43] although there is a somewhat higher excretion of a major melatonin metabolite, 6-hydroxymelatonin, in prepubertal compared to pubertal or adult subjects.
- Removal of the pineal gland and the consequent abolition of the nocturnal rise in melatonin secretion has no effect on the onset of puberty in rhesus monkeys.
- Women with amenorrhea due to anorexia nervosa (and presumed GnRH deficiency) have normal serum melatonin concentrations.
- Administration of melatonin (6 mg/day) for one month to normal men had no effect on serum concentrations of luteinizing hormone, follicle-stimulating hormone, testosterone, inhibin B, or luteinizing hormone pulse frequency as determined by frequent sampling studies over three nights.
Thus, there may be a coordinating role for melatonin in gonadal function in humans, but it is as yet poorly defined.
Melatonin has a more certain role in the regulation of human body rhythms, such as sleep and body temperature. As examples of the relation to body temperature, bright light, eg, unfiltered fluorescent light, causes a parallel shift in melatonin secretion and in the body temperature rhythm, and administration of melatonin to mimic its usual rise during sleep causes a fall in core body temperature similar to that which occurs during sleep. As to the relationship to sleep, blind individuals without light perception, whose melatonin rhythm is free-running because of the lack of retinal light stimuli, tend to take naps during daylight hours in consonance with their abnormal daytime melatonin peaks. It is possible that the effects upon sleep, as well as a diminution in cognitive function (reaction time), are secondary to the primary effect to lower body temperature.[51, 52] By analogy with animal data, environmental light probably entrains the SCN’s endogenous regulation of body rhythms via changes in the secretion of melatonin.
There are only a few observations that suggest abnormal secretion of melatonin in patients with sleep or mood disorders. In one study, for example, 20 patients with primary insomnia had significantly lower serum melatonin concentrations than an equal number of normal subjects (mean values: 45 versus 60 pg/mL [202 versus 262 pmol/L], respectively). However, serum melatonin was not measured at the time of the expected nocturnal peak value. Furthermore, in another study, there was no relationship between disordered sleep and urinary excretion of 6-sulfatoxymelatonin, the main metabolite of melatonin, in 56 older insomniac patients as compared with 52 normal subjects. A small study of older patients with Alzheimer’s dementia showed a correlation between a decreased total secretion of melatonin and the degree of irregular sleep-waking activity compared with age-matched controls; whether there was a causal connection was unclear.
Some patients with depression also have a lower than expected rise in serum melatonin at night. This effect, however, may not be causal because the administration of melatonin to depressed persons may deepen, rather than alleviate, the depression.
Alcohol withdrawal in chronic alcoholic patients has also been associated with low nocturnal serum melatonin concentrations (<30 pg/mL [<130 pmol/L]). Despite this apparent deficiency, from which one might predict disrupted sleep, there was a significant improvement in sleep quality.
As noted above, melatonin is widely available in the United States, usually as tablets containing 3 to 10 mg (to be taken once daily). It has been approved by the FDA as an orphan drug for use in correcting sleep disorders in blind persons with no light perception, a group of patients quite small in comparison to the millions who buy it. It is also listed in the Physicians Desk Reference for Non-prescription Drugs as a dietary supplement that “can help restore the melatonin we need for restful sleep.” There are wide variations in the bioavailability of a given dose, probably due to variations in hepatic metabolism.
The relatively large doses sold over-the-counter may be associated with side effects, such as hypothermia, gynecomastia, or seizures in children with existing neurologic disease.[7, 60] There are no controlled studies to indicate that more physiologic doses, ie, about one-tenth as much (0.3 mg), would avoid these side effects, but experience suggests that they would.
Some persons take melatonin in the belief that it will slow aging, based upon the observation that older persons may have lower nocturnal serum melatonin concentrations. Others think melatonin will prevent cancer, a belief apparently extrapolated from one animal experiment. There are sketchy data suggesting that melatonin may help patients who already have cancer but the results are at best preliminary.[3, 43, 61] There may be some benefit of melatonin for decreasing the frequency of cluster headaches, but this would require long-term therapy.
The main clinical uses are to enhance sleep and to avoid jet-lag. Do these short-term uses have data to support them? There are some supportive data, but “not proven” is probably the appropriate conclusion.
Effects On Sleep
When melatonin is taken in low doses, 0.2 to 1.0 mg, its peak serum concentrations more nearly mimic endogenous peak nocturnal values and it has few side effects. These low doses can promote sleep in normal persons. One study, for example, evaluated 20 normal men who were given melatonin (0.1 to 0.3 mg) at mid-day; melatonin decreased the time to sleep onset and increased sleep duration as compared with placebo. Similar effects were noted in other studies when melatonin was given in the evening.[64, 65, 66] (NOTE: Some of these investigators patented the use of low-dose melatonin for sleep and founded a pharmaceutical firm for its manufacture and sale.)
Most of the studies of melatonin on sleep have been in normal persons without sleep disorders and with presumably normal melatonin secretion. The potential benefit in older persons (who may have a lesser nocturnal rise in serum melatonin concentrations than younger adults) who have a sleep disorder has been investigated in the following studies. In one report, 12 older persons with insomnia took 2 mg of an extended-release preparation of melatonin each night for three weeks; there was some benefit on sleep efficiency, compared with placebo, but there was no significant effect on sleep latency (the time it took to fall asleep) or on total sleep duration. The same dose of melatonin increased both sleep latency and duration in 21 older patients with insomnia who were taking a benzodiazepine. A double-blind follow-up study of 34 such patients revealed that this dose of melatonin facilitated withdrawal of the benzodiazepine; the benefit persisted for six months provided the melatonin was continued. The benefits of melatonin on sleep latency, although significant, may be small (eg, four to ten minute improvement).[70, 71]
Data are scanty in younger adults with disturbed sleep. An uncontrolled preliminary study of REM sleep disorder suggested that melatonin (3 mg) given at bedtime improved the disturbed sleep in five of six patients. However, melatonin (5 mg) did not help emergency department physicians sleep better on the nights after working night-shifts.
Melatonin probably acts more as a drug than as replacement therapy, because there is a poor relationship between low serum melatonin concentrations and the sleep response after its administration. Uncontrolled data suggest that any benefit may last less than a year. Furthermore, higher doses (5 mg) of melatonin may actually disrupt sleep.
Even if there is benefit in patients with insomnia, melatonin has at least the potential to worsen depression. Because insomnia is one symptom of depression, it is possible that the long-term administration of melatonin could be harmful in some persons who sleep poorly.
Effects On Jet-Lag
Uncontrolled studies have suggested that melatonin, taken in doses of about 5 mg/day for a few days, can minimize jet-lag. In a sense, this could be considered replacement therapy because travel across several time-zones disrupts the normal pattern of nocturnal melatonin secretion.
Military services have an obvious interest in avoiding jet-lag when there is a need for rapid deployment over several time-zones on short notice. In one placebo-controlled, double-blind study, 29 male aircrew members crossed eight time-zones, traveling eastward, and undertook night operations upon arrival. The men were randomly assigned to melatonin, 10 mg daily, or placebo for one week before leaving, during the flight, and for five days after arrival. The melatonin-treated men had more appropriate sleep and waking times in the new environment, a more nearly normal duration of sleep, and performed better on a standardized test of vigilance. However, in a study of 257 physicians who traveled from the United States to Norway and were given two doses of melatonin (0.5 or 5.0 mg) or placebo, there was no benefit of melatonin.
Thus, the evidence in favor of a benefit of melatonin in the treatment of jet-lag is equivocal. One problem is the lack of agreement on the dose of melatonin and its dosing schedule. Some simply take 3 to 5 mg on departure; there are no data to support this regimen, and the effect, if any, is likely on sleep rather than on phase-shifting. Others follow one or another complicated dosage schedule, eg, 2 mg to 5 mg in the evening (about 10 PM) of the new local time, or a similar dose at various times in the evening for different numbers of time-zones crossed when flying eastward, or in the early morning when flying westward. Until there are better data, it is advisable to be cautious in the use of melatonin for jet-lag.
Melatonin secretion increases during darkness and sleep, which usually coincide in humans. The rise in endogenous melatonin may help entrain the circadian rhythm of sleep and body temperature to the external world. In contrast, melatonin’s role in gonadal function is uncertain, at least in humans. There is only scant evidence that an abnormality in melatonin secretion causes illness; hence, there are few data to support the use of melatonin as replacement therapy.
On the other hand, there may be a role for the pharmacologic use of melatonin. Its short-term administration in patients with mild sleep disorders may be effective and safe, but more data are needed to document both safety and efficacy and to determine appropriate doses. Short-term administration to minimize jet-lag is of uncertain effectiveness despite widespread anecdotal support. Long-term administration of melatonin for any medical condition, ie, for a year or more, is of unproven benefit and, at the doses commonly sold over-the-counter in the United States, has some potential for harm. There is no substantial evidence in humans for a therapeutic role of melatonin as an anticancer, antiaging, or immune stimulating agent.
Source: MedScape and © 2000 UpToDate
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Updated February 28, 1998
Delayed sleep phase syndrome (DSPS) is a fairly common disorder of sleep timing. People with DSPS tend to fall asleep at very late times, and also have difficulty waking up in time for normal work, school, or social needs.
- What Causes DSPS?.
- Getting Help.
- Treatment for DSPS.
- DSPS and Depression.
- About the Author – Su-Laine Yeo.
- About this Article – please read.
Main Symptoms of DSPS
- DSPS causes sleep-onset insomnia. Often, DSP individuals report that they cannot sleep until early morning. Unlike most other insomniacs, however, they fall asleep at about the same time every night, no matter what time they go to bed.
- Unless they have another untreated sleep disorder (such as sleep apnea) in addition to DSPS, patients can sleep well, and have a normal need for sleep. Therefore, they find it very difficult to wake up in the morning if they have only slept for a few hours. However, they sleep soundly, wake up spontaneously, and do not feel sleepy again until their next “night,” if they are allowed to follow their own late schedule, e.g. sleeping from 4 am to noon.
- Symptoms have been present for at least a month, and usually much longer.
In addition to the main symptoms of DSPS, most people with DSPS also have some or all of the following features:
- DSP individuals are night owls. They feel most alert and say they function best, are most creative, etc. in the evening and at night.
- They usually have tried many times to change their sleeping schedule. Failed tactics to sleep at earlier times may include relaxation techniques, early bedtimes, hypnosis, alcohol, sleeping pills, dull reading, and folk remedies. They often have asked family members to help wake them in the morning, or they have used several alarm clocks. Or family members – especially parents – have tried to get them up on time.
- Symptoms often begin in adolescence, childhood, or infancy.
- They are sleepy during the day, especially in the morning, if they have had to get up early. They sleep in on weekends (often past noon and for more than 10 hours) to make up for not getting enough sleep during the rest of the week. Some people with DSPS take naps during the day and feel refreshed afterwards.
- Many people with DSPS need at least 30 minutes to fall asleep, even when they go to bed at a time that is realistic for them.
- Some people with DSPS have occasional, sudden, and temporary reversions to sleeping at earlier times.
Could DSPS symptoms be a deliberate behaviour?
Yes. Some people choose to sleep at late times when they don’t have to get up early, e.g. when they are on vacations or when they work in the evening. If they can adjust to an earlier sleep/wake schedule when they need to, they do not have DSPS. Other individuals, particularly adolescents, choose to sleep late in order to avoid school or because they enjoy late-night partying or television. Superficially, school-refusal and DSPS can look the same. Even people with true DSPS often have problems in school, because their chronic sleep deprivation makes it difficult for them to arrive at class on time and then stay awake and concentrate. Closer examination reveals the following differences:
|Desired late sleep phase||DSPS|
|Can change to earlier sleeping and waking times when not in school.||Late sleeping continues throughout the year, and often drifts to even later times during vacations.|
|Does not co-operate with treatment.||Usually enthusiastic about beginning treatment.|
|Nearly always clinically depressed.||May be clinically depressed.|
|Unhappiness about attending school usually begins long before the pattern of sleeping late.||Absenteeism and other school problems develop, or significantly worsen, after the late sleeping pattern takes hold.|
Adolescents who sleep late to avoid school do not have a sleep disorder – but they do have a significant problem which they can’t resolve alone. Psychotherapy to treat the depression, and perhaps a change of school or school program, should be investigated.
How can DSPS be distinguished from other causes of insomnia, such as insomnia caused by stress or tension?
First, DSPS is a chronic condition. If untreated, it causes “insomnia” virtually every night. If you only occasionally have difficulty falling asleep (e.g. a few times a month), DSPS is not the cause.
The most striking difference between DSPS and chronic sleep-onset insomnia is that that people with DSPS have at least a normal – and often much greater than normal – ability to sleep during the morning, and sometimes in the afternoon as well. In contrast, those with chronic insomnia don’t find it much easier to sleep during the morning than at night. Another important difference is that the DSP individual falls asleep at more or less the same time every night, and sleep comes quite rapidly if the person goes to bed near the time he or she is usually falls asleep. Young children with DSPS resist going to bed before they are sleepy, but the bedtime struggles disappear if they are allowed to stay up until the time they usually fall asleep.
Another fairly common disorder which causes sleep-onset insomnia is Restless Legs Syndrome (RLS). Individuals with RLS experience uncomfortable sensations in their lower legs at night, which make them want to move their legs or get out of bed and walk around.
Why is it so hard for me to get up in the morning?
If you have a delayed sleep phase and you tried to wake up at a “normal” time this morning, such as 7:30 am, there are two reasons you probably found it difficult and unpleasant. First you didn’t spent enough time sleeping to fulfill your sleep requirement. The other reason is that the drive for sleep follows a cycle, determined by the biological clock. The middle of the night, or shortly after, is when the drive for sleep is greatest – and if you have a tendency to fall asleep at 3 or 4 am and get up around noon, 7:30 am is close to the middle of the night for you.
The variation in “drive for sleep” at different times of the day is physiologic, not just a matter of habit or choice. There are several other rhythms in the body which are closely related to sleep/wake patterns. For example, body temperature rises and falls during the day. You tend to fall asleep when your body temperature is falling; it reaches a minimum around the middle of the night (meaning, again, the individual’s subjective night) and then rises again toward morning. The concentration of melatonin in the blood rises during the evening, peaks during the night, and then decreases again. Hunger to some extent also follows circadian rhythms – if you get up too early you likely don’t feel like eating breakfast right away. Loosely speaking, when the biological clock says it is time to be asleep, the body gears down in many ways, and during that time it is hard to wake up or to be fully alert.
Besides DSPS, there are many other causes of difficulty waking up and daytime sleepiness. Some of the more common ones are listed below.
- The most common cause of daytime sleepiness and difficulty awakening, at all ages, is simply insufficient sleep. Teenagers often don’t get enough sleep – many adolescents need 9 or 10 hours of sleep every night and some need more.
- Sleep apnea is a very common, treatable disorder in which breathing is disrupted during sleep. Symptoms of sleep apnea include snoring, waking up with a headache, and waking up during the night. Self-scoring quiz: could you have sleep apnea?; Sleep Apnea FAQ
- Narcolepsy is another cause of chronic daytime sleepiness. The symptoms of narcolepsy often emerge during adolescence and include cataplexy (temporary loss of muscle control following strong emotion), sleep paralysis (temporary inability to move while falling asleep or waking up), waking up during the night, and hallucinations while falling asleep. Excessive daytime sleepiness, with a strong need to nap often, is usually the first symptom to develop.
- Some individuals, particularly children and adolescents, deal with depression by sleeping a lot more than they actually need to.
- Illness, particularly viral infections, can cause fatigue and sleepiness which disappear soon after the disease has run its course.
- Periodic Limb Movements are movements of the arms and legs during sleep
- Individuals with hypersomnia have difficulty awakening and persistent daytime sleepiness. Neither going to sleep earlier nor waking up later relieves the symptoms even though their nighttime sleep is technically normal. They do not have difficulty falling asleep at night. Like insomnia, hypersomnia has a variety of causes.
- Seasonal Affective Disorder (SAD) causes sleepiness, and depression that can be severe and lead to suicide. Other symptoms of SAD are craving for sweets and carbohydrates, and weight gain. The symptoms of SAD appear only in the fall and winter, and disappear in the spring.
In DSPS and other circadian rhythm sleep disorders, daytime sleepiness is greatly reduced when the individual’s preferred sleep/wake times are followed. Have you ever been able to wake up as late as you wanted to for more than a few days at a time? If you still often felt sleepy during the day, it is likely that something other than DSPS is contributing to your sleepiness. Excessive daytime sleepiness is usually treatable, and should be investigated by a professional trained in diagnosing and treating sleep disorders.
Pulmonary Diagnostics and Consulting Sleep Questionnaire
What Causes DSPS?
DSPS is believed to be a disorder of the body’s timing system – the biological clock. DSP patients have difficulty falling asleep and difficulty waking because their biological clocks are out of phase with the sleeping and waking times they try to carry out. DSPS is similar to jet lag, but much longer-lasting. It can develop suddenly or gradually.
You probably have heard of a biological clock which governs growth, reproductive cycles, and aging. There are also bodily rhythms, known as circadian rhythms, which are also controlled by a biological clock and which work on a daily time scale. You might have already noticed, in yourself or in others, that sleepiness doesn’t just keep increasing as it gets later. Rather, the drive for sleep follows a cycle, and the body is ready for sleep and for wakefulness at different times of the day.
Circadian Rhythms – What’s Normal?
Among people with healthy circadian clocks, there are “larks” or “morning people” who prefer to sleep and wake early, and there are “owls” who prefer to sleep and wake at late times. But whether they are larks or owls, people with normal circadian systems:
- can wake in time for what they need to do in the morning, and fall asleep at night in time to get enough sleep before having to get up.
- can sleep and wake up at the same time every day, if they want to.
- will, after starting a new routine which requires they get up earlier than usual, start to fall asleep at night earlier too within a few days. For example, someone who is used to sleeping at 1 am and waking up at 9 am begins a new job on a Monday, and must get up at 6 am to get ready for work. By the following Friday, the person has begun to fall asleep at around 10 pm, and can wake up at 6 am and feel well-rested. This adaptation to earlier sleep/wake times is known as advancing the sleep phase, and healthy people can advance their sleep phase by about one hour each day.
Researchers have placed volunteers in caves or special apartments for several weeks without clocks or other time cues. Without time cues, the volunteers tended to go to bed an hour later and to get up about an hour later each day. These experiments demonstrate that the “free-running” circadian rhythm in humans is about 25 hours long. To maintain a 24 hour day/night cycle, the biological clock needs regular environmental time cues, e.g. sunrise, sunset, and daily routine. Time cues are what keep our body clocks aligned with the rest of the world.
Understanding Circadian Rhythm Abnormalities
It is thought that DSPS is caused by an insufficient ability to reset the sleep/wake cycle in response to environmental time cues – perhaps the biological clocks of DSP individuals have an unusually long cycle, or perhaps they are not sensitive enough to time cues.
There are other circadian rhythm disorders:
- Jet lag affects people who fly across time zones.
- Shift workers who work at night often have trouble sleeping during the day.
- There is an advanced sleep phase syndrome, which causes difficulty staying awake in the evening and staying asleep in the morning. It is essenally the reverse of DSPS.
- Non 24-hour sleep-wake syndrome, also known as hypernychthemeral syndrome, causes patients to stay up later and later every night, then wake up later every morning. It occurs frequently among people who are totally blind. DSP individuals stay up late, but they can sleep at the same time every day. Non 24-hour sleep/wake syndrome is related to DSPS, only it is more severe and considerably more debilitating. It is believed to be rare.
- Finally, an irregular sleep-wake pattern presents as sleeping at very irregular times, and usually more than once per day (waking frequently during the night and taking naps during the day).
DSPS has in some instances followed an illness or head injury, and might run in families. But in most cases, it is not known what causes the biological clock to be confused. Because DSPS was discovered only in 1981, and there is little awareness of the disorder, it is difficult to get a reliable estimate of how widespread DSPS is. About 7% of adolescents have DSPS, and it is probably responsible for 7 -10% of cases of chronic insomnia.
DSPS doesn’t bother everyone who has it. Some people are happy and healthy with a late sleeping schedule, and have found ways to adjust their lifestyle to it. For this reason, many researchers consider DSPS to be a “disorder” only when it interferes with the individual’s work or social functioning.
Keeping a Sleep Log
If you think you might have DSPS and consider it a problem, take down the list of symptoms shown above, and discuss them with someone who knows you very well, preferably someone who has lived with you. You should also start to keep a sleep log so a doctor can evaluate your symptoms. This takes a few minutes every day. You should write down:
- Time you tried to fall asleep.
- Time you think you fell asleep.
- Any nighttime awakenings.
- Time you woke up.
- Time you got out of bed.
- Time you had to be up.
- Whether you got up by yourself, by an alarm clock, or because you were disturbed.
- A few words about how you felt during the day.
- Any daytime naps – how long and when.
- What medications you used.
It is easier to distinguish DSPS from other causes of inadequate sleep if the sleep log is recorded when the patient is not taking sleeping pills, sedatives of any kind, or stimulants such as caffeine. But if your doctor has already recommended one of these types of medication for you, continue to take it as directed until your doctor agrees it is safe for you to stop.
Finding a Sleep Specialist
You may have to look hard to find a physician who can recognize and treat DSPS. Try calling your local sleep disorders clinic, or the departments of psychiatry, neurology, and internal medicine at your local hospital. Ask, “Do you treat sleep disorders?” then, “Can you treat circadian rhythm sleep disorders, such as delayed sleep phases syndrome?” Don’t be discouraged if they cannot help you. Keep looking. The Sleep Medicine Home Page includes a list of sleep disorder clinics and national sleep medicine associations. You can also write to your local sleep medicine association and ask about accredited sleep clinics in your area.
At least two weeks of sleep logs are needed to diagnose DSPS. Many sleep clinics encourage new patients to bring a family member, roommate, or friend to the first visit. An overnight stay in a sleep lab is usually not necessary, except to rule out other sleep disorders.
Treatment for DSPS
Treatment for DSPS is specific. It is different from treatment of other types of insomnia, and recognizes the patient’s ability to sleep well while addressing the timing problem. Nightly use of sedative and hypnotic drugs is rarely useful in DSPS, and surgery is unheard of.
There is no permanent cure for DSPS. The treatment methods described here have all been reported in the scientific literature to relieve DSPS in some patients. This does not necessarily mean you should try them; it only means these methods are taken seriously as options for treating DSPS. No particular treatment will relieve DSPS in all cases, and you and your doctor may decide that some of the strategies listed below are too risky or too uncomfortable to be worthwhile. And please take note of the appropriate use disclaimer.
If your DSPS is properly diagnosed and treated, you should be able to sleep and to function just as well with the early sleep schedule as you do with a late one. Stimulant drugs (including caffeine) to keep you awake during the day should not be necessary.
The first part of DSPS treatment is stabilization of the sleep/wake schedule, for a week. That means sleeping regularly, without napping, at the time which is most comfortable for you. It is important to start treatment well-rested. Mild cases of DSPS can be controlled by waking up and going to bed 15 minutes earlier every day until the desired sleep schedule is reached, and then maintaining a strictly regular sleep/wake schedule seven days a week. If this doesn’t work for you, see a doctor.
- Light therapy:
Light therapy (phototherapy) is more widely used to treat Seasonal Affective Disorder, but it is also an effective method of adjusting sleep/wake timing. The principle behind it is that exposure to light in the morning advances the sleep phase, whereas light in the evening delays it.
For light therapy, you need a source of very bright light. Room lighting is not bright enough. Sunlight is good, if you have lots of windows or if you can get outside. You should never look directly at the sun, of course. Most convenient is an electric light box or light visor, available from some medical supply stores or by mail-order. A good light source will have the UV radiation filtered out. Remember that the intensity of light drops off exponentially with distance from the source. For example, if you double the distance between the light source and your eyes, the dose you receive is reduced by 75%. Treatment effectiveness also increases (up to a point) with the length of exposure – 30 minutes to two hours is often recommended.
Advantages of Light Therapy
- The light levels in commercial light therapy equipment are believed to be safe for eyes, at least in the short term and for people who do not already have eye disease.
- Does not require taking time off work or school.
- Light therapy daily or a few times a week is a simple way to maintain your sleep schedule once you have moved it to an earlier time.
Disadvantages of Light Therapy
- Certain medical conditions and medications are incompatible with light therapy. Check with your doctor if you are taking any kind of medication, or have any skin or eye disease.
- Headache is a possible side effect. It may help to avoid reading or having to focus your eyes during the light exposure. and to decrease the intensity of the light.
- Overdosage can make you feel “wired” and overstimulated – if this happens, decrease the time or intensity of the light treatment.
- The long-term effects of bright light treatment are not yet known.
- You can do other things in your morning routine while under exposure to light, but you may still need to wake up earlier than you normally would, so you can get enough light before leaving the house in the morning. You don’t have to get out of bed for light therapy, as long as you keep your eyes open.
- Equipment for light therapy can cost several hundred dollars (Canadian or US). If you have a doctor’s prescription for light therapy, and extended medical insurance, your insurance plan may cover it.
- Requires some time – a few days to two weeks – to take full effect. During this period, you will probably feel sleep-deprived.
Timing of Light Therapy and Sleep
Light exposure timed just before the middle of the night is most effective in delaying the sleep phase, and light timed just afterwards is most effective in advancing it. In this case, “night” refers to your night, so if you are used to sleeping between 4 am and noon, the middle of the night is around 8 am (give or take about an hour). The general rule is that light therapy for DSPS should begin as soon as you can get up in the morning. Minimizing your exposure to light in the evening may also be helpful.
There are different ways you can reschedule your sleep with the help of light treatment
- Cold-turkey phase advance. That is, if you want to be getting up at 7 am, you force yourself up at 7 am, and don’t take naps, every day until (you hope) you get used to it. Light therapy upon waking should accelerate the adjustment.
- Gradual phase advance. This means getting up a little earlier, e.g. by 15 minutes, every day or every other day, until you reach your desired wakeup time. It can take a long time if you are more than two hours away from the schedule you want.
- Sleep deprivation-phase advance (SDPA) consists of staying up all night then moving bedtime one or 1.5 hours earlier the next night. If you are more than 1.5 hours away from your desired schedule, you can do this once a week on the weekends until you’re there. SDPA doesn’t always work – some DSP individuals cannot fall asleep until their normal bedtime even after staying up all night.
- Cold-turkey phase advance with a nap. This involves getting up early for light therapy and going back to bed for a nap after the light treatment is over. You will probably find it easier psychologically to wake up early if you know you can go back to sleep again soon.
The original treatment for DSPS, chronotherapy involves going to sleep three hours later every day until you reach your desired bedtime.
- Day 1: sleep 4 am to noon.
- Day 2: sleep 7 am to 3 pm.
- Day 3: sleep 10 am to 6 pm.
- Day 4: sleep 1 pm to 9 pm.
- Day 5: sleep 4 pm to midnight.
- Day 6: sleep 7 pm to 3 am.
- Day 7 to 13: sleep 10 pm to 6 am.
- Day 14 and thereafter: sleep 11 pm to 7 am.
Chronotherapy is difficult, although for people with DSPS it is often much easier than just trying to wake up at 7 am from the first day. Other sleep-rescheduling methods are described under light therapy.
Advantages of Chronotherapy
- It works rapidly, especially if you are sleeping several hours later than you want to.
- Unlike other treatment methods, it has a beginning, a middle, and an end, so you can predict when it will work.
- It gives you a period to adjust psychologically to the new schedule. Sleeping earlier and getting up earlier means taking on a schedule that is unusual for you, whereas with chronotherapy, your schedule becomes strange for a few days, then becomes more and more like normal.
- During chronotherapy, patients often can fall asleep very quickly as soon as they get into bed, which helps their confidence.
- Chronotherapy is drug-free.
Disadvantages of Chronotherapy
- Staying awake until your next scheduled bedtime can be uncomfortable. During chronotherapy, you will probably be less productive than usual.
- You may wake up before you intend to and be unable to fall asleep again.
- You will have to take time off from your normal routine, perhaps using your vacation time.
- In some instances, individuals have remained on sleep cycles longer than 24 hours after chronotherapy – they develop non 24-hour sleep-wake syndrome. This does not always happen, but the degree of risk is unknown.
If you decide to go through chronotherapy, plan for it. Medical supervision is essential, and daily communication with a sleep specialist is strongly recommended while undergoing chronotherapy.
- Be sure to check with your doctor if you have another condition that chronotherapy could interfere with, such as if you’re taking insulin or other regular medication.
- Try to have an activity scheduled every day, and get out of the house as much as you can to reduce the isolation.
- Make a list of places that are open early in the morning and late at night. Get lots of exercise. Take the opportunity to do things you wouldn’t normally do, like watch the sunrise or stay up all night in a cafe.
- Make a list of things to do to keep yourself awake (watching videos is good). Tell your friends what you’re doing. Turn off the ringer on the telephone when you need to sleep.
- During chronotherapy, you might feel unusually warm or cold at times.
Melatonin is the newest treatment for sleep/wake timing disturbances. It is a hormone whose concentration in the blood rises as the body prepares for sleep. It has been synthesized and can be taken orally, as a pill, at night to induce sleepiness and a seemingly natural sleep.
Melatonin has two effects which are of interest to individuals with DSPS. For many people, it advances the timing of sleep in the short-term, making them feel sleepy soon after they take it. Melatonin is also believed to have a chronobiotic effect – it actually helps reset circadian rhythms. Melatonin is the only known drug which resets circadian rhythms at safe doses. Ordinary sleeping pills, such as benzodiazepines (Flurazepam, Valium, and others), do not have this chronobiotic effect. Although in the popular press melatonin has received more attention than light therapy as a chronobiotic treatment for jet lag, recent research has indicated that bright light is a more powerful circadian phase-resetter than melatonin.
Advantages of Melatonin
- It is easy to take melatonin. Sleep deprivation isn’t necessary, although if you take too much you will feel tired or hung-over the next day.
Disadvantages of Melatonin
- Although melatonin is widely considered to have low toxicity, long-term human testing has not been done. Melatonin could have side effects which appear after years of use, but which have not been discovered yet because melatonin is a new drug.
- Most people, if they could, would rather sleep without taking sleeping pills. It is possible for people with even severe DSPS to sleep at night without using melatonin at all. Ask yourself whether you are willing to take melatonin every night for many years. Would use of a sleeping pill make you lose the skill of falling asleep without medication?
- Buying, selling, or importing melatonin is restricted in some countries. If you do not know how to obtain melatonin, or whether you can legally bring it into your country, ask your local authorities.
- Some melatonin users have reported:
- increase in vivid dreaming and nightmares.
- tiredness the following day.
- restlessness instead of sleepiness after taking melatonin.
- mood changes.
- Melatonin has been shown to affect reproductive cycles and inhibit sexual development in animals. Its effects on humans are not known. Do not take melatonin if you are:
- a child or adolescent.
- pregnant or breastfeeding.
- There is some evidence to suggest that melatonin may have cardiovascular effects, and therefore might be detrimental in patients with cardiovascular disorders.
- Consult your doctor before taking melatonin if you:
- are depressed.
- have an autoimmune disease, diabetes, leukemia, or a lymphoproliferative disorder.
- are taking MAO inhibitor drugs or corticosteroids.
Dosage and Timing of Melatonin
If you decide to take melatonin for DSPS, take it at least 30 minutes before you want to fall asleep. Individuals vary widely in how much melatonin they need to take to bring about sleep. Start with a low dose of about 100 or 200 mcg (pronounced “micrograms”; 1000 mcg = 1 mg = 0.001 g), and if necessary work up to higher doses gradually.
- Vitamin B12:
High doses of vitamin B12 have been reported to relieve a few cases of DSPS and non-24-hour sleep-wake syndrome. Vitamin B12 neither helps you wake up nor fall asleep in the short term, and it is not yet clear why vitamin B12 would have an effect on circadian rhythms.
Reportedly, the dose needed for a significant effect in treating these circadian disorders is 2-3 mg per day, which is about 1000 times the ordinary recommended daily allowance. There have been no reported side effects from such large doses of vitamin B12. Vitamin B12 tablets are available from many drugstores and health food stores. The vitamin is also available in injectable form, but that is only for people who cannot absorb it at all from food.
Working the evening or night shift, or working at home, can make DSPS less of an obstacle. Some people nap, even taking four hours of sleep a day and four at night. Long daytime naps are discouraged by almost everyone because they’re believed to promote nighttime sleeplessness, but you may decide that a regular nap to make up for lost sleep at night is an acceptable pattern for you. If you’re a student, ask for an arrangement to take exams at times when your concentration is good.
Some Methods Unlikely to Work
Avoid alcohol at bedtime. It disrupts sleep.
Don’t try to fall asleep if you’re not sleepy. You could spend hours tossing and turning, making yourself miserable. If after twenty minutes, you don’t feel any closer to falling asleep, get out of bed and do something else to occupy yourself until you start to feel sleepy.
Avoid excessive caffeine, especially within two hours of bedtime. Aside from melatonin, sleeping pills (e.g. barbiturates, benzodiazepines, antihistamines, and over-the-counter “sleep-aids”) usually will not make you sleepy if you take them before your body is ready to sleep. If they do induce sleep, the DSPS symptoms usually return the next night anyway.
Good Luck With It…
DSPS is a difficult sleep disorder to treat. Some people outgrow DSPS after a few months, years, or decades, as their circadian systems mature. Unless this happens to you, you will always have a tendency to drift to later sleeping times, and you will then have to reset your body clock one way or another if you want to sleep and wake up at “normal” hours. Treating DSPS can be a lifelong adventure.
The most important way to prevent drift is to maintain an outrageously regular sleeping schedule, going to bed and getting up at the same time seven days a week. That means having to deal with the alarm clock every day – but the alarm clock will become much less of an enemy if your biological rhythms have been properly entrained. The main problem is that things inevitably happen in life that temporarily disrupt your sleep schedule – e.g. taking care of small children, occasional anxiety, illness or pain, and accidentally sleeping in. You can try to minimize the disruptions, but they will happen.
If you have had DSPS for many years, starting to sleep at earlier times will also demand a major psychological adjustment for you. You may have adapted your lifestyle to your night owl tendencies, and giving up your time alone in the early morning hours can be a difficult sacrifice. Remember that although it is important for you to sleep regularly seven days a week, you don’t have to do that twelve months a year. It might be possible and worthwhile for you to sleep early when you need to, e.g. when you have to work, and then choose to stay up late during vacations. You just have to be willing to go through sleep-rescheduling again at the end of your vacation. However, it would be easier on you and your body if you sleep as regularly as possible. Resetting the sleep phase to earlier times is difficult for people with DSPS!
DSPS and Depression
In the DSPS cases reported in the literature, about half of the patients have been depressed or have had other psychological problems. The relationship between DSPS and depression is unclear – it is probably unjustified to conclude that depression alone causes DSPS, since many patients are not depressed, and since treatment methods such as chronotherapy can be effective without directly treating the depression. It conceivable that DSPS often has a major role in causing depression, because it can be such a stressful and misunderstood disorder. A direct neurochemical relationship between sleep mechanisms and depression is another possiblity.
If you think you could have a psychological problem, get treatment for it AND for your sleep disorder – not necessarily from the same therapist. There is some evidence that effectively treating DSPS can improve the patient¹s mood (no surprise there) and make antidepressants more effective. In addition, treatment for your depression can make you more able to stay with a DSPS therapy.
About the author
April 22, 1999.
And why am I interested in DSPS? Well, I have it. I’ve had DSPS at least since I was fifteen, and night-owl leanings since I was an infant. The first time I saw a doctor about it was in 1989, but my sleep disorder was correctly diagnosed in 1995, when I was 21 years old. Light therapy works fairly well for me (chronotherapy has worked for me too) although I still struggle sometimes to get up early. Without this kind of intervention my life would be chaos.
I am not a physician, psychologist, sleep lab technician, biologist, or medical professional of any kind. If it influences whether you believe what’s in the DSPS page, that’s fine. The most important points in the DSPS page are that DSPS is a disorder of circadian rhythms with the symptoms listed there, and that treatment for it is different than for other types of insomnia. These facts are easily verified – see, for example, the DSM-IV classification of mental disorders, the International Clasification of Sleep Disorders, most general books about sleep medicine written in the past 10 years, or any of the literature references listed). The purpose of this website is not to present anything new, but to bring attention to medical research well-accepted within sleep medicine and chronobiology, but often sadly ignored elsewhere.
I graduated from McGill University and l’Université de Montréal in 1996 with a BSc. in chemistry. I live in Vancouver, where I work as a technical writer for a software company.
About this article
This document was written and distributed to provide information for the general public about aspects of sleep and sleep disorders. It is not medical advice, and individuals with a suspected or diagnosed sleep disorder should consult with a physician for advice regarding their own treatment.
Copyright 1996-1998, Su-Laine Yeo. The documents in this website (originally published at http://www.geocities.com/HotSprings/1123/dsps.html) may be redistributed on the Internet, in their entirety without alteration provided that this copyright notice is not removed. No part of these documents may be sold for profit, nor incorporated in other documents without the author’s permission.
Thank you Jerry Halberstadt, Michael Thorpy, and Louis Cuccia for your help and encouragement.
The Delayed Sleep Phase Syndrome page is independent of commercial interests. No compensation has been accepted for production or distribution of the information in this site. There is, however, one more grateful acknowledgement: Original free space for this site was provided by GeoCities.