Jet Lag is classified as a seconday circadian dysrhythmia.

Jet lag occurs with rapid travel across time zones, resulting in a misalignment between the timing of body's circadian rhythms with those of the external physical environment. Symptoms include general malaise, daytime sleepiness, difficulty sleeping, impaired performance, and gastrointestinal complaints. These symptoms usually last for several days until the traveler adapts to the new time zone.

Eastward travel (requiring advancing circadian rhythms and sleep-wake hours) is usually more difficult to adjust than westward travel. Eastward travel generally results in difficulty falling asleep and westward travel in difficulty maintaining sleep. Jet lag can also be made worse by poor air quality (in the plane and after the flight) and being forced to sit still for a long flight.

Jet Lag Factors

• Travelling East is worse
• Age (worse over 50)
• 25-30% of people minimally affected
• 25-30% of people highly susceptible
• Morning people more affected than night owls
  

Jet lag is a negative consequence of our circadian cycle which afflicts travelers who rapidly cross multiple time zones. The condition produces a number of unwanted effects including excessive sleepiness, poor sleep, loss of concentration, poor motor control, slowed reflexes, nausea, and irritability. Jet lag results from the inability of our circadian clock to make an immediate adjustment to the changes in light cues that an individual experiences when rapidly crossing time zones. After such travel, the body is in conflict. The biological clock carries the rhythm entrained by the original time zone, even though the clock is out of step with the cues in the new time zone. This conflict between external and internal clocks and signals is called desynchronization, and it affects more than just the sleep/wake cycle. All the rhythms are out of sync, and they take a number of days to re-entrain to the new time zone. Eastward travel generally causes more severe jet lag than westward travel, because traveling east requires that we shorten our day and adjust to time cues occurring earlier than our clock is used to.

British Airways' website has a page on recovering lost sleep due to jet lag. Its very simple advice just suggests an honest assessment of how many hours you need compared to how many you've slept recently. The flaw in this method is that people rarely truely know how much sleep they really need.

How hotels can help

A 2003 article in the Cornell Hotel and Restaurant Administration Quarterly recommends hotels serving international travelers take measures to help their guests recover from jet lag. These include measures to get the traveler’s circadian rhythm adjusted to local time and a good sleep during nighttime at the hotel. Measures include commonsense things like a comfortable mattress and temperature control, as well as the ability to produce total darkness in the room. The hotel should also provide opportunities to easily experience bright sunshine as this is an effective way to reset the circadian clock.

Jet-lag - a review

The Lancet, Nov 29, 1997 v350 n9091 p1611(6)

Jim Waterhouse; Thomas Reilly; Greg Atkinson.

Abstract: Melatonin and the regulation of light exposure may be effective in lessening jet lag. Traveling across time zones can disrupt the natural body clock and cause fatigue, sleep disturbances, and difficulty concentrating. Jet lag can reduce cognitive and athletic abilities. The body's clock in the hypothalamus relies on light, the hormone melatonin, and other time-givers to maintain a 24 hour sleep/wake rhythm. Supplemental melatonin can induce sleep in the evening in the new time zone, and appropriate light exposure during the day can help to reset the internal clock.

Full Text: COPYRIGHT 1997 The Lancet Ltd.

Rapid long-haul flights lead to jet-lag or circadian dyschronism,1-4 characterised by various symptoms including fatigue (and yet inability to sleep at the new night-time), headache, irritability, loss of concentration, and gastrointestinal disorders (indigestion, loss of appetite, and bowel irregularities).

No agreement exists as yet for standardisation of the symptoms of jet-lag. Comparison between studies can, therefore, be difficult. A more systematic approach to the problem has been adopted by Spitzer and colleagues,5 who obtained a high internal consistency with the items fatigue, difficulty in concentrating, clumsiness, decreased alertness in the daytime, difficulty with memory, general weakness, dizziness, lethargy, and daytime sleepiness.

Epidemiology

Individuals experience some or all of the symptoms of jet-lag to differing extents.1,2,6 Generally, symptoms are worse the older the traveller and the more time zones crossed; eastward travel is associated with worse symptoms than westward. The severity of the symptoms may also be related to phase of the menstrual cycle. Disturbances of this cycle itself are common in flight attendants.7

One of the main problems associated with jet-lag is sleep loss.8 After flights to the east the difficulty lies in getting to sleep at the new bedtime, whereas after flights to the west it tends to be premature awakening. Associated with the sleep difficulties is, at the least, a risk of performance decrement.9

The wide spectrum of negative effects implies that most individuals can be affected in a way that is specifically important at a personal level. Thus, holiday-makers might have their enjoyment spoiled; pilots and businessmen might be prone to errors; and athletes might be discouraged by poorer per- formances and lower motivation to train.

The association between errors or accidents and jet-lag has led to the sugges- tion that there is a causal link.9,10 Samel and colleagues' findings11 support this view. They studied pilots on long-haul flights to the east and west. Particularly with night flights to the east, pilot fatigue increased during the flight to values that could be associated with performance decrement. Moreover, electroencephalographic recordings indicated a mean occurrence of up to five "microevents" (defined as an 8 s period with a activity above a certain threshold, also known as a "microsleep") per hour during the "cruise" phase of the flight.

For people travelling to other time zones for sports competitions, there are two main problems caused by jet-lag.4 First, maximum performance might be poorer if the timing of contests does not coincide with the individual's circadian peak; second, serious training might be jeopardised owing to inappropriate times of training as well as increased fatigue and negative effects on mood and physical and mental performance. Wright and colleagues12 showed an increased time taken for both a sprint and a middle-distance run after an eastward flight crossing six time zones. British rugby players who travelled to Australia showed a disturbance in their circadian rhythm in grip strength, which normally peaks in the evening.4 Only by the fourth day were strength values in the evening higher than the morning scores. The normal cir- cadian rhythm was not restored until 2-3 days later. Similarly, leg strength showed a circadian rhythm disturbance in a group of athletes on the first full day after a westward transition across five time zones (figure 1).13 The time of peak strength shifted to its normal point of about 1700 h4 by 5 days after the flight.

Pathophysiology

The problems linked with jet travel are not due mainly to changes of culture, the time of the flight, the associated aggravation, or the length of the flight itself. The symptoms do not occur after long-distance flights to the south or north,2 and they can be duplicated in the laboratory, where the only change is to local time.4

The explanation for jet-lag is that it is due to transient dissociation between the environmental (local time in the new time zone) and internal (body time due to the internal body clock) times. The body clock is slow to adjust to a change in habits; this phenomenon also contributes to the malaise suf- fered by nightworkers. Figure 2 shows the temperature rhythm of a normal per- son before and immediately after flights through eight time zones to the east or west.

Body clock and its adjustment

Like other mammals, human beings have a body clock, a paired group of nuclei in the base of the hypothalamus--the suprachiasmatic nuclei (SCN).14 This body clock would have a period of longer than 24 h if it were not continually adjusted. This adjustment is achieved by Zeitgebers ("time-givers")--rhythms resulting, directly or indirectly, from the environment.15 In various mam- malian species, rhythms of the light/dark cycle, of food availability/unavailability, of activity/inactivity, and of social influences are all used, singly or in combination. In human beings, the rhythms are not yet fully known, but the light/dark cycle is undoubtedly important16 and all the other potential Zietgebers are normally present.

Light

The effect of light depends on the time at which it is presented. Thus, bright light pulses of 3 h centred immediately after the trough of the body tempera- ture rhythm produce a phase advance, pulses centred immediately before the temperature minimum produce a phase delay, and those centred away from it by more than a few hours have little effect.17 Experiments in which people were awoken but not exposed to bright light showed that the above shifts were not produced by changes to the sleep/activity schedule per se.18

Light pulses that are much dimmer (500 lux or less) also affect the clock, and can produce phase shifts of up to about 1 h per day.19 The importance of these findings is that even though most human beings are exposed mainly to domestic lighting, which is much weaker than natural daylight, such artificial light/dark cycles can still act as Zeitgebers.20

Melatonin

There is normally a robust circadian rhythm of melatonin secretion, starting at about 2100 h and ending at about 0800 h.21 There is evidence that melatonin can alter the phase of the body clock; thus, endogenous melatonin has been regarded as an internal Zeitgeber. Melatonin ingestion produces general effects on the body clock similar to those of light22 (phase advance, phase delay, no shift), but the timing of its effects is opposite to that of light. Thus, melatonin given in the afternoon tends to advance the body clock, whereas given in the early morning the hormone tends to delay the clock. Since bright light suppresses melatonin secretion, the effects of light and melatonin reinforce each other.22 Bright light in the early morning, just after the temperature minimum, advances the body clock directly, but it also has indirect effects through suppression of melatonin secretion, thus prevent- ing the phase-delaying effect that melatonin would exert at this time.

Other possible Zeitgebers

The feeding hypothesis3 proposes that a high-protein breakfast raises plasma tyrosine concentrations and that this effect promotes the synthesis and release of the neurotransmitters norepinephrine and dopamine, which activate the arousal system of the body. Similarly, a high-carbohydrate evening meal leads to a rise in plasma tryptophan concentration, which promotes the synthesis and release of serotonin; this neurotransmitter of the raphe nucleus has an important role in sleep regulation and is a precursor of melatonin. There is little evidence to support the feeding hypothesis. First, it was tested on a group of military personnel undergoing an eastward time-zone transition of 9 h but only small improvements in sleep and performance of mental tasks were observed.3 Second, experiments on rodents do not support the requirement that plasma concentrations of tyrosine or tryptophan are rate-limiting stages for the release of the neurotransmitters.

If hamsters are an appropriate model for human beings, physical activity should promote adjustment of the body clock,23 although whether this adjust- ment occurs through activity per se or via the arousal of the central nervous system (CNS) produced by activity is not resolved. Results with human beings have not yet proved convincing,23,24 though whether such a mechanism does not operate, the amount of activity needs to be greater, or individuals must be more "excited" by exercise remains to be established.

Inputs to the SCN

There is a direct pathway from the retina to the SCN, the retinohypothalamic tract,14 which seems to act via an excitatory aminoacid such as glutamate25 and induction of immediate early genes.26

There is another input pathway to the SCN via the intergeniculate leaflet, which is probably an important pathway for non-photic (activity) Zeitgeber input in hamsters.27 In human beings, this pathway might act as a means for enabling a general rhythmic flux of "excitement", whether derived from mental, physical, or social rhythms, to act as a Zeitgeber; however, this possibility has not been established.

Melatonin receptors have been found in the SCN.28 They are believed to be the means by which melatonin acts as an internal Zeitgeber.

Prevention and treatment

To be valuable, a method of prevention or treatment should be effective, cause no side-effects, and be convenient to the user; it should also be readily available. Several methods have been advocated:4,29,30 some aim to reduce the amount of jet-lag that might be experienced, others aim to alleviate the symptoms of jet-lag when they occur, and others are intended to promote adjustment of the body clock to the new time zone. Of these three approaches, the last is appropriate only if the traveller plans to stay for some days in the new time zone; for short stays (3 days or less), adjustment of the body clock is not possible and should be avoided.

Actions before, during, and immediately after the flight

If possible, flights should be arranged so that arrival is well in advance of an important event. As a guide, the symptoms of jet-lag have diminished substantially after about 5 days for travellers crossing nine or more time zones. Attempts should be made to find the most convenient travel schedules, and itineraries involving a stopover of a day or so are worthwhile. Jet-lag simulation studies have shown that division of the total time-zone transition into more than one part (for example, a 10 h shift into shifts of 7 h and 3 h) results in less severe jet-lag.31 Practically, however, the advantages of such a stopover should be weighed against the doubling of any stresses due to baggage transportation, passport controls, and seaching for accommodation.

To compensate for the dry air on board a plane, copious rehydration is advisable. Alcohol should not be taken, since it acts as a diuretic. Coffee also stimulates water loss and its arousal effect on the CNS means it should not be taken if sleep is desired. To alleviate stiffness or cramp caused by the restrained posture, static exercises for arms, trunks, and legs can be done while in the seat.4 Walking frequently down the aisle of the plane is particularly effective when the traveller wants to remain awake.

Taking naps and use of sleeping pills for more prolonged sleep are important issues. If adjustment of the body clock is not required, a nap or sleep during the night on the time zone just left is beneficial; if adjustment is required, sleep should be avoided unless it coincides with night at the destination or unless individuals have been deprived of sleep for a long time during transit.

In the days immediately after a flight across several time zones, when the body clock is not adjusted to the new local time, there will be an interval when the period of high arousal associated with the departure time zone over- laps with the arousal high point at the new local time. This interval should be used for important events in the first few days at the destination.

Promotion of sleep

Sleep hygiene (ie, ensuring that sufficient sleep is achieved) is most important. Naps have an important role; they not only top up the sleep total, but also can be used to improve alertness and performance during a single day.32 Thus, a nap can be taken immediately after a work spell (for recuperation) or in preparation for an important task. Naps can be taken when the individual feels most tired--probably during the trough of the circadian temperature rhythm at a time coincident with night on the departure time zone. However, a nap as long as 4 h at this time serves to anchor circadian rhythms to time in the departure time zone.33 Accordingly, such an approach is useful if the stay in the new time zone is short (3 days or less) and adjustment of circadian rhythms is not required. On the other hand, if adjustment of circadian rhythms is required, naps at this time should be avoided or, at least, kept short.

Immediately after waking from any sleep or nap there is a transient period of up to an hour when performance is depressed.32,34 This time of sleep inertia is an inappropriate one for important activities.

Benzodiazepines have been used to promote sleep in the new time zones.29,30,35 However, we found that temazepam had no effect on travellers' sleep or alleviation of jet-lag symptoms when given for 3 days after a westward flight across five time zones.13 Arrival in the late evening might make it easier to fall asleep after a westward flight, thereby diminishing any potential effect of the drug.

In practice, the difficulty is to make sure that travellers are fully awake and alert after waking up the next day. Most of the benzodiazepines are associated with residual effects on alertness and psychomotor performance.34 Temazepam may have lesser residual effects than diazepam, since its half-life is only 2-8 h compared with 24-48 h for diazepam. Zolpidem has a short half-life and affects short-term memory less than other drugs of this group, and may prove helpful. Stone and Turner concluded in their review35 that "advice on the use of hypnotics requires further clarification" but they ack- nowledged that the general usefulness of such drugs was beyond doubt.

Promotion of alertness

Promotion of alertness is another approach to the difficulties of jet-lag, but it has been investigated less than promotion of sleep.36 Amphetamines, caf- feine, modafinil (an a1-adrenoceptor agonist), and pemoline (which has dopamine-like properties) have been used to sustain alertness and performance at mental tasks during extended periods without sleep. Although they improve mental performance at several tasks, they also reduce the ability to initiate and sustain sleep. This effect might be counter-productive after time-zone transitions. There is evidence with amphetamines of abuse potential and that decision-making and psychomotor performance are compromised. With caffeine, heart arrhythmias and the development of drug dependence have been reported.37 By contrast, pemoline and modafinil have less deleterious effects on complex mental tasks and far less potential for abuse; modafinil has a much shorter half-life than pemoline. Further investigation is needed before any firm recommendation can be made about the use of drugs to promote alertness after time-zone transitions.

Adjustment of the body clock

If some means for adjustment of the body clock is to be used, its timing depends on that of the body clock, not local time. Thus, procedures normally effective in the evening or in the early morning might need to be applied at inconvenient times, and times just before or after the temperature minimum might be less inconvenient than first appears, since they no longer fall in the middle of sleep (figure 2).

Studies involving real38 or simulated38,39 time-zone transitions and com- puter-based modelling of the circadian response to such transitions40 have shown that westward flights, after which a delay of the body clock is required, are invariably followed by such a delay. For eastward time-zone transitions, after which an advance of the body clock is required, the responses are more complex; shifts of up to 9 h are normally accompanied by a phase advance, but eastward transitions longer than this (for example, UK to New Zealand) are generally associated with a delay of the body clock. Shifts of 12 h are almost invariably associated with adjustment by phase delay.39 The implication of these findings for travellers considering how to promote adjustment of the body clock to eastward time-zone transitions of more than 9 h is that such transitions should be considered as a westward shift of more than 12 h, which would require a delay of the body clock.

Chronobiotics

Redfern29 emphasised that a simple "jet-lag pill" is extremely unlikely, since the circadian system is so complicated with multiple input and output signals to and from the body clock. Many classes of drugs have the capacity to modify the circadian system (chronobiotics), including cholinergics, corticosteroids, antidepressants, and antimanics.41 However, many of these have been tested only on animals. We discuss only benzodiazepines and melatonin.

The sleep-inducing effects described above do not constitute evidence that benzodiazepines are chronobiotics, although their usefulness is not diminished. There are GABA type a receptors in the SCN, which may suggest a direct effect of benzodiazepines on the body clock. There is evidence from hamsters27 that benzodiazepines can shift the body clock and speed up adjust- ment to a new time zone, but benzodiazepines increase locomotor activity in hamsters, and the doses used were far higher than normal doses in human beings.41 Thus, whether benzodiazepines act as chronobiotics in human beings remains unclear.

Melatonin reduces subjective symptoms of jet-lag after real or simulated flights in easterly and westerly directions42,43 and improves sleep in the laboratory environment.44 It is, at the least, therefore, a valuable pallia- tive. However, an important question is whether melatonin promotes adjustment of the body clock.

Melatonin can advance or delay the body clock according to its time of ingestion.22 However, melatonin also has a temperature-lowering effect,45,46 pos- sibly through its actions on the peripheral vasculature, and the hypnotic action may be a consequence of this effect. Therefore, melatonin may act as a chronobiotic separately from its hypnotic action and temperature-lowering properties.

Despite uncertainty over the mechanisms of melatonin action, oral administration of the hormone is believed to be the best pharmacological cure for jet-lag available, although the possibility of unknown side-effects requires further study. However, there are some caveats. The temperature-lowering effect of melatonin seems to occur whenever it is administered. The hormone should therefore be taken in the early evening (at about 2000 h) on the new local time, irrespective of the direction of travel and number of time zones crossed. However, if melatonin is to act as a chronobiotic, its time to ingestion--whether to advance or delay the body clock--depends on the journey undertaken.22,47 The main conclusions are that promotion of phase delays after a westward shift requires ingestion during the new local night; that after eastward transitions of 4-8 h local time, the phase-advancing and hypnotic effects require ingestion at similar times; and that ingestion of melatonin at 2000 h local time with eastward transitions in excess of about 9 h leads to phase delays rather than phase advances.

Such results indicate that melatonin's effectiveness could be due to its phase-shifting (chronobiotic effects), sleep-inducing effects, or a combina- tion; this ambiguity awaits resolution.

If melatonin does have a hypnotic action, like the benzodiazepines, it may induce undesirable residual effects, especially if taken during the day. Effects in vigilance and other mental performance test with doses as low as 5 mg have been reported.48 However, Zhdanova et al49 allowed sleep after melatonin ingestion, and found no residual effects on mood and psychomotor performance after waking. Thus, the effect of melatonin on performance may depend on whether or not sleep is allowed to intervene, as well as on the type of task being assessed.

Melatonin has no licence in Europe or Australia at present. It is available from health-food retailers in the USA, but is not sanctioned for professional prescription. As a result, it is not prescribed by clinicians, with set dosing regimens and regular monitoring of any adverse effects. Furthermore, no studies on the effects of long-term administration of this hormone have been done.

Non-pharmacological phase shifting

There are tables (14) and computer programs (50) that advise on when to attempt exposure to, or avoidance of, bright light. They are based on the observations that bright light in the morning (0500-1100 h) on body time advances the clock, and bright light in the evening (2200-0400 h) on body time delays it. As a supplement to this treatment, there are also times when light should be avoided (those times that produce a shift of the body clock in the direction opposite to that desired). However, the times of light-seeking and light-avoidance may not coincide with the natural alternation between daytime and night. Avoidance of bright light, by staying indoors or wearing dark glasses, is comparatively easy; seeking of bright light is more difficult. Light boxes, which mimic sunlight in spectral emission and brightness, are generally cumbersome. Portable light sources with their own power are becoming available. Full scientific reports of their acceptability to users and their effectiveness in promoting appropriate phase shifts are awaited. The finding that light of an intensity found domestically can influence the phasing of the body clock19,20 might obviate the need for these devices.

If exposure to natural light is important, and if some combination of "excitement" (produced by physical, social, and mental activity) also acts as a Zeitgeber, perhaps adjustment of the timing of lifestyle to that of the new time zone would be sufficient. After westward transitions of up to eight time zones, this regimen will be useful, since local evening light will tend to cause a phase delay of the body clock, and local morning light (0800-1200 h) is too late to cause a phase advance. After eastward transi- tions, however, such a regimen of adjusting immediately to local natural light can be faulty if it promotes phase delays rather than advances.

After the first day in the new time zone, times of treatment need modification as the body clock begins to adjust. For melatonin, when a phase advance is required, melatonin should be taken 1 h earlier each day until

1500 h is reached; treatment can then be stopped. The difficulties with westward transitions and melatonin treatment have already been mentioned; in principle, however, ingestion should be 1 h later each day until 0600 is reached. For light after a westward shift, there is no need to deviate from the timing of natural light (see above); after an eastward shift, times of avoiding and seeking bright light can be made earlier by about 15 h per day until they coincide with natural lighting.

References

1 Arendt J, Marks V. Physiological changes underlying jet lag. BMJ 1982; 284: 144-46.

2 Wegmann H, Klein K. Jet-lag and aircrew scheduling. In: Folkard S, Monk T, eds. Hours of work. Chichester: John Wiley, 1985: 263-76.

3 Graeber RC. Jet lag and sleep disruption. In: Krugger MH, Roth T, Dement C, eds. Principles and practice of sleep medicine. Philadelphia: WB Saunders, 1989: 324-31.

4 Reilly T, Atkinson G, Waterhouse J. Biological rhythms and exercise. Oxford: Oxford University Press, 1997.

5 Spitzer RL, Terman M, Terman J, Williams JBW. Columbia jet lag scale. Biometrics Res NY State Psychiatric Institute, 1997.

6 Moline ML, Pollack CP, Monk TH, et al. Age-related differences in recovery from simulated jet lag. Sleep 1992; 15: 28-40.

7 Suvanto S, Hrma M, Ilmarinen J, Partinen M. Effects of 10 h time zone changes on female flight attendants' circadian rhythms of body temperature, alertness and visual search. Ergonomics 1993; 36: 613-25.

8 Gander PH, Nguyen D, Rosekind MR, Connell LJ. Age circadian rhythms, and sleep loss in flight crews. Aviat Space Environ Med 1993; 64: 189-95.

9 Dinges D. An overview of sleepiness and accidents. J Sleep Res 1995; 4 (suppl 2): 4-14.

10 Akerstedt T. Work hours, sleepiness and accidents. J Sleep Res 1995; 4 (suppl 2): 1-3.

11 Samel A, Wegmann HM, Vejvoda M. Jet lag and sleepiness in aircrew. J Sleep Res 1995; 4 (suppl 2): 30-36.

12 Wright JE, Vogel JA, Sampson JB, Knapik JJ, Patton JF, Daniels WL. Effects of travel across time zones (jet lag) on exercise capacity and performance. Aviat Spac Environ Med 1983; 54: 132-37.

13 Reilly T, Atkinson G, Budgett R. Effects of temazepam on physiological and performance variables following a westerly flight across five time zones. J Sports Sci 1997; 15: 62.

14 Moore R. Organisation of the mammalian circadian system. In: Chadwick D, Ackrill K, eds. Circadian clocks and their adjustment. Ciba Foundation Symposium 183. Chichester: Wiley, 1995: 88-106.

15 Aschoff J. Circadian clocks. Amsterdam: North Holland Press, 1965.

16 Czeisler C. The effect of light on the human circadian pacemaker. In: Chad- wick D, Ackrill K, eds. Circadian clocks and their adjustment. Ciba Foundation Symposium 183. Chichester: Wiley, 1995: 254-302.

17 Minors D, Waterhouse J, Wirz-Justice A. A human phase-response curve to light. Neurosci Lett 1991; 133: 36-40.

18 Drennan M, Kripke DF, Gillin JC. Bright light can delay human temperature rhythm independent of sleep. Am J Physiol 1989; 257: R136-41.

19 Boivin D, Duffy J, Kronauer R, Czeisler C. Dose-response relationship for resetting of human circadian clock by light. Nature 1996; 379: 540-42.

20 Minors DS, Waterhouse JM. Deriving a 'phase response curve' from adjustment to simulated time zone transitions. J Biol Rhythms 1995; 9: 257-83.

21 Arendt J. The pineal. In: Touitou Y, Haus E, eds. Biological rhythms in clinical and laboratory medicine. Berlin: Springer-Verlag, 1992: 348-62.

22 Lewy AJ, Ahmed S, Jackson JML, Sack RL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 1992; 9: 380-92.

23 Reebs S, Mrosovsky N. Effects of induced wheel-running on the circadian activity rhythm of Syrian hamsters: entrainment and phase-response curve. J Biol Rhythms 1994; 4: 39-48.

24 Redlin U, Mrosovsky N. Exercise and human circadian rhythms: what we know and what we need to know. Chronobiol Int 1997; 14: 221-29.

25 Ebling F. The role of glutamate in the photic regulation of the suprachias- matic nucleus. Prog Neurobiol 1996; 50: 109-32.

26 Hastings M, Ebling F, Grosse J, et al. Immediate-early genes and the neural bases of photic and non-photic entrainment. In: Chadwick J, Ackrill K, eds. Circadian clocks and their adjustment. Ciba Foundation Symposium 183. Chichester: Wiley, 1995: 175-97.

27 Turek F, Losee-Olson S. Dose response curves for the phase-shifting-effect of Triazolam on the mammalian circadian clock. Life Sci 1987; 40: 1033-38.

28 Reppert S, Weaver D, Rivkees S, Stopa E. Putative melatonin receptors in a human biological clock. Science 1988; 242: 78-81.

29 Redfern PH. 'Jet-lag': strategies for prevention and cure. Human Psychopharmacol 1989; 4: 159-68.

30 Atkinson G, Reilly T, Waterhouse J, Winterburn S. Pharmacology and the travelling athlete. In: Reilly T, Orme M, eds. The clinical pharmacology of sports and exercise. Amsterdam: Elsevier, 1997: 293-301.

31 Tsai TH, Okumura M, Yamasaki M, Sasaki T. Simulation of jet lag following a trip with stopovers by intermittent schedule shifts.

J Interdiscipl Cycle Res 1988; 19: 89-96.

32 Dinges D. Adult napping and its effect on ability to function. In: Stampi C, ed. Why we nap. Boston: Birkhauser, 1992: 118-34.

33 Minors D, Waterhouse J. Anchor sleep as a synchronizer of rhythms on abnormal routines. Int J Chronobiol 1982; 7: 165-88.

34 Naitoh P, Kelly T, Babkoff H. Sleep inertia: best time not to wake up? Chronobiol Int 1993; 10: 109-18.

35 Stone B, Turner C. Promoting sleep in shiftworkers and intercontinental travellers. Chronobiol Int 1997; 14: 133-43.

36 Akerstedt T, Ficca G. Alertness-enhancing drugs as a countermeasure to fatigue in irregular work hours. Chronobiol Int 1997; 14: 145-48.

37 Robertson D, Curatolo P. The cardiovascular effects of caffeine. In: Dew P, ed. Caffeine. New York: Springer-Verlag, 1984: 77-85.

38 Gundel A, Wegmann HM. Transition between advance and delay responses to eastbound transmeridian flights. Chronobiol Int 1989; 6: 147-56.

39 Mills J, Minors D, Waterhouse J. Adaptation to abrupt time shifts of the oscillator(s) controlling human circadian rhythms. J Physiol 1978; 285: 455-70.

40 Gundel A, Spencer MB. A mathematical model of the human circadian system and its application to jet lag. Chronbiol Int 1992; 9: 148-59.

41 Dawson D, Armstrong SM. Chronobiotics--drugs that shift rhythms. Pharmacol Ther 1996; 69: 15-36.

42 Samel A, Wegmann HM, Vejada M, Maas H, Gundel A, Schutz M. Influence of melatonin treatment on human circadian rhythmicity before and after a simu- lated 9-hr time shift. J Biol Rhythms 1991; 6: 235-48.

43 Arendt J, Deacon S. Treatment of circadian rhythm disorders--melatonin. Chronobiol Int 1997; 14: 185-204.

44 Wurtman RJ, Zhdanova I. Improvement of sleep quality by melatonin. Lancet 1995; 346: 1491.

45 Cagnacci A, Elliott JA, Yen SSC. Melatonin: a major regulation of the cir- cadian rhythm of core temperature in humans. J Clin Endocrinol Metab 1992; 75: 447-52.

46 Cagnacci A. Influences of melatonin on human circadian rhythms. Chronobiol Int 1997; 14: 205-20.

47 Lewy A, Sack R, Blood M, Bauer V, Cutler N, Thomas K. Melatonin marks cir- cadian phase position and resets the endogenous circadian pacemaker in humans. In: Chadwick D, Ackrill K, eds. Circadian clocks and their adjustment. Ciba Foundation Symposium 183. Chichester: Wiley, 1995: 303-21.

48 Reid K, Vandenheuvel C, Dawson D. Daytime melatonin administration--effects on core temperature and sleep onset latency.

J Sleep Res 1996; 5: 150-54.

49 Zhdanova I, Wurtman R, Lynch H, et al. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 1995; 57: 552-58.

50 Houpt TA, Boulos Z, Moor-Ede MC. Midnight sun--software for determining light exposure and phase-shifting schedules during global travel. Physiol Behav 1996; 59: 561-68.

Sleep Disorders

Dyssomnias

Parsomnias

"It’s been a hard day’s night
I’ve been workin´ like a dog
It’s been a hard day’s night
And I’ll be sleepin´ like a log…. "

(John Lennon and Paul McCartney)