Melatonin and its relevance to jet lag

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Summary

Jet lag is a disorder in which body rhythms are out of phase with the environment because of rapid travel across time zones. Although it often produces minor symptoms it can cause serious problems in those who need to make rapid critical decisions including airline pilots and business travelers. In this article the authors review basic knowledge underlying the body clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, and the manner in which it regulates the sleep/wake cycle. The regulation of melatonin by the SCN is described together with the role of the melatonin receptors which are integral to its function as the major hormonal output of the body clock. Several factors are known that help prevent and treat jet lag, including ensuring adequate sleep, appropriate timing of exposure to bright light and treatment with melatonin. Because travel can cross a variable number of time zones and in two different directions, recommendations for treatment are given that correspond with these different types of travel. In addition to use of bright light and melatonin, other factors including timed exercise, timed and selective diets and social stimuli deserve study as potential treatments. Moreover, new melatonin agonists are currently under investigation for treatment of jet lag.

Introduction

Jet lag disorder is generated by rapid travel across multiple time zones, travel that is too rapid for adaptation of the circadian system. In those who travel rapidly across multiple time zones body rhythms are still at least partly in phase with the previous environment.1, 2, 3, 4 The speed of resynchronization depends on the number and direction of time zones crossed. In addition there is a major component of fatigue as preparations for travel and many components of travel itself are tiring.4 These two components interact to produce the majority of jet lag symptoms.5 Symptoms may also depend on individual differences in phase tolerance.

Jet lag falls under the category of Circadian Rhythm Sleep Disorder (CRSD) in the International Classification of Sleep Disorders (ICSD-2).6 The most common jet lag symptoms include sleep and rhythm desynchronization, anxiety and depressed mood, gastrointestinal and cardiovascular complaints, dizziness and menstrual irregularity in women. However, some individuals seem to have phase tolerance7, while others are quite sensitive. Another factor is morning type vs. evening type (“lark” vs. “owl”). Those who are prone to sleep in may be more likely to adjust more readily to westward flight.8

Melatonin is known as the hormone of darkness; in all mammals it is secreted during the hours of darkness and falls precipitately with light onset. Secretion of melatonin from the pineal gland is controlled by the circadian rhythm generating system, but melatonin also impacts on the circadian system to influence the regulation of rhythms.

Following the demonstration that administration of melatonin could synchronize body rhythms9 numerous studies in man showed that melatonin can synchronize the sleep/wake and other body cycles.10 Moreover, even blind individuals will respond to this effect of melatonin11 and sighted individuals with desynchronized rhythms can also be treated successfully.12 Body rhythms are out of synchrony with the environment in jet lag and several studies have reported the beneficial effect of melatonin in this disorder.

In this article we review current understanding of factors regulating the circadian system, the manner in which the circadian system regulates melatonin and the sleep/wake cycle, the ways in which melatonin interacts with the circadian system and the sleep/wake cycle, studies of melatonin use in jet lag and other circadian disorders and finally outline some strategies to combat jet lag using melatonin or melatonin -like agents in combination with other approaches.

Section snippets

Regulation of circadian rhythms

Circadian timing provides temporal organization of most biochemical, physiological and neurobehavioral events in a manner beneficial to the organism.13 Thus prior to waking, plasma cortisol, sympathetic tone and body temperature rise, anticipatory to increased activity and postural change.

Circadian rhythms are found in virtually all cells and tissues in the body.14, 15, 16 There is a hierarchy of pacemakers with the suprachiasmatic nucleus (SCN) as the master pacemaker. The SCN comprises a

Regulation of melatonin

In humans, as in other mammals, melatonin is synthesized in the pineal gland and enters the blood stream in a rhythmic manner with high levels during night time and low levels during daytime.40, 41, 42 Melatonin is also produced in other tissues43 but they make little or no contribution to melatonin in the circulation.44, 45 The melatonin and other circadian (circa 24 h) rhythms are usually entrained (phase-locked) to the light dark cycle, however in the absence of light they free run with a

Regulation of the sleep/wake cycle

Although the function of sleep is still not well understood we know that sleep deprivation leads to severe cognitive and physiological consequences.59 It can be defined as a natural state characterized by a reduction in voluntary motor activity, a decreased response to stimulation (i.e., increased arousal threshold), and stereotypic posture which is easily reversible.60

It has been proposed that the sleep/wake cycle can be explained by a two process model; one a homeostatic drive for sleep

Targets for melatonin

Binding sites for melatonin were initially identified in a wide variety of central and peripheral tissues using 125I-2-iodo-melatonin.72, 73 Molecular cloning of the first high affinity melatonin receptor (MT1) by Reppert and coworkers74 was accomplished using a cDNA library constructed from a dermal cell line of melanophores, the first tissue in which melatonin's action had been demonstrated. This initial finding led to the discovery that there is another Gi-protein coupled melatonin receptor

Entrainment by light

It has long been known that some blind subjects can not be entrained to a 24 h day.95, 96 Several studies have now established that the dominant environmental factor (Zeitgeber) entraining the human circadian system is light.97, 98 Exposure to bright light was shown to cause resetting of the body clock,98 with the magnitude and direction of the phase shift dependent on the timing of the light exposure.99, 100, 101 Even intermittent bright light was highly effective in resetting the human

Treatment of jet lag symptoms

Because jet lag consists both of sleep loss and desynchronization with the environment, a comprehensive strategy for the treatment of both aspects seem warranted.

Conclusions

Melatonin is an established agent that is useful in providing both a synchronizing action and a soporific effect in jet lag. Its utility has been especially well documented for eastward flight of 5–9 h as are the appropriate timing and dosage of administration. It may also be useful for shorter periods of eastbound travel for those prone to jet lag symptoms. Recommended strategies for eastbound travel that include melatonin treatment are shown in Table 3. For westward flight many fewer studies

Conflict of interest

S.R. Pandi-Perumal declares a non-competing interest. He is the President and Chief Executive Officer of Somnogen Inc, a New York Corporation. The authors have no financial or personal relationship with other people or organizations that could inappropriately influence their work.

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    Present address: President and CEO, Somnogen Inc, 8790 112th Street, New York, NY 11418-2317, USA.

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