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By Dónal P. O’Mathúna, PhD
Globalization and multinational business have made it more common for people to fly across several time zones. Those flying on vacation or to visit family expect it will take a few days to get over the jet lag. However, those on business, diplomatic, sports, or military trips often are expected to perform as normal almost as soon as they get off the plane. Many strategies are proposed to avoid the symptoms of jet lag, including dietary and exercise adjustments and carefully regulating one’s exposure to bright light.1 However, much interest recently has been given to the use of melatonin, a hormone involved in the natural sleep-wake cycle. This review examines whether studies support the use of melatonin in combating jet lag. These results may also have wider implications for those regularly switching between shifts at work.
Jet lag has been regarded as a nuisance that had to be accepted as part of long-haul air travel. However, the symptoms mitigate against the purpose of sending people long distances for business. These include fatigue, irritability, loss of concentration, and reduced productivity during daytime, as well as difficulties getting to sleep and staying asleep.2 Jet lag can be distinguished from travel fatigue because of the differing effects of flying east-west as opposed to north-south. The severity of the symptoms depends on the number of time zones crossed, and the direction of travel (eastward travel is usually more difficult than westward).3 It typically takes 4-6 days to re-establish normal sleep patterns after flying through six or more time zones.
The body operates on circadian rhythms that influence hormone levels, core body temperature, and the autonomic nervous system.1 These rhythms are under the influence of exogenous factors (lifestyle and environment) and endogenous factors (body clocks). The body clock is adjusted daily to keep in phase with solar time via a process called entrainment.1 Factors affecting entrainment are the daily cycles of light-dark, physical activity-inactivity, and feeding-fasting. The symptoms of jet lag arise when exogenous and endogenous factors are not entrained.
Things that speed up re-synchronization will alleviate or prevent jet lag. Some studies have found that light, activity, and food can impact jet lag;1 however, the effects are relatively small and hence the focus of research has been directed toward pharmacological influences, and melatonin in particular.
Mechanism of Action
Melatonin is synthesized in the pineal gland under the control of a circadian clock. This clock is located in the base of the hypothalamus in an area called the suprachiasmatic nucleus.4 The clock is impacted by light, with darkness stimulating the production of melatonin and light inhibiting its production. How melatonin exerts its effects is unclear.
Normally, body temperature reaches a minimum between 4 a.m. and 5 a.m., when melatonin levels are highest. Exogenous melatonin given 8-13 hours before this time will advance the phase of the rhythm in the desired direction during eastward travel.5 If the melatonin is taken between 11 p.m. and 4 a.m., the phase can be moved in the opposite direction. Bright light has the opposite effect.1 However, these trends are complicated by the finding that after eastward flights some people adjust by phase advance and others by phase delay.6
A Cochrane review examined all randomized controlled trials (RCT) of melatonin for jet lag that were published up until 2000.3 A total of 10 trials met the inclusion criteria for the review. The primary outcomes in all trials were subjective ratings of jet lag measured using various instruments. Two trials also measured endogenous cortisol and melatonin serum levels, and another measured core body temperature. The studies varied extensively in design. The melatonin daily dose ranged from 0.5 mg to 8 mg. Melatonin usually was taken at bedtime in the destination time zone on the day of the flight and for 2-7 days afterwards. Eight of the 10 trials found melatonin significantly better than placebo at reducing jet lag symptoms after journeys crossing five or more time zones. The optimal dose appeared to be 5 mg daily, with higher doses being no more effective and lower doses failing to improve sleep quality.
For the five trials that reported global jet lag scores, the mean score after placebo was 48 and after melatonin it was 25.2 The scores for eastward flights were 51 with placebo and 31 with melatonin, while for westward flights the scores were 41 with placebo and 22 with melatonin. Thus, the effect size was similar flying in either direction, although the jet lag symptoms themselves were less severe going westward.
A search of Medline revealed two additional studies published after the review was completed. One trial studied the rate at which the melatonin levels in eight men became entrained after flying eastward through 11 time zones.7 Baseline readings were obtained when the men flew without taking any substances. At a later occasion, the men flew again and took 3 mg melatonin daily and were exposed to bright light at the time in their destination that corresponded to midnight in their place of origin. Plasma melatonin levels were re-entrained 15 minutes per day faster when the subjects took melatonin.
The most recent study was a double-blind RCT involving three groups with nine subjects in each.8 The subjects were given either 300 mg sustained-release caffeine, 5 mg melatonin, or placebo. The subjects spent six days in a controlled environment and then flew eastward through seven time zones. Nighttime sleep was measured using polysomnography and daytime drowsiness by subjective reports and wrist actigraphy (which records wrist activity as a measure of overall sleep and wake patterns). The results found that those taking melatonin slept longer and better than those taking placebo or caffeine (P < 0.05). During the daytime, there were no significant differences between the groups for the first two days, but after that those taking caffeine were less drowsy than either those taking melatonin or placebo. Oral temperatures were taken as an objective measure of re-entrainment. Temperature and plasma melatonin levels were re-synchronized two days after arrival in those taking melatonin, but only started to re-synchronize on day 3 in those taking caffeine or placebo.
The Cochrane reviewers also searched for reports of adverse effects among those taking melatonin.3 About 10% of the research subjects experienced hypnotic effects that were relatively mild and subsided quickly. Other adverse effects included headaches, disorientation, nausea, and gastrointestinal problems. The reviewers found 25 other adverse event reports, leading them to conclude that melatonin should not be taken by people with epilepsy.3
Six cases have been reported of bleeding problems in people taking warfarin who then took melatonin, resulting in the precaution that melatonin should not be taken by people also using anticoagulants.3 The antidepressant fluvoxamine increases endogenous melatonin levels by inhibiting its elimination.4 Endogenous melatonin release can be suppressed by relatively common drugs such as aspirin, ibuprofen, and beta blockers.9
Melatonin is available in the United States as a dietary supplement and has been formulated in many different ways. A study of nine U.S. melatonin products found ample evidence of poor quality.10 Immediate-release tablets should disintegrate within 30 minutes. In this study, two products failed to disintegrate within four hours and two more failed to disintegrate within 20 hours. One of the controlled-release products had released 90% of its melatonin within four hours.
Melatonin has demonstrated itself to be effective in relieving jet lag symptoms in several RCTs. Although most studies have been relatively small, and were conducted with a variety of designs, the results are clearly in favor of melatonin’s effectiveness. Few adverse effects were reported, and those noted were short-lived and reversible. All of the studies were conducted over relatively short periods of time. No information is available on the effects of repeated use of melatonin or of its long-term effects.
For extended flights, 5 mg melatonin daily can be recommended to alleviate symptoms of jet lag (see Table). Best results have been reported with westward flying when melatonin is taken in the evening of departure to start phase delay and then at bedtime at the destination for a few days. Eastward flying is less predictable with the usual recommendation being to initiate melatonin at local bedtime after arriving at the destination. There is no evidence that starting melatonin in the days before departure brings additional benefit. Those experiencing excessive drowsiness should reduce the dosage and be cautious driving or operating machinery. Practitioners should work with patients to identify supplements of proven quality. The data reviewed here are specific for jet lag and cannot be directly applied to the use of melatonin for treating insomnia or for those engaged in variable shift work. Research on the use of melatonin for insomnia will be reviewed in a later issue.
|Table: Recommendations for re-synchronizing sleep patterns after travel|
After Westward Flight
|| After Eastward Flight
Dr. O’Mathúna is a lecturer at the School of Nursing, Dublin City University, Ireland.
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