​Circadian rhythm change

The body clock and alterations in circadian rhythm are dependent on the effect of rhythmic cues, with the change between daylight and darkness being the most important.4 8 After flying across several time zones, it is thought that without countermeasures the body clock may take approximately 1 day for each hour of time zone change to adapt.1 The rate of adaptation varies between people and with the direction of the time zone change. Other cues that can affect the body clock include the use of melatonin, exercise and the timing of meals. Depending on when they are used, such cues can advance or delay the body clock, and the direction and degree of the change depends on the timing of the cue.8 Exposure to bright light at the wrong time of day may delay adaptation to a new time zone.3 9 However, the strength of the correlation between changes in circadian timing and jet lag symptoms has been questioned.7

​Management of jet lag

Non-­drug interventions to manage jet lag include: maximising the external environmental cues that push the circadian phase towards the rhythm of light and dark at the destination; keeping home-based sleep hours rather than adopting destination sleep hours for brief trips (2 days or less); and a combination of morning exposure to bright light and shifting the sleep schedule 1 hour earlier each day for 3 days before eastward travel.4 6 10 11 For travel across up to eight time zones, one author has suggested that travellers should have exposure to bright light in the late evening and avoid bright light in the early morning of the departure time zone for westward travel, or have exposure to bright light in the early morning and avoid bright light in the evening of the departure time zone for eastward travel before the flight and for the first 3 to 4 days.2 8

The evidence to support many of these interventions is inconclusive or conflicting.6 A systematic review (13 studies; 392 participants) assessed the effect of light exposure, physical activity, diet, chiropractic treatment, or a combination of light, sleep hygiene and noise reduction to counteract jet lag.12 Nine studies found no significant change in the outcomes, three reported mixed findings, and one non-randomised observational study suggested that there was a benefit of dietary changes (alternate days of feasting and fasting) 4 days before travel. Overall, the quality of the evidence was low or moderate and the studies small and subject to confounding factors.

Pharmacological interventions that have been tried for jet lag include drugs that alter circadian rhythms (eg, melatonin), hypnotics for short-term alleviation of sleep problems (eg, temazepam) and drugs that help to maintain alertness (eg, modafinil).1 2 4 Melatonin is probably the most widely studied pharmacological agent for jet lag.2

Evidence for efficacy

Most of the clinical trials on the use of melatonin for jet lag were published between 1986 and 2005.17 Out of ten study reports included in the MHRA’s assessment, only five described the composition and formulation of melatonin. Although data from the studies have been included in several systematic reviews, not all of the reviews included a meta-analysis and some did not provide a detailed breakdown of the outcome measures reported in the studies.3 7 17–22

Melatonin for jet lag

A Cochrane review, published in 2002, included 10 trials (984 participants) that compared melatonin with placebo. In all 10 trials, the time at which melatonin was taken after arrival at the destination remained the same each day. The primary outcome measure was a subjective rating of the severity of jet lag using a visual analogue scale (VAS) that ranged from 0 (insignificant) to 100 (very bad).18 23 For the primary outcome, the authors were only able to combine data from four studies (142 participants) for eastward travel and two studies (90 participants) for westward travel (Table 1).18 Compared with placebo, melatonin resulted in a mean difference in the rating of jet lag of −19.5 (95% CI −28.1 to −10.9) for eastward flights and −17.3 (95% CI −27.3 to −7.3) for westward flights. In eight trials, melatonin taken close to bedtime at the destination decreased jet lag from journeys crossing five or more time zones. The authors noted that there was no difference between melatonin doses of 0.5 mg and 5 mg daily, except that people fell asleep faster and slept better after taking 5 mg daily. The results for other outcome measures (eg, fatigue, daytime tiredness, onset of sleep at destination, onset and quality of sleep, psychological functioning) could not be combined because trials used different methods of measurement and reporting. Adverse effects of melatonin were not adequately assessed, and many symptoms were difficult to distinguish from manifestations of jet lag.18

A more recent meta-analysis, published in 2015, combined data for eastward and westward flights from the same four studies that were analysed in the Cochrane review (Table 1).19 Jet lag symptom scores (0–100) were 27 and 45 with melatonin and placebo, respectively (mean difference −17.7, 95% CI −23.9 to −11.5). The authors concluded that the use of oral melatonin probably reduces symptoms associated with jet lag.

In a review of the evidence of the treatment of circadian rhythm sleep disorders, the authors included 12 double-blind placebo-controlled trials of melatonin for jet lag that were published between 1986 and 2004.3 Although they summarised the results of the studies, they did not include a meta-analysis of the data. Melatonin doses ranged from 0.5–10 mg, typically taken at local bedtime, for up to 3 days before departure and up to 5 days on arrival. Most studies assessed melatonin for eastward flights. Of the eight studies that specifically examined symptoms of jet lag, six reported an improvement with melatonin. One study found that melatonin was more effective than placebo 3 days after travel, but not after 6 days. In another study, the participants may not have been at the new time zone long enough before flying home. Melatonin improved the duration and subjective and objective measures of sleep quality. In a dose comparison study, 5 mg immediate-release melatonin was found to be more effective at relieving symptoms of jet lag than a 2 mg slow-release formulation, though only marginally more effective than a 0.5 mg immediate-release formulation. Adverse effects were largely not evaluated in most of the studies, but in general, harmful effects were not found to be different between active treatment and placebo groups.3

​Melatonin for eastward flights

Data from two studies that were excluded from the Cochrane meta-analysis were added to the other four studies of eastward travel, to calculate a standardised effect size for overall jet lag symptoms.7 The result favoured melatonin over placebo (standardised effect size −0.48, 95% CI −0.8 to −0.1; p=0.008), but the effect size for melatonin was not statistically significant for four of the six studies.7 24 25 The paper’s authors questioned the usefulness of melatonin for reducing jet lag symptoms.7

Melatonin to improve sleep

Three systematic reviews have assessed the efficacy and safety of exogenous melatonin in improving sleep or managing sleep disorders accompanying sleep restriction, such as jet lag and shiftwork.20–22 One review (nine studies, 427 participants) assessed sleep onset latency as the primary outcome in people with sleep restriction.20 Only three of the studies involved people with jet lag (326 participants). Based on the data from all nine studies, the effect of melatonin on sleep onset latency was not statistically significant (weighted mean difference −1.0 min, 95% CI −2.3 to 0.3). The most commonly reported adverse events were headache, dizziness, nausea, and drowsiness but these did not differ significantly between melatonin and placebo. The review did not assess the effect of melatonin on measures of daytime fatigue. A second review included 139 studies but only six involved people with jet lag.21 The authors concluded that melatonin did not affect sleep onset latency or sleep efficiency in people with jet lag, and that its effectiveness may involve alleviation of daytime fatigue associated with jet lag. The third review that assessed melatonin’s effect on optimising sleep or improving sleep quality included 55 studies of which eight (972 participants) involved people with jet lag.22 The authors provided an overview of the outcomes from the eight studies of people with jet lag and concluded that the evidence provided a weak recommendation for using melatonin to rebalance the sleep–wake cycle in people with jet lag.

​Pregnancy and breast feeding

There are limited data on the use of melatonin in pregnant women and the company advises that it is not recommended during pregnancy or in women of childbearing potential not using contraception.14 15 Melatonin should not be used by women who are breast feeding.

Drug interactions

Melatonin is metabolised mainly by the hepatic cytochrome P450 CYP1A enzymes, primarily CYP1A2.14 15 As fluvoxamine increases melatonin levels it should not be used with melatonin. Other drugs that may increase systemic melatonin levels include 5- or 8-methoxypsoralen, cimetidine, estrogens, and CYP1A2 inhibitors (such as quinolones). CYP1A2 inducers (such as carbamazepine and rifampicin) may reduce plasma concentrations of melatonin. Melatonin may enhance the sedative effect of benzodiazepine and non-benzodiazepine hypnotics and may affect the anticoagulation activity of warfarin.