Key messages

• Melatonin probably reduces symptoms related to jet lag syndrome in travelers crossing more than five time zones.
• It is not clear whether the use of melatonin is associated with adverse effects (nausea, tiredness, drowsiness and headaches), because the certainty of the evidence is very low. If these adverse effects were to exist, they would be probably mild in nature.
• The risk-benefit and cost-benefit ratio would probably favour its use in the prevention and treatment of jet lag syndrome.

What is the evidence.
See evidence matrix  in Epistemonikos later

We found four systematic reviews [1],[2],[3],[4] that included 11 randomized controlled trials reported in 16 references [5],[6],[7],[8],[9],[10],[11],[12],[13],[14], [15],[16],[17],[18],[19],[20].

What types of patients were included

All studies involved healthy adults.

One study [8] included members of the United States Air Force and a second one [13] involved airline staff. All other studies included different passengers who volunteered to participate.

Ten studies assessed the use of melatonin in eastward flights [5],[6],[8],[9],[10],[11],[12],[16],[19],[20], while four did so for westward flights [5],[11],[12],[13]. 

What types of interventions were included

All studies used melatonin. Ten studies used 5 mg [5],[6],[8],[10],[11],[12],[13],[16],[19],[20]. One administered 10 mg [9]. Three studies assessed slow-release melatonin; one study 300 mg [8], one study used 0.5 mg followed by 2 mg [20] and one study 0.5 mg [16].

Similarly, while two studies administered melatonin before the flight [6],[12], six did so upon arrival [9],[10],[11],[16] ,[19],[20] and three did so both before and after flying [5],[8],[13].

All studies administered melatonin before the desired time of sleep onset at the final destination.

In one study both groups received zolpidem in addition to melatonin [19].

All studies compared melatonin against placebo.

What types of outcomes
were measured

The systematic reviews included the following outcomes:

• General jet lag symptoms for eastward and westward flights.
• Number of participants with more than 60% of jet lag symptoms in eastward flights.

Additionally, some reviews reported two other outcomes related to exogenous circadian rhythm sleep disorders in general and not only jet lag [2]:

• Sleep latency
• Sleep quality

Only one review conducted a meta-analysis of the following adverse effects [2]: headaches, drowsiness, tiredness, and nausea. These adverse effects were also compared to the use of melatonin studies in non-jet lag cases. All other reviews reported adverse effects without providing a pooled effect measure. 

To whom this evidence does and does not apply

• This evidence applies to healthy adults who travel across more than five time zones.

• The outcomes included in this summary are those considered by the authors to be critical in the decision-making process regarding the use of melatonin in the prevention and treatment of jet lag.

• The studies did not report serious adverse effects, or any consistently different effects to those patients using placebo. Considering the fact melatonin is probably a safe intervention the benefits of its use probably outweigh the risks.
• This does not apply to more serious adverse effects observed with the association of melatonin to hypnotics, other central nervous system stimulants, in the presence of other comorbidities, or when using any medication with a possible interaction with melatonin (e.g. anticonvulsants or warfarin).

• Most patients would be probably inclined in favour of the use of melatonin. In patients with a higher risk of adverse effects it may be necessary to individually assess the treatment decision.
• Some patients will consider jet lag symptoms too mild to treat. It is especially important to discuss the benefits and risks of the intervention in these cases. 

• This is a low-cost, time-limited intervention; in this way, it may be favourable regarding costs and benefits.
• In addition, if melatonin contributes to reducing the symptoms caused by jet lag, it is possible that it may also reduce the use of other symptom-relief medication, thus reducing the total costs. 

Differences between this summary and other sources

• The conclusions presented in this summary agree with most of the identified systematic reviews.
• Only one of the systematic reviews [4] argues the use of melatonin in secondary sleep disorders (including jet lag) is not effective. This review assessed the latency and quality of sleep, REM sleep time and wakefukness after sleep onset; however, it does not evaluate global jet lag symptoms, and groups jet lag syndrome as part of the secondary sleep disorder spectrum. Additionally, it does not include all of the studies included in this summary.
• The conclusions in this summary are consistent with the recommendations of the American Academy of Sleep Disorder [21], which state the administration of melatonin at the right time is indicated in the prevention and treatment of jet lag symptoms in travellers crossing multiple time zones. It also mentions that no serious adverse effects have been reported yet. 

• The probability of future evidence changing the conclusions of this summary is low due to the certainty of the evidence.
• There are three ongoing or unpublished studies [22],[23],[24], which evaluate the use of melatonin in jet lag specifically [23],[24], or in transitory sleep disorders that include jet lag syndrome [22]. All of these studies could provide valuable information.
• It seems relevant to compare the use of melatonin with hypnotics or other interventions other than placebo.