Tables & Graphs
This review should be cited as: Herxheimer A, Petrie KJ. Melatonin for the prevention
Oxford: Update Software.
A substantive amendment to this systematic review was last made on 22 August 2000.
Cochrane reviews are regularly checked and updated if necessary.
results from the body's internal rhythms being out of step with the day-night cycle at the
destination. Melatonin is a pineal hormone that plays a central part in regulating bodily
rhythms and has been used as a drug to re-align them with the outside world.
regimens for alleviating jet-lag after air travel across several time zones.
EMBASE, PsychLit and Science Citation Index electronically, and the journals
'Aviation, Space and Environmental Medicine' and 'Sleep' by hand. We searched citation
lists of relevant studies for other relevant trials. We asked principal authors of relevant
studies to tell us about unpublished trials. Reports of adverse events linked to melatonin
use outside randomised trials were searched for systematically in 'Side Effects of
Drugs' (SED) and SED Annuals, 'Reactions Weekly', MEDLINE, and the adverse drug
reactions databases of the WHO Uppsala Monitoring Centre (UMC) and the US Food &
Selection criteria: : Randomised trials in airline passengers, airline staff or military
personnel given oral melatonin, compared with placebo or other medication. Outcome
measures should consist of subjective rating of jet-lag or related components, such as
subjective wellbeing, daytime tiredness, onset and quality of sleep, psychological
functioning, duration of return to normal, or indicators of circadian rhythms.
Data collection and analysis: : Ten trials met the inclusion criteria. All compared
melatonin with placebo; one in addition compared it with a hypnotic, zolpidem. Nine of
the trials were of adequate quality to contribute to the assessment, one had a design fault
and could not be used in the assessment.
Reports of adverse events outside trials were found through MEDLINE, 'Reactions
Weekly', and in the WHO UMC database.
bedtime at the destination (10pm to midnight), decreased jet-lag from flights crossing
five or more time zones. Daily doses of melatonin between 0.5 and 5mg are similarly
effective, except that people fall asleep faster and sleep better after 5mg than 0.5mg.
Doses above 5mg appear to be no more effective. The relative ineffectiveness of 2mg
slow-release melatonin suggests that a short-lived higher peak concentration of
melatonin works better. Based on the review, the number needed to treat (NNT) is 2.
The benefit is likely to be greater the more time zones are crossed, and less for westward
The timing of the melatonin dose is important: if it is taken at the wrong time, early in
the day, it is liable to cause sleepiness and delay adaptation to local time.
The incidence of other side effects is low. Case reports suggest that people with
epilepsy, and patients taking warfarin may come to harm from melatonin.
Reviewers' conclusions: : Melatonin is remarkably effective in preventing or reducing
jet-lag, and occasional short-term use appears to be safe. It should be recommended to
adult travellers flying across five or more time zones, particularly in an easterly
direction, and especially if they have experienced jet-lag on previous journeys.
Travellers crossing 2-4 time zones can also use it if need be.
The pharmacology and toxicology of melatonin needs systematic study, and routine
pharmaceutical quality control of melatonin products must be established.
The effects of melatonin in people with epilepsy, and a possible interaction with
warfarin, need investigation.
Jet-lag is a common complaint of travellers who fly across a number of time zones (Winget 84). The
of jet-lag are primarily daytime fatigue and sleep disturbance, but also include loss of mental
efficiency , weakness
and irritability (Comperatore 90). Jet-lag is caused by desynchronisation between the body's
system and the new day-night cycle at the traveller's destination. The sleep loss caused by the travel
contributes to jet-lag. After a flight through six or more time zones most travellers will take 4-6 days
a normal sleeping pattern and not to feel tired during the day. The severity of jet-lag symptoms
largely depends on
the number of time zones crossed and the direction of travel. They are worse the greater the number
of zones crossed.
Westbound travel generally causes less disruption, as it is easier to lengthen than to shorten the
natural circadian cycle.
Melatonin is a hormone released by the pineal gland during darkness. Exposure to bright light cuts
off melatonin release;
the onset of dim light triggers resumption of release. It seems to play a key role in regulating the
body's circadian rhythms
and has been used therapeutically to re-entrain disturbed circadian rhythms. Exogenous melatonin
tends to produce a
phase advance when it is taken in the late afternoon (Lewy 92, 95), since its effect is additive with
that of endogenous