There may also be a difference between arrival home and arrival away. The literature on the
psychology of physical symptoms would lead one to expect more reported jet-lag symptoms after
arrival home than arrival away, because people tend to notice symptoms less when their attention is
drawn outwards in a new and more exciting environment (Pennebaker 82). Future studies (but not
intervention studies) should examine whether this is true for jet-lag.
The melatonin literature has a number of gaps in terms of the type of people who may benefit from
melatonin on jet lag in children. Children typically have the highest circulating melatonin levels of
any age group, and this seems likely to be important in their normal development. It has been
suggested that an excess of melatonin may be related to delay in the development of reproductive
function (Zhdanova 00), but it seems very unlikely that short-term use of a low dose would affect
this. Rather melatonin use should be avoided in children because of a general lack of data on either
benefits or safety in this population.
It should be noted that individuals differ greatly in the experience of jet-lag, with some travellers
extremely affected while others who may have flown the same route may report no jet-lag
symptoms. This suggests that individual differences may strongly influence the effectiveness of
melatonin. This also remains an unexplored area of research.
The sleep disturbance and circadian dysrhythmia that characterise jet-lag have the potential to be
treated with melatonin in combination with other hypnotic medicines. To date only one trial (98
Suhner b) has tested this, using the non-benzodiazepine hypnotic zolpidem. The study found that
melatonin plus zolpidem, while reducing sleep disturbance after a transmeridian flight, also produced
a significantly higher rate of side effects than in groups taking zolpidem or melatonin alone. No trial
combining melatonin with a benzodiazepine hypnotic has yet been published.
Possible adverse effects of melatonin have not been adequately assessed, and many symptoms are
difficult to distinguish from symptoms or manifestations of jet-lag itself.
Melatonin differs from most or all other drugs in that the timing of the dose is critical and determines
the effect: given at the wrong time it will delay circadian adaptation to local time (Lewy 92, 95).
Adverse effects that may occur during treatment for a few days appear to be transient, as would be
expected from its pharmacokinetics. The most common risk factor seems likely to be taking
melatonin at the wrong time of the day at too high a dose - which in addition to causing a phase shift
in the wrong direction would cause excessive daytime sleepiness, particularly if combined with
another soporific drug. However, the published and unpublished case reports we have examined
suggest that some serious adverse effects may occur, albeit rarely.
The pharmacology and toxicology of melatonin and pharmaceutical aspects of its formulation have
not been systematically studied, very likely because the drug cannot be patented and the cost of the
work cannot readily be recouped from sales of the drug. Such data are needed in the public interest,
to enable melatonin of assured good quality to be provided.
Implications for practice
Melatonin is remarkably effective in preventing or reducing jet-lag, and occasional short-term use by
adults appears to be safe. Doses between 0.5mg and 5mg appear to be similarly effective, apart from
the greater hypnotic effect of higher doses. For many people 5mg may be a higher dose than
necessary: 2 or 3mg may therefore be preferable to start with. It is effective when taken at bedtime
melatonin before the day of travel does not hasten or improve adaptation to local time at the
destination and is not recommended.
Melatonin should be recommended to adult travellers crossing five or more time zones, especially if
they have experienced jet-lag on previous journeys. People making such a journey for the first time
may reasonably take it if jet-lag might seriously interfere with their activity at the destination -
whether this is work or leisure. Travellers crossing 2-4 time zones can also use it if need be. The use
of melatonin on the day of travel and for up to four days after arrival could greatly increase the
effectiveness and efficiency of short-term business or diplomatic travel, and military deployment.
The major barrier to the use of melatonin is that in most countries it is not licensed and cannot be
easily obtained. It is in the public interest that the necessary safety testing is done as soon as
possible, and quality controls are established, so that it can be legally marketed.
Reports of adverse events possibly related to use of melatonin suggest that two categories of people
should not use the drug without an informed discussion with someone who has read this review:
those with epilepsy, and anyone taking warfarin or another oral anticoagulant. In the absence of data
of the value and the safety of melatonin in children, its use in them should be avoided.
The toxicological work and the methods of pharmaceutical quality control required for licensing and
regulatory control of melatonin are urgently needed.
Data on safety in practice, including possible interactions with other drugs in common use (including
alcohol and caffeine) should be collected systematically. Interactions between melatonin and vitamin
K antagonists such as warfarin may threaten life and need experimental study now.
Studies are needed to find out whether melatonin is useful and safe in children and in old people, and
if so how it would best be used.
Future trials should report the results not only as group means, but also in terms of the proportion of
people helped and not helped.
Further suggestions are made above in the discussion.
We thank Andrea Suhner, Iain Chalmers and Paul Montgomery for valuable comments, Jeffrey
Aronson for advice on searching for published ADR reports, and the staff of the WHO Uppsala
Monitoring Centre for providing unpublished reports from their database.
None [AH]; Keith Petrie has undertaken two of the trials reviewed.
* *Arendt J, Aldhous M, English J, Marks V, Arendt JH, Marks M, Folkard S. Some
effects of jet-lag and their alleviation by melatonin. Ergonomics 1987;30:1379-1393.