Melatonin for the prevention and treatment of jet lag Herxheimer A, Petrie kj

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and alcohol intake during the flight on adaptation also deserve study.  

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 

the medication. So far only limited data exist on elderly travellers, and none on the effect of 

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.  

Reviewers' conclusions 

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 

on the day of arrival at the destination, and on the following 2-5 days at the same time. Taking 

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.  

Implications for research 

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. 

Potential conflict of interest 

None [AH]; Keith Petrie has undertaken two of the trials reviewed. 


References to studies included in this review  

87 Arendt (published data only)  

* *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. 

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