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

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melatonin. However, taken in the early morning, exogenous melatonin causes a phase delay by 

antagonising the effect  

of bright light.  


This review aims to evaluate whether melatonin taken by mouth can prevent or alleviate jet-lag 

associated with air  

travel across several time zones. The review also examines the evidence for the effectiveness of 


dosage regimens. 

Criteria for considering studies for this review 

Types of studies 

Randomised trials 

Types of participants 

Airline passengers, airline staff or military personnel. 

Types of intervention 

Oral melatonin, compared with placebo or other medication, taken before during and/or after travel. 

Types of outcome measures 

The primary outcome measure is subjective rating of jet-lag, and components or correlates of this, 

such as  

fatigue, daytime tiredness, onset of sleep at destination, onset and quality of sleep, psychological 


duration of return to normal, and measures indicating the phase of circadian rhythms. 

Search strategy for identification of studies 

See: Collaborative Review Group search strategy


We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and PsychLit 

electronically, using the terms melatonin, jet-lag, jet lag, aviation, air travel, airtravel. The Science 

Citation Index was searched to identify trials that had cited the studies. The journals 'Aviation, Space 

and Environmental Medicine' and 'Sleep' from 1986 -1999 were searched by hand, including the 

conference abstracts published there. We searched citation lists of relevant studies for other relevant 

trials. We asked principal authors of relevant studies to tell us about unpublished trials. 

We also searched for reports of suspected adverse effects of melatonin that were not reported in the 

studies retrieved in the above searches.  

We checked Martindale 99, Meyler's Side Efects of Drugs (SED 96), and Side Effects of Drugs 

Annuals (SEDA) up to vol 22 (1999);  

searched 'Reactions Weekly' from 1990 to 1999, using the annual indexes to find all items 

mentioning melatonin;  

obtained the reports mentioning melatonin from the WHO Uppsala Monitoring Centre and the US 

Food and Drug Administration's Special Nutritionals Adverse Events Monitoring System 

(SN/AEMS) (http//; 

and searched MEDLINE using the MESH term 'Melatonin-adverse effects'.  

We did not search EMBASE because that is used in the production of SED and SEDA.  

Methods of the review       

All relevant RCTs were considered and the full reports obtained, as was subsequent published 

correspondence about  

them. Several authors were contacted and asked for supplementary information. 

The trials that met the inclusion criteria are referred to in this review by the year of publication 

followed by the first author's name, eg '87 Arendt', except when they are mentioned informally in the 

text. This has been done so that they can be listed in chronological order in the Table of 

characteristics of included studies, to make it easier for readers to see how the design of the studies 

has developed over the years. The other references are cited and listed in the conventional style.  

*Quality assessment: allocation concealment and blinding was looked for, described and evaluated 

Methods of measurement used in the trials are described and their relevance, validity and 

reproducibility discussed 

*Data were extracted independently by each author; differences were reconciled 

*Data synthesis: the following comparisons are made - 

(1) melatonin v. placebo; 

(2) treatment with melatonin only after arrival at destination ('post' regimen) v. treatment before, 

during and after travel ('pre+post' regimen); 

(3) eastward flights v. westward flights (with placebo and with melatonin); 

(4) passengers v. airline staff v. military personnel; 

(5a) low doses (5mg or less) v. high (8mg or more); 

(5b) low doses v. very low doses (0.5mg); 

(5c) rapid-release melatonin v. slow-release melatonin;  

(6) short (48 hr or less) v. long (over 48 hr) treatment.  

A meta-analysis was performed of visual analogue scores of jet-lag symptoms from 5 trials that were 

sufficiently similar in design.  

Adverse events noted in the course of the trials are summarised and assessed. 

Reports of adverse events linked with melatonin in other contexts, i.e. outside RCTs, were screened. 

Those that were considered potentially relevant to the use of melatonin for jet-lag are summarised 

and evaluated. To be considered potentially relevant, reports had to be related to use of melatonin for 

14 days or less, or use for jet-lag, and to include enough contextual information about the event to 

raise reasonable suspicion that melatonin might have contributed to it.  

Description of studies 


Tables of studies


Nine trials, published between 1986 and 1999, met the inclusion criteria. All compared melatonin 

with placebo, and one (98 Suhner b) in addition included a comparison with zolpidem, a hypnotic. 

One study, in US soldiers on an overseas rapid deployment mission, was excluded because it tested 

their adaptation to night operations at the destination in the Middle East, and not adaptation to the 

new time zone (Comperatore 96). 

One trial (93 Petrie) directly compared a 'pre+post' with an 'post' regimen, in airline cabin staff who 

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