Abstract & Commentary
Synosis: Melatonin is remarkably effective in preventing or reducing jet lag, and occasional short-term use appears to be safe.
Source: Herxheimer A, Petrie KJ. Cochrane Database Syst Rev. 2002;(2):CD001520.
Jet lag commonly affects air travelers who cross several time zones. It 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.
To assess the effectiveness of oral melatonin taken in different dosage regimens for alleviating jet-lag after air travel across several time zones, Herxheimer and colleagues searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, PsychLit, and Science Citation Index electronically, and the journals Aviation, Space and Environmental Medicine, and Sleep by hand. They searched citation lists of relevant studies for other relevant trials and asked principal authors of relevant studies about unpublished trials. Reports of adverse events linked to melatonin use outside randomized 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 and Drug Administration. Randomized trials in airline passengers, airline staff, or military personnel given oral melatonin compared with placebo or other medication were reviewed. Herxheimer et al looked for outcomes of subjective rating of jet lag or related components, such as subjective well-being, daytime tiredness, onset and quality of sleep, psychological functioning, duration of return to normal, or indicators of circadian rhythms.
Ten trials met the inclusion criteria. All compared melatonin with placebo; in addition, one 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.
Nine of the 10 trials found that melatonin, taken close to the target bedtime at the destination (10 pm to midnight), decreased jet lag from flights crossing 5 or more time zones. Daily doses of melatonin between 0.5 and 5 mg are similarly effective, except that people fall asleep faster and sleep better after 5 mg than 0.5 mg. Doses larger than 5 mg appear to be no more effective. The relative ineffectiveness of 2 mg slow-release melatonin suggests that a short-lived higher peak concentration of melatonin works better.
Based on the review, the number needed to treat is 2. The benefit is likely to be greater the more time zones are crossed, and appears to be less for westward flights. 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.
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 travelers flying across five or more time zones, particularly in an easterly direction, and especially if they have experienced jet lag on previous journeys. Travelers crossing 2-4 time zones also can 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.
Comment by John La Puma, MD, FACP
Aaron H. Burstein, PharmD, a pharmacokineticist at the Clinical Center, Pharmacy Department of the National Institutes of Health has reported that "Melatonin should be used cautiously and/or avoided in patients with autoimmune diseases and allergies [potential for immune system stimulation], cardiovascular disease [potential for coronary artery vasoconstriction in animal models], depression [exacerbation of dysphoria], and neurologic conditions including epilepsy . . . administration with fluvoxamine, a known inhibitor of CYP1A2 and CYP2C19, resulted in great increases in melatonin concentration."
Melatonin’s interactions with chlorpromazine, benzodiazepine, and succinylcholine have been documented, as have quality problems with many tablets.1 Nevertheless, this top-of-the-science review confirms what many travelers have already discovered: For jet lag, melatonin works if taken correctly, in small doses.
Recommend melatonin products that have USP, DSVP, or NSF on the bottle, and have passed consumerlab.com tests for purity and quality; and to patients who do not take and who are unlikely to take the medications outlined above. Daily doses should not exceed 5 mg.
Dr. LaPuma is Director, CHEF Clinic Research & Education President, Meeting Meals, Santa Barbara, Calif.
1. Hahm J, et al. J Am Pharm Assoc. 1999;39:27-31.