quality in the melatonin group. In the trial in soldiers, melatonin helped circadian adaptation and
maintained sleep durations of 7-8 hours at the destination, while on placebo sleep was 5-7 hours. In
cognitive tests done soon after waking, the melatonin group made about half as many errors as the
placebo group. Symptoms of jet-lag were not directly assessed.
Of the four trials of the 'post' regimen, 98 Suhner (a) found that melatonin very clearly improved
self-rated sleep quality, shortened sleep latency and reduced fatigue and daytime sleepiness. Two
other trials found trends in the same direction that either did not reach statistical significance (92
Nickelsen) or are not adequately reported (98 Suhner b). 97 Spitzer found no differences between the
treatment groups, most likely because the participants' baseline rhythms had not adapted to the time
zone from which they left.
These data suggest that the 'pre+post' regimens have no important advantage over 'post' regimens
that might outweigh the inconvenience of dosing before the day of travel, but they have not been
directly compared in ordinary travellers.
Comparison (3): eastward flights v. westward flights
Two trials have compared eastward with westward flights as a part of their design. The Auckland -
London trial (89 Petrie) did so, but is not suitable for this comparison as the travellers crossed 12
time zones and it takes over 24 hours to complete the journey. Nickelsen's volunteers flew from
Frankfurt to North America, returning at least 2 weeks later; they did not cross over. In this study jet-
lag was worse after the eastward flight (overall VAS, combining results with melatonin and
withplacebo : eastward 5.9, westward 3.0). Jet-lag scores were modestly lower on melatonin than on
placebo in both directions.
Comparison (4): passengers v. airline staff
Seven of the 8 trials were in travellers, one in airline cabin crew (93 Petrie). Both groups showed
some benefit from melatonin, but their duties and activities at the destination differed. For the
travellers these were undefined and very diverse. The airline cabin crew entered the trial with very
disordered circadian rhythms, and this probably made it harder to achieve and detect any
improvement in jet-lag. Even so a benefit was shown.
Comparison (5a): low doses (5mg or less) v. high (8mg or more)
One trial, that of Claustrat, compared melatonin 8mg with placebo. Nothing in the results of this trial
suggests a greater effect than was seen with lower dosage.
Comparisons (5b, 5c): low doses v. very low doses (0.5mg): rapid-release melatonin v. slow-release
Suhner (a) compared doses of 5mg and 0.5mg in ordinary (fast-release tablets) and 2mg in a slow-
release tablet. The 5mg dosage improved self-rated sleep quality, shortened sleep latency, and
reduced fatigue and daytime sleepiness after intercontinental flight. The lower dosage of 0.5mg was
almost as effective; only the hypnotic properties of melatonin, sleep quality and sleep latency were
greater with the 5mg dosage.
The 2mg slow-release form was less effective than either of the fast-release tablets.
Comparison (6): short (48 hr or less) v. long (over 48 hr) treatment
All nine trials were of treatment for longer than 2 days; none examined a treatment duration of two
days or less.
Reported symptoms/ side effects
Eight RCT reports note symptoms, but only Suhner's two studies looked for symptoms
systematically. The first (Suhner a) found no statistically significant differences in the incidence of
symptoms between melatonin and placebo. Some symptoms - daytime sleepiness, dizziness,
headache and loss of appetite - were most frequent on day 1 after the flight and became less frequent
zolpidem+melatonin group felt significantly sleepier in the morning, while the melatonin group felt
least sleepy. The combination group also felt significantly more confused and more nauseated than
all other treatment groups. Ear/ nose/ throat problems were most frequent in melatonin users;
pruritus was least frequent in this group.
Most adverse events or symptoms in the other six studies can be regarded as no more than sketchy
qualitative pointers. However, hypnotic effects after melatonin occurred in 5 of the studies, affecting
about 10% of the participants. Others included headache or 'heavy head' (2 studies), disorientation
(88 Arendt), nausea, and gastrointestinal problems. One individual experienced difficulty in
swallowing and breathing within 20 minutes of taking the first dose of 0.5mg melatonin, symptoms
which subsided after 45 minutes (98 Spitzer). This person stopped taking the capsules, but agreed to
take another single dose on another occasion to see if the symptoms would recur. They did, but were
somewhat milder. All the adverse events reported in the trials occurred during treatment and appear
to have been short-lived.
Reports of adverse effects from sources other than clinical trials
Potentially relevant adverse events have been reported (from sources other than clinical trials in jet-
lag) in 6 published papers and 19 unpublished case records from the WHO Uppsala Monitoring
Centre (UMC). The reports obtained from the website of the US FDA SN/AEMS lacked essential
details and could not be used. Table 2 lists the 25 single cases by the systems affected - CNS,
circulation, blood clotting, skin. (Cases identified only by a number and a country are from the UMC
register.) Many of the reports do not state whether or not the individual concerned was healthy, or
for what purpose melatonin had been taken.
The reports that are in our view worth noting by potential users of melatonin are marked with an
asterisk. They concern people with epilepsy, patients taking warfarin or another oral anticoagulant,
and anyone getting a skin rash after using melatonin.
Four types of events that may signal a true effect of melatonin deserve investigation. Possible effects
on mental function, sleep, seizure activity, and the circulation are complex, likely to vary greatly
with circadian phases, and will be difficult to elucidate. The simplest possibility to study, and
perhaps the most urgent, is that melatonin potentiates warfarin. The reports of fixed drug eruption, an
allergic manifestation, appear be convincing and must be taken seriously.
Nine of the ten trials found that melatonin taken close to bedtime at the destination decreased jet-lag
from journeys crossing five or more time zones. The one study that did not (98 Spitzer) was
handicapped by starting from an inappropriate baseline. No differences were detected between daily
doses of 0.5 and 5mg melatonin, except that people fall asleep faster and sleep better after 5mg than
0.5mg. A higher dose (92 Claustrat) is not clearly more effective than 5mg. The relative
ineffectiveness of 2mg slow-release melatonin (98 Suhner a) suggests that a pulse of melatonin,
briefly giving a higher concentration in the blood, works better.
The effect on jet lag shown in the meta-analysis is striking. The benefit is likely to be even greater
for flights across more time zones, but less for westward flights.
No trials have directly assessed the use of melatonin with other strategies for reducing jet-lag, but an
additive effect would seem likely. Light exposure and light avoidance at the destination have to be
scheduled appropriately in order to support the adaptation process to the new time zone. This
schedule depends on the number of time zones crossed and the direction of flight. Tables and
computer progarmmes exist that give guidelines when to seek and when to avoid light. Furthermore,
the rapid adoption of the new daily pattern at the traveller's destination in terms of meal times,
exercise and sleep periods will also aid overall adaptation. The value of melatonin to travellers using
sensible re-entrainment principles needs to be established in future research. The effects of caffeine