3rd Qtr 1998 NewsShare

Melatonin for jet lag?

Melatonin is a serotonin derivative produced by the pineal gland. Variations in its secretion are thought to modulated circadian rhythms. Commercially synthesised melatonin is now being used to prevent jet, although, it is not licensed as a medicine in the UK. Here we review the value of melatonin for this use.

Background
Jet lag is an ill defined cluster of symptoms that includes daytime tiredness, poor concentration and disturbed sleep. It arises after flight across several time zones when the travellers’ circadian rhythms (such as the sleep-wake cycle) are not synchronous with local time. Flying eastward seems more disturbing than flying westward and problems increase with the number of time zones crossed. Endogenous melatonin (N-acetyl-5-methoxytryptamine) is synthesised and secreted at night, with serum concentrations rising soon after the onset of darkness, reaching a peak between 2am and 4am then falling gradually towards the morning1. Exposure to light inhibits melatonin secretion in a dose dependent manner2. It is claimed that pharmacological doses of melatonin (taken at the correct time) can ‘reset’ the internal body clock to fit in with local time at the travellers’ destination3. Within an hour of an oral dose of 1-5mg , serum melatonin concentrations are 10-100 times the normal nighttime peak, returning to baseline values after 4-8 hours1. Melatonin is rapidly inactivated mainly in the liver.

Availability
Melatonin is not licensed for use as a medicine in the UK or other EU member states. It is sold over the counter in many countries such as the USA and Singapore where it is categorised as a dietary supplement. Manufacturers there do not have to demonstrate that the product is pure or even that it contains any melatonin4. In the UK, melatonin requires a manufacturing or wholesale dealer (import) licence. Wholesalers can supply melatonin to pharmacies but only in response to a prescription for an individual (named) patient. Melatonin is an endogenous substance which cannot be patented although the process by which it is manufactured can. No manufacturer has applied for a product licence for melatonin. Because it is not a licensed medicine, it cannot be promoted.

Clinical Trials
We know of six double-blind controlled trials of melatonin in the management of jet lag; four involved passengers on long haul flights5-8, one, cabin crew9, and one, military personnel10. Their designs differed and in total, fewer than 200 people were involved. The daily doses of melatonin (by mouth) were 5mg5-7,9, 8mg8 and 10mg10. In most of the trials, visual analogue scales were used to assess the intensity of jet lag. Other variables recorded included the travellers’ adaptation of hormonal patterns, mood, sleep patterns, psychological functioning, tiredness and recovery of energy or alertness.

Two of the trials involved passengers taking melatonin or placebo two5 or three6 days before the flight (‘early melatonin’) on the day of the flight and for three6 or four5 days after arrival. In the first study, which involved travellers flying eastward over eight time zones, none of the eight passengers who took melatonin experienced jet lag (determined by score of <50/100) whereas six of the nine taking placebo did (p<0.01). The second was a crossover study involving an eastward flight (over 12 time zones) and the return journey6. Jet lag was reported as a score on a 6-point scale: the mean score was 3.4 for placebo and 2.2 for melatonin (p<0.01). Melatonin reduced symptoms of jet lag in both directions. Normal sleep pattern, energy level and absence of daytime tiredness were reached after about 3 days of taking melatonin and after 4 to 5 days of taking placebo.

In the other two passenger studies, melatonin or placebo was started on the day of travel (‘late melatonin’) and then taken at the destination bedtime for three8 or seven7 days after arrival. In the first study, passengers flew westward initially (over 6-11 time zones) and then returned home7. The study was not crossover in design. There was no significant difference in the jet lag scores between the melatonin and placebo treatment groups. Melatonin did not speed the return of cortisol hormonal patterns after the westward flight, but helped readaptation after the trip home, the effect increasing with the number of time zones. In the second study, jet lag was assessed in passengers on their return flight eastward from North America to France8. Of the 15 participants in each group, 11 taking melatonin and 5 taking placebo were reported to consider their treatment effective (p value not stated). Tiredness, sleep latency and quality, efficiency at work and mood after arrival were similar in both treatment groups.

The trial involving cabin crew compared ‘early melatonin’ and ‘late melatonin’ with placebo on their return (westward) trip9. Mean jet lag scores indicated that benefit occurred only when the first dose was taken on arrival (‘late melatonin’). Out of a maximum of 100 (extreme jet lag) the mean scores were 65 for placebo, 67 for ‘early melatonin’ and 38 for ‘late melatonin’ (p<0.05) on a visual analogue scale. The participants in this study differed from those in the others in that their circadian rhythms had been severely desynchronised for the preceding 9 days. The final study involved military personnel flying eastward on a training mission and found that those taking melatonin slept for longer t the appropriate time than those taking placebo10. Participants on placebo seemed to have difficulty staying asleep. Mood and subjective fatigue were similar in the two groups. However, those taking placebo made more errors during a vigilance test.

Unwanted Effects
Unwanted effects reported in trials of melatonin have included mild sedation, sleepiness and “heavy head”. In the cabin crew trial, 5 of 18 participants in the ‘early melatonin’ group reported sleeping difficulties, brief drowsiness or occasional headaches. These symptoms are similar to those of jet lag itself and complicate the interpretation of the trial results. No serious adverse effects have been associated with melatonin but the number of people involved in trials has been small and no long term data exist.

Conclusion
On the limited published evidence available, oral melatonin possibly reduces the severity and duration of jet lag. There is little or no data on the product’s toxicity or long-term safety and no clear evidence on when or how it should be taken. We cannot recommend the use of melatonin for the management of jet lag without more evidence of its value and while it does not have a product licence to ensure its quality and safety.

(M = meta analysis, R - randomised controlled trial)

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