Alleviation of jet lag by melatonin: preliminary results of controlled double blind trial Jet lag is an ill defined phenomenon resulting from rapid flight across several time zones.' It is considered to be due to desynchronisation of circadian rhythms, such as the sleep-wake cycle, with local time and to lack of sleep. ' A means of rapidly resynchronising body rhythms to local time would benefit people who suffer badly from jet lag. Various remedies for alleviating jet lag have been proposed: manipulation of dietary intake and, more recently, appropriate exposure to'bright light have been used, though both are time consuming.2 3 We previously suggested that melatonin, a methoxyindole secreted by the pineal gland, might be simpler and more effective in treating jet lag.4 In view of its resynchronising properties in animals,5 its ability to transduce light-dark information, its hypnotic effects in man, and its low toxicity we examined whether it helped people adapt to new time zones.

Seventeen healthy volunteers (10 women and 7 men, aged 29-68) were flown from London to San Francisco between 20 November 1985 and 25 January 1986 and remained there for 14 days prior to flight home. Subjects took melatonin (N= 8, 5 women, 3 men) or placebo in a double-blind design, at 18.00h local time for three days before the return flight and at bedtime (22.00-24.0011) in Great Britain for four days. For three days before departure and on days 1-7,14,15,21 and 22 after their retum subjects collected 6-hourly sequential urine samples and kept a daily sleep log. 'They recorded mood and oral temperature 2 hourly and performed logical reasoning and letter cancellation tests 4 hourly from 08.00h (or wake up time) to 24,OOh (or bedtime) whichever was the earlier. Urine was also collected for 48 h prior to departure from the U.S.A.. On day 7 after their return subjects rated 'jet lag' (IOcm visual analogue scale-VAS) from 0 (insignificant) to 100 (very bad). Melatonin significantly improved 'jet lag' (p=0.009). Comparisons by ANOVA between jet-lagged placebo subjects (N = 7) and melatonin (N = 8) showed decreased sleep latency with melatonin (p=0.0397) which correlated positively with jet lag ratings, p < 0.001. Sleep quality was significantly improved in the melatonin group and correlated negatively with jet-lag ratings (p<0.001). No important differences were found in temperature, or performance data. Baseline differences were present in some pcrformancc ratings but no othcr variables. Mclatonin treated subjects tended to be more alert than placebo subjects, especially at bedtime. They were also less depressed. Endogenous melatonin and cortisol rhythms resynchronized more rapidly in melatonin subjects (p=0.0216 and p=0.0299 respectively, absolute acrophase shifts). Cortisol rhythms indicated adaptation to U.S.A. time in 14 days. These data suggest that MT can alleviate jet-lag after Eastward flight over eight time zones. Presumably its affects are primarily on sleep latency, quality, and directly or indirectly on some hormonal rhythms.

The plasma concentrations of melatonin in man, fasting and fed, were determined after ingestion of three different oral preparations. A dose of 2 mg was given as either a gelatine capsule, a solution in corn oil or as a slow‐release pill. Gelatine capsules and the corn oil preparation gave reproducibly timed peak plasma concentrations, 30 to 60 min after ingestion regardless of nutritional status, and plasma melatonin remained at or above endogenous night‐time levels for 3‐4 h with mean elimination half‐lives of 0.54 to 0.67 h. The slow‐release preparation usefully extended high plasma melatonin concentrations for 5‐7 h after ingestion but the timing of peak concentrations was very dependent on nutritional status. These preparations should be of use in the study of timed melatonin administration in man.

Previous studies have shown that bright light (2500 lux) suppresses nocturnal secretion of melatonin, while dim light (500 lux) has little or no effect. We have studied the effect of varying intensities of light on 5 normal male volunteers (age 18-28). The experiment was divided into 3 parts which took place at weekly intervals. Subjects remained under artificial light (fluorescent strip 150-250 lux) between 2000 h-2300 h, they then retired to bed in darkness. On each occasion, between 0030 h and 0100 h, the subjects were required to get up and were treated with light of different intensities; (a) less than 1 lux, (b) 300 lux and (c) 2500 lux respectively. Subjects returned to bed in darkness until 0700 h. Blood was sampled hourly from 2000 h-1000 h with additional samples at 2330 h, 0015 h, 0030 h, 0045 h, 0115 h and 0130 h. Plasma melatonin and 6-sulphatoxymelatonin (aMT6s), the major melatonin metabolite, were measured by radioimmunoassay. Dim (300 lux) and bright (2500 lux) light, both significantly suppressed melatonin levels compared to less than 1 lux (P less than 0.05 and P less than 0.01 respectively) at the following time points 0100 h, 0115 h and 0130 h. One subject did not show suppression with 300 lux. There was also a significant suppression of aMT6s levels, compared to less than 1 lux, after both 300 lux and 2500 lux at 0115 h (P less than 0.05, P less than 0.01), 0130 h (P less than 0.01, P less than 0.01) and 0200 h (P less than 0.01, P less than 0.001) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY. A radioimmunoassay (RIA) for urinary 6-sulphatoxymelatonin (aMT6s) using an 1251_aMT6s tracer is described. Iodinated aMT6s used as the label was synthesised by direct iodination of aMT6s using 1.3,4.6 tetrachloro 3.6 diphenylglycouril as the oxidant. The assay shows low cross reactivity with related compounds. Serial dilutions of 1:25() and I: 125 diluted urine gave parallel displacement curves.Comparison of the new RIA using 12.~I-aMT6s with the RIA using 3H-aMT6s label gave good correlation. as did comparison with a gas chromatography mass spectroscopy (GCMS) for total free and conjugated 6-hydroxymelatonin.It is reported that 6-sulphatoxymelatonin is the major urinary metabolite of the pineal hormone melatonin in humans. I. 2 It is synthesised in the liver as a conjugate of 6-hydroxymelatonin the primary metabolite of melatonin." It has been shown to be a good index of pineal melatonin secretion and hence pineal function.v" Since urine is convenient to collect, it provides a simple non-invasive method for long-term study of the pineal, and opens up the possibility of studying melatonin in many clinical situations.We have previously reported a direct RIA for aMT6s in plasma and urine using a tritiated tracer." Whilst this assay is sensitive specific and reproducible, it is expensive in time and reagents.This report describes an assay using an iodinated tracer which is as specific and more sensitive than the previously reported assay. It uses a much simpler method of label production and avoids costly and cumbersome scintillation counting. Materials and methods MATERIALS