Stephen Deacon

Efficacy of melatonin treatment in jet lag, shift work, and blindness.

Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The pres suggest, however, that although leep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.

Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans.

Melatonin is able to phase-shift the endogenous circadian clock and can induce acute temperature suppression. It is possible that there is a direct relationship between these phenomena. In a double-blind, placebo-controlled crossover study, 6 healthy volunteers maintained a regular sleep/wake cycle in a normal environment. From dusk until 24:00 h on days (D) 1-4 subjects remained in dim artificial lighting (< 50 lux) and darkness (< 1 lux) from 24:00-08:00 h. At 17:00 h on D3 either melatonin (0.05 mg, 0.5 mg or 5 mg) or placebo was administered. Melatonin treatment induced acute, dose-dependent temperature suppression and decrements in alertness and performance efficiency. On the night of D3, earlier sleep onset, offset and better sleep quality were associated with increasing doses of melatonin. The following day, a significant dose-dependent phase-advance in the plasma melatonin onset time and temperature nadir (D4-5) was observed with a trend for the alertness rhythm to phase-advance. A significant dose-response relationship existed between the dose of oral melatonin, the magnitude of temperature suppression and the degree of advance phase shift in the endogenous melatonin and temperature rhythms, suggesting that acute changes in body temperature by melatonin may be a primary event in phase-shifting mechanisms.

Posture influences melatonin concentrations in plasma and saliva in humans

Melatonin is extensively used as a circadian marker rhythm and thus any factors influencing its concentrations other than endogenous rhythmicity must be assessed. We report here the effects of posture on melatonin concentrations in plasma and saliva. The study was performed during the rising phase of the melatonin rhythm between 21:00 and 01:30 h. From 23:00 h, 7 healthy subjects remained sitting until 24:00 h and in dim light (< 10 lux) until 01:30 h. From 24:00 h, they assumed a different postural position in one of the following stages: Stage 1a: 24:00-00:30 h-standing, 00:30-01:00 h-supine, 01:00-01:30 h-standing; Stage 1b-reverse of Stage 1a; Stage 2a: 24:00-01:30 h-supine; and Stage 2b: 24:00-01:30 h-standing. Blood and saliva samples were obtained every hour from 21:00-24:00 h and then every 10 min from 24:00-01:30 h. Plasma and salivary melatonin concentrations, measured by radioimmunoassay, increased when moving from a supine to a standing position and decreased when these positions were reversed. These changes, as seen with other blood components, can be explained through the influence of gravity which causes a decrease in plasma volume on standing and an increase in plasma volume on lying down.

Treatment of Circadian Rhythm Disorders–Melatonin

Melatonin has clear acute and delayed effects on sleep and circadian rhythms. Decrements in core temperature and alertness have been found at different times of day following low pharmacological and physiological doses of melatonin. When correctly timed, melatonin induces both phase advances and phase delays of the circadian system in humans. When timed to advance, the decrement in temperature and alertness and the degree of shift are closely related to dose. In both simulation and field studies, correctly timed melatonin can alleviate some of the problems of shiftwork and jet lag, notably enhancing sleep and alertness and hastening adaptation of rhythms to the imposed schedule. Performance effects and changes in sleep architecture need to be fully evaluated. The optimization of dose and formulation is also an area that requires further work. Whether or not recently developed melatonin analogs (72) will prove more or less useful than melatonin in adapting to phase shift remains to be seen. If incorrectly timed, melatonin has the potential to induce deleterious effects. While short-term studies indicate that it has very low toxicity, there are no long-term safety data. All of the studies reported here concern healthy adult volunteers and the use of a preparation licensed for human experimental use and available on a named patient basis on prescription. There are no data on uncontrolled preparations available over the counter in some countries. Its effects in pregnancy, interaction with other medications, and many other considerations remain to be addressed. Thus, while melatonin is useful in well-controlled conditions, the indiscriminate use of unlicensed preparations is not advisable.

Adaptation of the 6-sulphatoxymelatonin rhythm in shiftworkers on offshore oil installations during a 2-week 12-h night shift

The circadian rhythms of most shiftworkers do not adapt to night shift. We have studied oil workers on a rotating system involving 2 weeks day shift (0600-1800 h) and 2 weeks night shift (1800-0600 h) throughout a day and night shift sequence. Urine samples were collected 3-hourly whilst awake, with an over-sleep collection, for the measurement of 6-sulphatoxymelatonin by radioimmunoassay. In three separate groups results showed adaptation by delay of the 6-sulphatoxymelatonin rhythm in the first week of night shift. The rates of phase shift (mean +/- SEM) were 1.51 +/- 0.16 h/day (n = 5), 1.32 +/- 0.41 h/day (n = 5) and 1.77 +/- 0.31 h/day (n = 17). Specific environmental and social factors together with the shift schedule on oil rigs may facilitate adaptation to a 12 h night shift within a week.

Acute phase-shifting effects of melatonin associated with suppression of core body temperature in humans.

Appropriately administered melatonin is able to phase shift circadian rhythms, to induce transient sleepiness and to suppress core body temperature. The relationships between these phenomena have not been fully explored. In a double-blind, placebo-controlled crossover study, 8 healthy males maintained a regular sleep-wake cycle in a natural environment throughout. From dusk until 2400 h on days (D) 1-4 subjects were in dim artificial lighting (< 100 lux) with darkness (< 1 lux) from 2400-0800 h. Sunglasses were worn during the day when outside. At 1700 h on D3 either melatonin (5 mg) or placebo was administered. Saliva samples were collected at 30 min intervals, 1600-2400 h on D3 and D4, and subjective alertness rated at 30 min intervals from 1600-2400 h on D3 and hourly from 0800-2400 h D4. Sleep quality was rated on nights 2, 3 and 4 and core temperature was recorded throughout. Melatonin induced a significant suppression of temperature and alertness peaking 2.5 h after the dose, together with improved sleep quality on the night of D3 and a phase advance of the endogenous melatonin rhythm on D4. The degree of phase shift was related to the amount of temperature suppression in 6 of 7 subjects with detectable melatonin, suggesting that temperature suppression is an integral part of the phase-shifting mechanism.

Phase-shifts in melatonin, 6-sulphatoxymelatonin and alertness rhythms after treatment with moderately bright light at night

OBJECTIVES Shift work and rapid travel across several time zones leads to desynchronization of internal circadian rhythms from the external environment and from each other with consequent problems of behaviour, physiology and performance. Field studies of travellers and shift workers are expensive and difficult to control. This investigation concerns the simulation of such rhythm disturbance in a laboratory environment. The main objectives are to assess the ability of controlled exposure to moderately bright light and darkness/sleep to delay circadian rhythms in volunteers without environmental isolation and, secondly, to evaluate the use of different indices of melatonin (MT) secretion together with self‐rated alertness as marker rhythms.

Adapting to phase shifts, I. An experimental model for jet lag and shift work

An experimental model was developed to measure various behavioral and physiological parameters in a laboratory paradigm mimicking phase shifts that could occur in time-zone transitions and shift work rotas. Volunteers were exposed to 9-h pulses of bright light (1,200 lx) as follows: day (D)1: 1800-0300 h, D2: 2100-0600 h, and D3, 4, 5: 2400-0900 h, each period followed by 8 h darkness. Immediately following the last treatment, subjects resumed their baseline sleep/wake schedule in a normal environment, thus experiencing a rapid 9-h advance phase shift of local time cues. During the gradual delay shift, a progressive delay shift in the rhythms of urinary 6-sulphatoxymelatonin (aMT6s), temperature and alertness was evident (maximum shift: 9.13 +/- 0.83 h, 9.09 +/- 1.06, and 10.62 +/- 0.96 h, mean +/- SD, respectively). There were no important detrimental effects on behavioral variables. After the rapid 9-h phase advance, sleep patterns, temperature amplitude, aMT6s acrophase, alertness, and performance took at least 5 days to reestablish normal baseline patterns. This model provides an effective and inexpensive model to study adaptation strategies in real life.

Adapting to phase shifts, II. Effects of melatonin and conflicting light treatment

The effects of melatonin (MT) and placebo (P) on adaptation to a rapid 9-h advance phase shift, in the presence and absence of inappropriate bright light (BL) exposure were examined. Volunteers were initially subjected to a gradual 9-h delay phase shift over 5 days (D1-D5) using a combination of bright light and darkness/sleep. Readaptation to a subsequent rapid 9-h advance phase shift was studied using: 1) MT, 5 mg, 2300 h, D6-D8, 2) BL, 2,000 lx, 0800-1200 h, D7-D8, 3) MT+BL and 4) P, 2300 h, D6-D8. MT treatment was timed to phase advance and BL to phase delay. BL delayed the 6-sulphatoxymelatonin rhythm in five out of seven subjects. Two subjects delayed and five phase advanced with both MT and MT+BL. MT consistently improved subjective sleep, alertness, and performance even in the presence of inappropriate BL and before phase readaptation had occurred. BL improved alertness and performance transiently. The beneficial effects of MT are not wholly mediated through an effect on the biological clock.

Atenolol facilitates light-induced phase shifts in humans

During time-zone travel, the endogenous melatonin rhythm is often out of phase with the new local time cues. Since endogenous melatonin could act as an endogenous zeitgeber, when its secretory rhythm is out of phase it may hinder adaptation by natural zeitgebers. It is possible that by temporarily suppressing the production of melatonin, by beta-blockers for example, adaptation may be facilitated. In a double-blind, crossover study eight healthy volunteers (aged 23-30 years) took 100 mg atenolol or placebo at 1900 h on Day (D) 1. Volunteers were then exposed to bright light (approx. 1000 lux) from 0000 to 0400 h during the following night and remained in dim light (<50 lux) or darkness until 1200 h on D3. Salivary melatonin (MT) and urinary 6-sulphatoxymelatonin (aMT6s) were measured every 30-60 min and every 2 h (except when asleep), respectively. Subjective alertness and core body temperature (cBT) were also measured. aMT6s and MT were significantly suppressed under atenolol treatment on the night of D1 only. Atenolol significantly phase delayed the salivary melatonin onset by 1.8+/-0.6 h and 1.28+/-0.35 h compared with the onsets on D1 placebo leg and D2 placebo leg (i.e. onset times before and after light treatment), respectively. There were no detrimental effects on cBT or alertness. Temporary suppression of melatonin by beta-blockers may facilitate adaptation to phase shifts.