#readwise # Jet Lag: Therapeutic Use of Melatonin and Possible Application of Melatonin Analogs  ## Metadata - Author: [[PubMed]] - Full Title: Jet Lag: Therapeutic Use of Melatonin and Possible Application of Melatonin Analogs - URL: https://pubmed.ncbi.nlm.nih.gov/18342269/ ## Highlights - Familiar to almost every intercontinental traveler is the experience of fatigue upon arrival in a new time zone, but almost as problematic are a number of other jet lag symptoms. These include reduced alertness, nighttime insomnia, loss of appetite, depressed mood, poor psychomotor coordination and reduced cognitive skills, all symptoms which are closely affected by both the length and direction of travel. The most important jet lag symptoms are due to disruptions to the body's sleep/wake cycle. ([View Highlight](https://read.readwise.io/read/01gxfwrtjj7nh2peqw0vn6870c)) - Clinical and pathophysiological studies also indicate that jet lag can exacerbate existing affective disorders. ([View Highlight](https://read.readwise.io/read/01gxfws731g52z76z7r8wpsc4y)) - dysregulation of melatonin secretion and occurrence of circadian rhythm disturbances may be the common links which underlie jet lag and affective disorders ([View Highlight](https://read.readwise.io/read/01gxfwt95b4s94kzzggwkm3m0n)) - Largely because of its regulatory effects on the circadian system, melatonin has proven to be highly effective for treating the range of symptoms that accompany transmeridian air travel. ([View Highlight](https://read.readwise.io/read/01gxfwvka1grp45pg2ea02gcr9)) - Melatonin acts on MT(1) and MT(2) melatonin receptors located in the hypothalamic suprachiasmatic nuclei, the site of the body's master circadian clock. Melatonin resets disturbed circadian rhythms and promotes sleep in jet lag and other circadian rhythm sleep disorders, including delayed sleep phase syndrome and shift-work disorder. ([View Highlight](https://read.readwise.io/read/01gxfwwktmn0ehkq8mjqhgjt1g)) - Although post-flight melatonin administration works efficiently in transmeridian flights across less than 7-8 times zones, in the case longer distances, melatonin should be given by 2-3 days in advance to the flight. To deal with the unwanted side effects which usually accompany this pre-departure treatment (acute soporific and sedative effects in times that may not be wanted), the suppression of circadian rhythmicity by covering symmetrically the phase delay and the phase advance portions of the phase response curve for light, together with the administration of melatonin at local bedtime to resynchronize the circadian oscillator, have been proposed. ([View Highlight](https://read.readwise.io/read/01gxfwxsebmyrgnvr451hfgamr)) - Circadian rhythms can be shifted by stimuli known as zeitgebers (time cues). Depending on the time that they occur they will have either a delaying or an advancement effect on circadian rhythms. The direction and magnitude of the change in timing is described by the phase response curve. A reliable estimation of endogenous period is given by measuring the early increase in melatonin concentration occurring at late evening (‘‘dim light melatonin onset’’). By using this parameter, the phase shift effects of exogenous melatonin administration can be explored in individuals with normal vision as well as in blind people. In individuals with normal vision who are entrained to a 24-h light/dark cycle, melatonin administration in the afternoon and evening causes a phase advance. By contrast, melatonin administration in the late night or early morning causes a phase delay. During most of daylight period, the effect of melatonin on rhythm periodicity is neutral. A melatonin phase response curve has been constructed by administering a daily 0.5-mg dose for 4 days. - The first placebo-controlled study on the use of melatonin in alleviating the symptoms of jet lag was conducted during an eastbound transmeridian flight over 8 time zones. In this study melatonin at 5-mg dose was administered in the early evening (18:00 h) 3 days prior to the flight, and for 4 days (post-flight) at 23:00 h at bedtime hour of the new local time zone. The results of the study indicated that both subjective measures, such as jet lag ratings, self-recorded sleep parameters, mood ratings, as well as objective measures such as endogenous melatonin and cortisol rhythms, adapted more rapidly in the melatonin-treated group than in the placebo-treated group. - A metaanalysis of 10 trials (Cochrane data base) concluded that melatonin **taken at bedtime in the place of destination (22:00 h to midnight)** was effective for decreasing the jet lag symptoms in air travelers who crossed 5 or more time zones. Generally, **an intake of daily doses ranging from 0.5 to 5.0mg was found to be effective**. It was concluded that melatonin is ‘‘remarkably’’ effective for preventing or reducing jet lag. - One of us (DPC) made use of this phenomenon and melatonin administration in a took advantage of this situation to obtain an almost immediate resynchronization of circadian rhythms in a group of jet air travelers who had just made a transmeridian flight over 12 time zones. Upon arrival at their destination the travelers were given melatonin at the local bedtime to resynchronize the circadian oscillator to the new time environment. To disturb minimally their own schedules and habits, the travelers asked to ensure that they were exposed to outdoor light. The goal was to attempting to cover symmetrically the phase delay and the phase advance portions effects of light which have been reported to influence the phase response curve in humans of the phase response curve reported for light in humans. It is hypothesized that this strategy immediately brought about a suppression of circadian rhythmicity, thus sensitizing the circadian clock to additional chronobiological manipulation. Again in this case, the time of melatonin administration was selected on the basis of introducing the least possible disturbance to daily routine. Additionally non-photic stimulation (i.e., physical exercise) that practically coincided with outdoor light exposure was used as another manipulation for the intention of masking the circadian oscillator. - This multifactorial strategy was used for accelerating the resynchronization of circadian rhythms in a group of elite sports competitors after a transmeridian flight which crossed 12 time zones. The participants were traveling from Buenos Aires to Tokyo to play in the final games of an international soccer competition. **The day before leaving Buenos Aires all participants were given 3 mg of melatonin orally daily at a time equating to their expected bed times in Tokyo.** This schedule of melatonin administration was adhered to throughout and continued with it for all the study. Additionally, the participants were also asked to complete the daily sleep log diaries. **Upon arrival in Tokyo the subjects performed daily physical exercise at outdoors but only during certain times of the day (from 08:30 to 11:30 h in the morning and from 15:00 to 18:00 h in the afternoon)**. It was hypothesized that this restriction in light exposure centered at the hypothetical minimum in body temperature produced a contradictory signal for the clock (i.e. phase advance with the first light exposure, phase delay with the second) thus helping to eliminate the endogenous rhythm. The only relevant circadian signal therefore was that given by exogenous melatonin at the local time. Exposure to sunlight and physical exercise were avoided at other times of the day. - For the eastbound flight, all subjects received 3mg of melatonin daily 30min before their expected bedtime at Sydney from the day prior to the trip. All subjects were advised to perform their normal routine and to walk outdoors for at least 30 min at two restricted times of the day (Table 1). For the westbound flight the volunteers took melatonin (3mg) on the day of flight to Buenos Aires at the expected sleeping time at Buenos Aires. On reaching Buenos Aires, all volunteers were advised to perform their normal routines and were advised to walk outdoors for at least 30min at the same two restricted periods of the day as in Sydney. ![[Screenshot 2023-04-08 at 10.30.52.png|300]] - Collectively, the data herein reviewed indicate that oral administration of melatonin is the best pharmacological treatment available for jet lag. Its effectiveness may be due to its phase-shifting effect or sleep inducing effect or both. Jet lag symptoms are closely influenced by the effects of changes in the light/dark cycle, and because these changes are a major zeitgeber affecting the body clock, they can consequently alter the pattern of melatonin secretion. The evidence of numerous studies now demonstrates that the strategically timed administration of exogenous melatonin is a simple but powerful technique for adjusting the body clock and thereby reducing jet lag symptoms that annually affect millions of air travelers.