Combating Jet Lag with Melatonin
Most scientifically sound methods for reducing the effects of jet lag are based on two facts:
- In healthy individuals, circadian rhythm is synchronized with daylight.
- Effects of the daylight-dark cycle on circadian cycle are mediated by melatonin.
Specifically, melatonin is secreted by the pineal gland in response to the absence of light. Melatonin triggers a cascade of chemical and physiological responses that ultimately result in sleep, usually within about 30 minutes. As dawn breaks and light begins to impinge on the brain's “circadian pacemaker,” melatonin production drops off dramatically, and the waking portion of the daily sleep-wake cycle begins.
Strategies to manipulate the sleep-wake cycle, such as those used to alleviate symptoms of jet lag, therefore depend on strategic manipulation of exposure to bright light and intake of supplemental melatonin at key times. Some studies have also examined the usefulness of stimulants (eg, caffeine).
Jet Lag: A Dangerous Deficiency in Melatonin
Melatonin's role in human health is far more profound than once suspected. We now know that melatonin has remarkable properties as an antioxidant and a modulator of immune system functioning. As an antioxidant, it works on several levels. Production of the body's natural antioxidant enzymes (eg, superoxide dismutases, peroxidases, catalase, and glutathione peroxidase) is promoted by melatonin. Also, melatonin triggers other cell-signaling pathways that result in decreased production of harmful, inflammation-producing chemicals (eg, nitric oxide synthases and lipoxygenases).
Melatonin receptors are found throughout the body, including the gastrointestinal and reproductive tracts. It is now known that melatonin is produced by a number of tissues, including skin, gut, liver, kidney, and white blood cells (Hardeland 2005b; Iwasaki 2005; Kvetnoy 2002).
Another study examined the effects of pineal gland removal on the skin of laboratory rodents. Changes in skin thickness and texture, among others, were seen in animals whose pineal glands had been removed, but not in control animals that underwent a sham operation. When supplemental melatonin was given to the affected rodents, their skin dramatically improved. These results suggest that melatonin is a highly efficient anti-aging factor; as its levels decrease with age, melatonin use may minimize age-related skin changes (Esrefoglu 2005).
Other studies have suggested that melatonin plays an important role in preserving neurological function in rats with spinal cord injuries (Gul 2005; Liu 2004). Melatonin has been studied as a support for age-associated neurological disorders (Srinivasan 2005). Some of its metabolites are believed to improve mitochondrial functioning and quell inflammation (Hardeland 2005a).
Thus, melatonin plays an indispensable role in synchronizing the body's internal clock with the external environment and is also a vital component of overall health and well-being (Claustrat 2005). Jet lag, which involves a disruption not only of the sleep-wake cycle but of melatonin secretion as well, is not to be underestimated as a potential threat to health.
The "Chronosense": An Internal Timekeeper
Melatonin, which stimulates sleep, is only part of the equation when it comes to jet lag. Light is also a major factor in regulating the natural circadian clock. German researchers have proposed a previously unsuspected role for the eye in the function of the circadian clock. While structure and function of the eye as the sensory organ of vision are well known, it apparently also serves as an organ of time sense (Erren 2004).
This role relies on a sensory pigment that allows non-image-forming photoreception in mammals. Researchers refer to the nexus of this photopigment and retinal nerve as the “chronoreceptor,” which mediates the sense of time, or “chronosense.” Although the exact photopigment responsible for chronoreception has not yet been identified with certainty, a chemical called melanopsin is emerging as a likely candidate (Erren 2004; Silva 2005; Fu 2005).
These newly discovered chronoreceptors provide the brain with readings that correspond to changes in the intensity of both natural and artificial light. Light signals travel from the eye through a small subset of retinal ganglion cells to a region of the hypothalamus (specifically, to the suprachiasmatic nucleus), and from there to the pineal gland. The suprachiasmatic nucleus is also the site of the circadian pacemaker.
Scientists in Brazil demonstrated that the chronosense, or light-dark entrainment, occurs even in blind primates otherwise unresponsive to visible light. This finding suggests the biological importance of adjusting circadian rhythm to the daily light-dark cycle (Silva 2005). The importance of chronosense was further supported when researchers discovered that newborns are functionally blind at birth, yet the newborn retina is nevertheless sensitive to light, and there is a functioning connection between the chronoreceptors and the circadian pacemaker in the brain (Sernagor 2005).
Minimizing Jet Lag: A Plan of Attack for Rapid Reentrainment
In 2003, leading British jet lag researchers published a review of clinical trials that used bright light with and without melatonin in an effort to hasten circadian rhythm reentrainment after simulated or actual flights crossing more than five time zones. They cited 10 randomized, controlled trials that compared the effects of melatonin versus placebo in participants undergoing simulated or actual long-distance travel (Herxheimer 2003).
Eight of 10 trials found a clear reduction in jet lag when melatonin was taken. Five of the studies recorded global jet lag scores between zero (none) and 100 (extreme). The mean score after placebo was 48. Mean score after melatonin was 25, indicating that jet lag severity was reduced by about half among melatonin users.
Scientists concluded that 2 to 5 mg of melatonin taken at bedtime after arrival is an effective means of minimizing jet lag (Herxheimer 2003). Melatonin administration at bedtime should probably continue for the following two to four days for maximum effectiveness. In addition, careful attention to meal times and light exposure may hasten reentrainment. Conversely, inappropriate meal times, injudicious use of alcohol or caffeine, and exposure to bright light at the wrong times may hinder the process.
Light was identified as the most important external cue. Specifically, after a westward flight, it is important to stay awake during daylight hours at the new destination and sleep only after it gets dark. After an eastward flight, it is important to remain awake in the morning but avoid bright morning light. It is also recommended to be outdoors as much as possible in the afternoon at the new destination.
Getting some moderate exercise (Miyazaki 2001) and perhaps indulging in sightseeing at times when bright light exposure is advised may also reinforce the reentrainment process. Doses of melatonin ranging between 0.5 mg and 5 mg are similarly effective in facilitating reentrainment, but one research team found that participants fall asleep more rapidly and sleep somewhat more soundly after 5 mg melatonin than after 0.5 mg. The team also reported that fast-acting rather than timed-release forms of melatonin are more effective for reentrainment purposes (Herxheimer 2001).
It is unclear whether alcohol or caffeine affects adaptation, and the answer may at least partially depend on what an individual is accustomed to. But, these beverages appear more likely to hinder than help adaptation. It is recommended, therefore, that alcohol and caffeine be used sparingly, at best, until full reentrainment is achieved (Herxheimer 2003).
An Alternate Strategy: Preentrainment
Preentrainment is another strategy to help avoid jet lag. Preentrainment is the technique of adjusting to a new time zone before departure. Researchers in Chicago conducted a study in 2003 using 28 healthy young participants who received one of three protocols, all designed to advance each subject's habitual sleep schedule by one hour per day, for three days, with or without the use of morning bright light. The goal was to arrive at the new destination with circadian rhythms already partially reentrained to local time, thus minimizing jet lag symptoms and facilitating full reentrainment after arrival (Burgess 2003).
On each of the three study days, participants were exposed to differing amounts of morning light for the first 3.5 hours after waking. Normal wake time was incrementally advanced one hour each day, simulating the wake time of eastward time zones. Phase shifting (reentrainment of the circadian cycle toward the destination goal) was measured by monitoring changes in melatonin content of saliva before and after each light session.
As expected, participants who received the greatest amount of bright light upon waking experienced the most dramatic phase shift, which equaled about two hours. Even intermittent bright light, which allows a subject enough time to conveniently perform morning chores (eg, showering), resulted in a phase shift of nearly two hours with minimal side effects and only a slight reduction in sleep duration (Burgess 2003).
The scientific team proposed that its three-day treatment may be especially helpful to eastward travelers, particularly those who travel across multiple time zones and arrive in the morning. They cited previous studies confirming the benefit of early morning bright light exposure, showing that appropriately timed bright light can increase the phase advance more than dim light (Boivin 1996; Honma 1995; Miyazaki 2001; Wyatt 1999; Burgess 2003).
In early 2005, the same research team conducted a follow-up study (Eastman 2005). The goal was again to phase shift participants before an anticipated long-haul eastward flight. As in the previous study, participants were subjected to bright light therapy upon waking for three days. In this study, however, participants were divided into two groups. One group was awakened two hours earlier than their usual wake time each day; the second group was awakened one hour earlier than usual each day. Both groups were exposed to intermittent bright light therapy for 3.5 hours each morning upon waking.
Participants' phase advances were measured by monitoring changes in saliva melatonin content. Participants who altered their wake time by two hours experienced a mean phase shift of 1.9 hours versus 1.4 hours for the group waking up one hour earlier. The advantage of advancing the wake schedule by two hours was not statistically significant compared with the one hour approach. In fact, participants in the two hour group eventually experienced misalignment between circadian rhythms and sleep schedules and had difficulty falling asleep. This did not occur among participants in the one hour group (Eastman 2005).
Researchers speculated that a schedule alternating 15 minutes bright light followed by 15 minutes dim light might work as well, or better than the study's 30 minutes bright/30 minutes dim protocol because it is the initial pulse of bright light that has the greatest effect on entrainment (Eastman 2005). Finally, the study's authors noted that the recent discovery that the human circadian system is most sensitive to short wavelength (blue) light of about 460 nanometers (nm) might mean that lamps of lesser intensity and with a greater concentration of this blue light may work as well, or better than a standard, commercially available bright light.
Preentrainment with Light and Melatonin
In late 2005, the same research team published the results of a study in which varying doses of supplemental melatonin, administered in the afternoon, were added to participants' bright light exposure upon waking (Revell 2005). Participants received four 30-minute sessions of exposure to bright light from a light box, alternated with 30 minutes of dim room light. This schedule was intended to allow participants the flexibility of completing morning chores conveniently. In the afternoon, participants received either 0.5 mg or 3.0 mg melatonin. Wake time was advanced by one hour each day for three days.
Results were similar to those reported in the 2003 study. Participants phase advanced by about 2.5 hours, with no appreciable jet lag symptoms. No statistically significant difference was found between participants receiving the smaller or larger doses of melatonin (Revell 2005). Thus, morning bright light exposure and an afternoon dose of melatonin of at least 0.5 mg, combined with an incremental advance in wake time of one hour per day for three days prior to travel, may be the most effective approach to preventing, or at least ameliorating jet lag before flying across more than five time zones.