Melatonin for Jet Lag
By Joshua Ofman, MD, MSHS, and Jay Udani, MD
Jet lag is a common problem for many air travelers. Currently there is no standard definition of this malady, but most studies include the symptoms of fatigue, difficulty concentrating, decreased daytime alertness, memory problems, weakness, lethargy, and daytime sleepiness after a long flight.1 For many people, jet lag is an inconvenience that can spoil a good vacation. For business travelers, airline crew, and athletes, however, the ill effects of jet lag can lead to poor decision making and decreased performance capabilities the next day, and the day after that.
Melatonin has been touted to cure jet lag, as well as easing insomnia, preventing cancer, and boosting the immune system. Melatonin has even made the cover of Newsweek magazine.2 Is there anything this wonder drug can't do?
History
Synthetic melatonin is sold in the United States as a "food supplement" because it is found in small amounts naturally in some foods (e.g., bananas and rice)3 and because supplements sold in the U.S. market before October 15, 1994, were exempted from federal drug laws and are considered as foods by the Dietary Supplement Health and Education Act of 1994.2 There are no natural extract versions of melatonin currently available. The U.S. retail market for melatonin is estimated at $200-350 million annually.3
Pharmacology
Melatonin has its maximum plasma concentration at 30-60 minutes after ingestion. There has been no LD50 level identified in animal studies.2 Oral melatonin has a short half-life, and doses as high as 50 mg are cleared within eight hours.3 After two weeks of daily melatonin intake, lipid storage does occur.3
Mechanism of Action
Melatonin is a hormone produced in the mammalian pineal gland and is vital to the regulation of circadian rhythms in vertebrates. The pineal gland converts tryptophan to serotonin, which is then converted to melatonin.4 This conversion is depressed when the retina is exposed to daytime sunlight, which is five times brighter than indoor light.3 Thus, daylight and melatonin provide alternating signals to the body to regulate circadian rhythms. Completely dark rooms give higher melatonin levels than ones with just a crack of light. It is postulated that melatonin acts on the suprachiasmatic nuclei of the hypothalamus, but the actual mechanism and exact target sites of melatonin are unknown.3,5 Melatonin has multiple known activities in humans, including a sedative-hypnotic effect and a phase shifting effect on circadian rhythms. Melatonin has also been shown to retrain temperature, hormonal, and electrolyte rhythms.5
Clinical Trials
There have been a number of clinical trials involving melatonin for jet lag over the past 10 years, subjected to two main critiques: 1) that the predominant outcomes measured are subjective criteria using a variety of visual analogue scales and questionnaires instead of measuring physiologic measures, such as melatonin levels to assess phase shifts; and 2) that none of the trials control for the phase shifting effects of light.6 In fact, light exerts a significantly more powerful effect on circadian phase shifting than melatonin3 and has been shown to be effective in reducing jet lag and decreasing the time to phase shift adaptation in night shift workers.7
Three randomized, placebo-controlled trials report the beneficial effects of melatonin on jet lag. The study subjects included healthy volunteers,8 experienced international travelers with a history of eastward travel jet lag,9 and cabin crew members with a mean of 8.9 years of flight experience who were involved in long-haul flights.10 Each trial used slightly different dosing regimens, but all found that melatonin produced statistically significant improvement in overall jet lag, number of days to establish a normal sleep pattern, recovery of alertness, daytime or morning tiredness, and time to achieve normal energy levels. Reported minor side effects included drowsiness, headaches, and depression.
The two largest studies of melatonin were not available in English language translations at the time of this publication; thus, detailed analysis of study methods is not possible. The largest study to date enrolled 320 people who received 5 mg fast-release melatonin, 5 mg slow-release melatonin, low-dose (0.5 mg) fast-release melatonin, or placebo after arrival for four days at bedtime. Only the 5 mg fast-release melatonin achieved significant improvements in sleep latency, sleep quality, daytime sleepiness, and fatigue.11 The other study included 249 subjects given melatonin 5 mg at bedtime, melatonin 0.5 mg at bedtime, melatonin 0.5 mg on a shifting schedule, or placebo. Subjects traveled westward from Oslo to New York and, after four days, returned to Oslo on the treatment leg of their journey. This study did not find any significant differences between the groups; however, only four days elapsed before returning, and it is unlikely that the subjects were completely acclimated to their new circadian rhythm before embarking on the eastward return trip.12
A review of five placebo-controlled field studies analyzed 586 subjects who were randomized to melatonin or placebo.5 No formal data synthesis was performed, but the data on the visual analogue scales comparing the symptoms of jet lag in placebo and melatonin groups were pooled. The author concluded that melatonin is effective, with an overall 50% reduction in the symptoms of self-reported jet lag (P < 0.0001), and that treatment is most effective when traversing more than eight time zones (P < 0.01).
Formulation/Dose
Synthetic melatonin is available as tablets and liquid. It is listed in the 1998 Physicians' Desk Reference. It is also available in dosages ranging from 0.1 mg to 10 mg.13 Melatonin is also available in regular and sustained-release formulae. The minimum dose required for the phase shifting effect is 0.5 mg. As with nearly all other supplements, there are no standards regarding purity. A recent study performing chemical analysis of six brands of melatonin purchased in health food stores found that four of the six contained "uncharacterizable impurities."4
There are some companies that claim "pharmaceutical grade" synthetic melatonin, but no evidence is available to substantiate these claims. Currently there is no standard or recommendation regarding which brand of synthetic melatonin is the purest. The dosages used in the clinical studies ranged from 0.5 mg to 8 mg per day. The amount of melatonin secreted by the pituitary is less than 0.1 mg per day. These supraphysiologic dosages appear safe for short-term usage, but long-term studies on safety has not yet been performed.1 The table shows a price comparison of melatonin and other drugs for jet lag.
Table
Price Comparison of Melatonin and Other Drugs for Jet Lag
| Melatonin | 60 1 mg tablets | $3-$4 |
| 60 3 mg tablets | $7-$9 | |
| 60 5 mg tablets | $11-$13 | |
| Restoril (temazepam) | 30 15 mg tablets | $21.53 |
| Ambien (zolpidem) | 10 10 mg tablets | $19.58 |
Note: Restoril and Ambien prices are average wholesale prices. Melatonin prices are based on survey of websites offering herbs and supplements for sale. Please see accompanying article for dosing details on melatonin.
Adverse Effects
The most common side effects of melatonin reported in large studies are daytime drowsiness and fatigue.5 In smaller studies and individual case reports, the following side effects have also been reported: morning grogginess, vivid dreams and nightmares,14 daytime sleepiness, fatigue, headache, nausea, confusion,15 psychosis,16 inhibition of fertility, suppression of male sexual drive, hypothermia, and retinal damage.3 These potentially dangerous complications cannot be commented upon further, as they are the result of single case reports. The National Nutritional Foods Association recommends that melatonin not be given to pregnant or nursing women or to patients with serious illness, autoimmune disorders, depression, or diabetes. It is also recommended that patients not drive after ingesting melatonin due to its sedating effects.13 Flumazenil and naloxone can blunt the effects of synthetic melatonin in animal studies, but other drug interactions are not known. Benzodiazepines, clonidine, dexamethasone, and beta adrenergic agents are all known to suppress the endogenous release of melatonin from the pituitary, but their effects on oral synthetic melatonin are unknown.4
Conclusion
The preponderance of evidence supports the use of melatonin for the short-term treatment of jet lag. Melatonin appears to reduce tiredness, increase alertness, and enhance the recovery to normal sleep patterns. Caution must be exercised, however, since melatonin is a recombinant human hormone, and the safety of long-term use has not been evaluated. Additionally, since its formulation and packaging are not regulated, supplements may contain impurities.
We recommend the use of melatonin for the treatment of jet lag using the following protocol: 0.3 mg synthetic melatonin tablets: For eastward travel, take pre-flight melatonin in the late afternoon of departure and take post-flight melatonin for four days after arrival at local bedtime. For westward flight, take melatonin at local bedtime for four days after arriving with a second smaller dose if there is early morning awakening.5 We recommend that melatonin not be taken by pregnant or nursing women, or by anyone with a serious medical illness including autoimmune disorders, depression, or diabetes. We also recommend not taking melatonin for more than one month at a time and not more than 0.5 mg per day, as long-term studies are not yet available.
References
1. Waterhouse J, et al. Jet-lag. Lancet 1997;350: 1611-1616.
2. Gowley G. Melatonin mania. Newsweek November 6, 1995.
3. Lamberg L. Melatonin potentially useful but safety, efficacy remain uncertain. JAMA 1996;276(13): 1011-1014.
4. Holliman B, et al. Problems in assessment of acute melatonin overdose. S Med J 1997;90(4):451-453.
5. Arendt J, et al. Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms 1997;12(6):604-617.
6. Anonymous. Is melatonin a treatment for insomnia and jet lag. Available 5/4/98 at: http://www.sleepfoundation.org/publications/melaton.htm.
7. Lamberg L. Studies of sleep in strange places may benefit people with common ills. JAMA 1996; 276(8):587-589.
8. Petrie K, et al. Effect of melatonin on jet lag after long haul flights. BMJ 1989;298:707-710.
9. Claustrat B, et al. Melatonin and jet lag: Confirmatory result using a simplified protocol. Biol Psychiatry 1992;32:705-711.
10. Petrie K, et al. A double-blind trial of melatonin as a treatment for Jet Lag I International Cabin Crew. Biol Psychiatry 1993;33:526-530.
11. Suhner A, et al. Optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1997;14:41.
12. Spitzer RL, et al. Failure of melatonin to affect jet lag in a randomized double blind trial. Soc Light Treatment Biol Rhythms Abstr 1997;9:1.
13. Anonymous. Statement by the National Nutritional Foods Association. Available 6/9/98 at http://www.melatonin.com.htm.
14. Grafius S, et al. Melatonin: A trusty travel companion? The Physician and Sportsmedicine. November 1996;24(11).
15. Anonymous. Mayo health Oasis. Available 5/4/98 at http://www.mayohealth.org/mayo/9411/htm/pills_qa.htm.
16. Force RW, et al. Psychotic episode after melatonin. Ann Pharmacother 1997;31:1408.
Dr. Udani is Chief Resident, Internal Medicine, Cedars-Sinai Medical Center, Los Angeles.
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