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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2015;15(Suppl 3):e6343 doi: 10.5867/medwave.2015.6343
Is melatonin useful for jet lag?
Francisco Tortorolo, Florencia Farren, Gabriel Rada
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Abstract

Jet lag syndrome is an exogenous circadian rhythm sleep disorder, frequently reported in travelers who cross multiple time zones in a short period of time. Oral melatonin -a pineal neurohormone normally produced during darkness and responsible for regulating the body's circadian rhythms- has been used as treatment for this condition. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified four systematic reviews including 11 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded the use of oral melatonin probably reduces symptoms associated with jet lag syndrome. It is not clear whether its use produces adverse effects; however, these would be probably mild.


 
Problem

Jet lag syndrome is an exogenous circadian rhythm sleep disorder, frequently reported in travelers who cross multiple time zones in a short period of time. It is characterized by symptoms such as sleep disturbances, daytime fatigue, irritability, anxiety, nausea, diarrhea and sweating. This condition is caused by a desyncronization between the traveler´s endogenous circadian rhythm and the day-night cycle at the final destination, which tends to wear off with time. The severity of jet lag syndrome depends on the number of time zones and direction travelled.

The exogenous administration of oral melatonin -a pineal neurohormone normally produced during darkness and responsible for regulating the body´s circadian rhythms- has been used as treatment for jet lag syndrome. This oral supplement is sold as an inexpensive over-the-counter drug, and considered relatively safe to use.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 databases, to identify systematic reviews and their included primary studies. With this information, we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • Melatonin probably reduces symptoms related to jet lag syndrome in travelers crossing more than five time zones.
  • It is not clear whether the use of melatonin is associated with adverse effects (nausea, tiredness, drowsiness and headaches), because the certainty of the evidence is very low. If these adverse effects were to exist, they would be probably mild in nature.
  • The risk-benefit and cost-benefit ratio would probably favour its use in the prevention and treatment of jet lag syndrome.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found four systematic reviews [1],[2],[3],[4] that included 11 randomized controlled trials reported in 16 references [5],[6],[7],[8],[9],[10],[11],[12],[13],[14], [15],[16],[17],[18],[19],[20].

What types of patients were included

All studies involved healthy adults.

One study [8] included members of the United States Air Force and a second one [13] involved airline staff. All other studies included different passengers who volunteered to participate.

Ten studies assessed the use of melatonin in eastward flights [5],[6],[8],[9],[10],[11],[12],[16],[19],[20], while four did so for westward flights [5],[11],[12],[13]

What types of interventions were included

All studies used melatonin. Ten studies used 5 mg [5],[6],[8],[10],[11],[12],[13],[16],[19],[20]. One administered 10 mg [9]. Three studies assessed slow-release melatonin; one study 300 mg [8], one study used 0.5 mg followed by 2 mg [20] and one study 0.5 mg [16].

Similarly, while two studies administered melatonin before the flight [6],[12], six did so upon arrival [9],[10],[11],[16] ,[19],[20] and three did so both before and after flying [5],[8],[13].

All studies administered melatonin before the desired time of sleep onset at the final destination.

In one study both groups received zolpidem in addition to melatonin [19].

All studies compared melatonin against placebo.

What types of outcomes
were measured

The systematic reviews included the following outcomes:

  • General jet lag symptoms for eastward and westward flights.
  • Number of participants with more than 60% of jet lag symptoms in eastward flights.

Additionally, some reviews reported two other outcomes related to exogenous circadian rhythm sleep disorders in general and not only jet lag [2]:

  • Sleep latency
  • Sleep quality

Only one review conducted a meta-analysis of the following adverse effects [2]: headaches, drowsiness, tiredness, and nausea. These adverse effects were also compared to the use of melatonin studies in non-jet lag cases. All other reviews reported adverse effects without providing a pooled effect measure

Summary of findings

The information on the use of melatonin is based on 11 randomized studies. Ten studies reported global jet lag symptoms [5],[6],[9],[10],[11],[12],[13],[16],[19],[20]. However, only four studies provided data in a way that could be added to a meta-analysis [5],[6],[9],[11]. Generally, all studies reported side effects, but only three did so systematically [10],[19],[20]

  • Melatonin probably reduces the global symptoms associated to jet lag syndrome in travellers crossing more than five time zones. The certainty of the evidence is moderate.
  • It is not clear whether the use of oral melatonin is associated to adverse effects (nausea, tiredness, drowsiness and headaches) because the certainty of the evidence is very low. However, no serious adverse effects were reported in any of the participants across the studies.

Other considerations for decision-making

To whom this evidence does and does not apply

  • This evidence applies to healthy adults who travel across more than five time zones.
About the outcomes included in this summary
  • The outcomes included in this summary are those considered by the authors to be critical in the decision-making process regarding the use of melatonin in the prevention and treatment of jet lag.
Balance between benefits and risks, and certainty of the evidence
  • The studies did not report serious adverse effects, or any consistently different effects to those patients using placebo. Considering the fact melatonin is probably a safe intervention the benefits of its use probably outweigh the risks.
  • This does not apply to more serious adverse effects observed with the association of melatonin to hypnotics, other central nervous system stimulants, in the presence of other comorbidities, or when using any medication with a possible interaction with melatonin (e.g. anticonvulsants or warfarin).
What would patients and their doctors think about this intervention
  • Most patients would be probably inclined in favour of the use of melatonin. In patients with a higher risk of adverse effects it may be necessary to individually assess the treatment decision.
  • Some patients will consider jet lag symptoms too mild to treat. It is especially important to discuss the benefits and risks of the intervention in these cases. 
Resource considerations
  • This is a low-cost, time-limited intervention; in this way, it may be favourable regarding costs and benefits.
  • In addition, if melatonin contributes to reducing the symptoms caused by jet lag, it is possible that it may also reduce the use of other symptom-relief medication, thus reducing the total costs. 

Differences between this summary and other sources

  • The conclusions presented in this summary agree with most of the identified systematic reviews.
  • Only one of the systematic reviews [4] argues the use of melatonin in secondary sleep disorders (including jet lag) is not effective. This review assessed the latency and quality of sleep, REM sleep time and wakefukness after sleep onset; however, it does not evaluate global jet lag symptoms, and groups jet lag syndrome as part of the secondary sleep disorder spectrum. Additionally, it does not include all of the studies included in this summary.
  • The conclusions in this summary are consistent with the recommendations of the American Academy of Sleep Disorder [21], which state the administration of melatonin at the right time is indicated in the prevention and treatment of jet lag symptoms in travellers crossing multiple time zones. It also mentions that no serious adverse effects have been reported yet. 
Could this evidence change in the future?
  • The probability of future evidence changing the conclusions of this summary is low due to the certainty of the evidence.
  • There are three ongoing or unpublished studies [22],[23],[24], which evaluate the use of melatonin in jet lag specifically [23],[24], or in transitory sleep disorders that include jet lag syndrome [22]. All of these studies could provide valuable information.
  • It seems relevant to compare the use of melatonin with hypnotics or other interventions other than placebo.

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Melatonin for jet lag

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

El jet lag es un trastorno exógeno del sueño y el ritmo circadiano que ocurre frecuentemente en viajeros que cruzan múltiples zonas horarias en un tiempo reducido. La administración de melatonina oral, neurohormona epifisiaria relacionada con la regulación de ritmos circadianos, se ha utilizado con el fin de disminuir los síntomas que caracterizan esta condición. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, encontramos cuatro revisiones sistemáticas que en conjunto incluyen 11 estudios aleatorizados. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que la administración de melatonina oral probablemente disminuye los síntomas asociados al jet lag, y que no está claro si se asocia a efectos adversos, aunque estos serían leves.

Authors: Francisco Tortorolo[1,2], Florencia Farren[2,3], Gabriel Rada[1,3,4,5,6]

Affiliation:
[1] Departamento de Medicina Interna, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Red de Salud UC-Christus, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[3] Proyecto Epistemonikos, Santiago, Chile
[4] Programa de Salud Basada en Evidencia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[5] GRADE working group
[6] The Cochrane Collaboration

E-mail: radagabriel@epistemonikos.org

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citation: Tortorolo F, Farren F, Rada G. Is melatonin useful for jet lag?. Medwave 2015;15(Suppl 3):e6343 doi: 10.5867/medwave.2015.6343

Publication date: 21/12/2015

PubMed record

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  1. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520. | PubMed |
  2. Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, et al. Melatonin for treatment of sleep disorders. Evid Rep Technol Assess (Summ). 2004 Nov;(108):1-7. | PubMed |
  3. Costello RB, Lentino CV, Boyd CC, O'Connell ML, Crawford CC, et al. The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature. Nutr J. 2014 Nov 7;13:106. | CrossRef | PubMed |
  4. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ. 2006 Feb 18;332(7538):385-93. | PubMed |
  5. Arendt J, Aldhous M. Further evaluation of the treatment of jet-lag by melatonin: a double-blind crossover study. Annual Review of Chronopharmacology. 1988 1988;5:53-5. | Link |
  6. Arendt J, Aldhous M, English J, Marks V, Arendt JH, Marks M, et al. Some effects of jet-lag and their alleviation by melatonin. Ergonomics. 1987;30(9):1379-93. | CrossRef |
  7. Arendt J, Aldhous M, Marks V. Alleviation of jet lag by melatonin: preliminary results of controlled double blind trial. Br Med J (Clin Res Ed). 1986 May 3;292(6529):1170. | PubMed |
  8. Beaumont M, Batéjat D, Piérard C, Van Beers P, Denis JB, Coste O, et al. Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. J Appl Physiol (1985). 2004 Jan;96(1):50-8. | PubMed |
  9. Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: confirmatory result using a simplified protocol. Biol Psychiatry. 1992 Oct 15;32(8):705-11. | PubMed |
  10. Edwards BJ, Atkinson G, Waterhouse J, Reilly T, Godfrey R, Budgett R. Use of melatonin in recovery from jet-lag following an eastward flight across 10 time-zones. Ergonomics. 2000 Oct;43(10):1501-13. | PubMed |
  11. Nickelsen T, Lang A, Bergau L. The effect of 6-, 9-and 11-hour time shifts on circadian rhythms: adaptation of sleep parameters and hormonal patterns following the intake of melatonin or placebo; 1991 | Link |
  12. Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. BMJ. 1989 Mar 18;298 (6675):705-7. | PubMed |
  13. Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry. 1993 Apr 1;33(7):526-30. | PubMed |
  14. Skene DJ, Aldhous M, Arendt J. Melatonin, jet-lag and the sleep-wake cycle. Sleep. 1989 1989;88:39-41. | Link |
  15. Spitzer RL, Terman M, Malt U, Forbes S, Terman JS, Williams JBW, et al. Failure of melatonin to affect jet lag in a randomised double blind trial. Society for Light Treatment and Biological Rhythms: SLTBR Abstracts; 1997. | Link |
  16. Spitzer RL, Terman M, Williams JB, Terman JS, Malt UF, Singer F, Lewy AJ. Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial. Am J Psychiatry. 1999 Sep;156(9):1392-6. | PubMed |
  17. Suhner A, Schlagenhauf P, Hoefer I, Johnson R, Tschopp A, Steffen R. Efficacy and tolerability of melatonin and zolpidem for the alleviation of jet-lag. En: Suhner A. Melatonin and jet-lag. Dissertation ETH No. 12823. Zurich, Switzerland: Swiss Federal Institute of Technology; 1988:85-103.
  18. Suhner A, Schlagenhauf P, Hoefer I, Johnson R, Tschopp A, Steffen R. Efficacy and tolerability of melatonin and zolpidem for the alleviation of jet-lag. 6th Conference of the International Society of Travel Medicine, Montreal, Canada; 1999.
  19. Suhner A, Schlagenhauf P, Höfer I, Johnson R, Tschopp A, Steffen R. Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med. 2001 Jul;72(7):638-46. | PubMed |
  20. Suhner A, Schlagenhauf P, Johnson R, Tschopp A, Steffen R. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag.Chronobiol Int. 1998 Nov;15(6):655-66. | PubMed |
  21. Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, Boehlecke B, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007 Nov;30(11):1445-59. | PubMed |
  22. Brigham, Women's H. Melatonin Treatment for Induced Transient Insomnia. 2009 September 2009. Clinicaltrials.gov [on line]. | Link |
  23. Development EKSNIoCHaH. Effects of Hydrocortisone, Melatonin, and Placebo on Jet Lag; 2004. Clinicaltrials.gov [on line]. | Link |
  24. Non-Light NHLABIEoCLa. Treatments for Jet Lag and Sleep Disorders; 2006. Clinicaltrials.gov [on line]. | Link |
Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520. | PubMed |

Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, et al. Melatonin for treatment of sleep disorders. Evid Rep Technol Assess (Summ). 2004 Nov;(108):1-7. | PubMed |

Costello RB, Lentino CV, Boyd CC, O'Connell ML, Crawford CC, et al. The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature. Nutr J. 2014 Nov 7;13:106. | CrossRef | PubMed |

Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ. 2006 Feb 18;332(7538):385-93. | PubMed |

Arendt J, Aldhous M. Further evaluation of the treatment of jet-lag by melatonin: a double-blind crossover study. Annual Review of Chronopharmacology. 1988 1988;5:53-5. | Link |

Arendt J, Aldhous M, English J, Marks V, Arendt JH, Marks M, et al. Some effects of jet-lag and their alleviation by melatonin. Ergonomics. 1987;30(9):1379-93. | CrossRef |

Arendt J, Aldhous M, Marks V. Alleviation of jet lag by melatonin: preliminary results of controlled double blind trial. Br Med J (Clin Res Ed). 1986 May 3;292(6529):1170. | PubMed |

Beaumont M, Batéjat D, Piérard C, Van Beers P, Denis JB, Coste O, et al. Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. J Appl Physiol (1985). 2004 Jan;96(1):50-8. | PubMed |

Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: confirmatory result using a simplified protocol. Biol Psychiatry. 1992 Oct 15;32(8):705-11. | PubMed |

Edwards BJ, Atkinson G, Waterhouse J, Reilly T, Godfrey R, Budgett R. Use of melatonin in recovery from jet-lag following an eastward flight across 10 time-zones. Ergonomics. 2000 Oct;43(10):1501-13. | PubMed |

Nickelsen T, Lang A, Bergau L. The effect of 6-, 9-and 11-hour time shifts on circadian rhythms: adaptation of sleep parameters and hormonal patterns following the intake of melatonin or placebo; 1991 | Link |

Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. BMJ. 1989 Mar 18;298 (6675):705-7. | PubMed |

Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry. 1993 Apr 1;33(7):526-30. | PubMed |

Skene DJ, Aldhous M, Arendt J. Melatonin, jet-lag and the sleep-wake cycle. Sleep. 1989 1989;88:39-41. | Link |

Spitzer RL, Terman M, Malt U, Forbes S, Terman JS, Williams JBW, et al. Failure of melatonin to affect jet lag in a randomised double blind trial. Society for Light Treatment and Biological Rhythms: SLTBR Abstracts; 1997. | Link |

Spitzer RL, Terman M, Williams JB, Terman JS, Malt UF, Singer F, Lewy AJ. Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial. Am J Psychiatry. 1999 Sep;156(9):1392-6. | PubMed |

Suhner A, Schlagenhauf P, Hoefer I, Johnson R, Tschopp A, Steffen R. Efficacy and tolerability of melatonin and zolpidem for the alleviation of jet-lag. En: Suhner A. Melatonin and jet-lag. Dissertation ETH No. 12823. Zurich, Switzerland: Swiss Federal Institute of Technology; 1988:85-103.

Suhner A, Schlagenhauf P, Hoefer I, Johnson R, Tschopp A, Steffen R. Efficacy and tolerability of melatonin and zolpidem for the alleviation of jet-lag. 6th Conference of the International Society of Travel Medicine, Montreal, Canada; 1999.

Suhner A, Schlagenhauf P, Höfer I, Johnson R, Tschopp A, Steffen R. Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med. 2001 Jul;72(7):638-46. | PubMed |

Suhner A, Schlagenhauf P, Johnson R, Tschopp A, Steffen R. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag.Chronobiol Int. 1998 Nov;15(6):655-66. | PubMed |

Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, Boehlecke B, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007 Nov;30(11):1445-59. | PubMed |

Brigham, Women's H. Melatonin Treatment for Induced Transient Insomnia. 2009 September 2009. Clinicaltrials.gov [on line]. | Link |

Development EKSNIoCHaH. Effects of Hydrocortisone, Melatonin, and Placebo on Jet Lag; 2004. Clinicaltrials.gov [on line]. | Link |

Non-Light NHLABIEoCLa. Treatments for Jet Lag and Sleep Disorders; 2006. Clinicaltrials.gov [on line]. | Link |

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