Melatonin Dietary Supplements: Useful for Jet Lag, Not for Other Conditions

Melatonin is a hormone naturally produced by the pineal gland, a pea-sized structure in the brain. It is released during the hours of darkness, with peak concentrations in the blood occurring between 2 a.m. and 4 a.m. Melatonin helps regulate the sleep-wake cycle.[1] Exposure to light decreases natural melatonin release, which can disrupt the sleep-wake cycle.

Melatonin is widely available as an over-the-counter dietary supplement in the U.S., but in some other countries it is available only as a prescription medication. It is promoted for treatment of sleep disorders, including jet lag and sleep-wake disturbances related to shift work, as well as seasonal affective disorder and dementia, among other things. Available evidence from well-designed clinical trials supports the use of melatonin for treating jet lag, but not other conditions.

Assessment of proposed uses

Jet lag

Jet lag is a common disorder in airline travelers crossing multiple time zones, resulting in the body’s sleep-wake cycle not being in sync with the day-night cycle of the destination.[2] It is more severe the more time zones that are crossed during a flight and when travelling in an eastward direction. After flying through six or more time zones, most people need four to six days to reestablish a normal sleep-wake cycle.

Symptoms of jet lag include daytime fatigue and sleepiness, decreased mental acuity, sleep disturbance, weakness and irritability.

The authors of a systematic review published in 2002 in the Cochrane Database of Systematic Reviews (Cochrane) analyzed data from 10 randomized clinical trials that compared use of melatonin with use of a placebo for treatment of jet lag.[3] Eight of the 10 trials demonstrated that melatonin taken at bedtime (between 10 p.m. and midnight) at the destination significantly reduced jet lag symptoms from flights crossing five or more time zones. Melatonin doses from 0.5 to 5 milligrams (mg) were similarly effective, except that the 5-mg dose resulted in falling asleep faster and sleeping better than the 0.5-mg dose.

The 2002 Cochrane review’s authors concluded that “melatonin is remarkably effective in preventing or reducing jet lag, and occasional short-term use appears to be safe.” They emphasized that the benefit of melatonin is likely to be greater the more time zones that are crossed and for eastward travel.[4] Although noting that adverse effects were uncommon, the authors also cautioned that taking melatonin early in the day, rather than at nighttime, will worsen the symptoms of jet lag and delay resolution of the condition.

Shift-work–related sleep disturbances

Employment that requires working shifts outside a typical daylight period (such as 8 a.m. to 5 p.m.) — especially for individuals whose work shift schedules alternate between nighttime shifts and daytime shifts — disrupts the sleep-wake cycle, resulting in sleepiness at work, reduced sleep length and compromised sleep quality.[5] Sleepiness at work can lead to occupational accidents and injuries, and disrupted sleep-wake cycles can contribute to chronic health problems, including a probable increased risk of cancer.[6]

The authors of a 2014 Cochrane systematic review assessed data from nine randomized, placebo-controlled trials that evaluated the use of melatonin for improving shift-work–related sleep problems.[7] They found that there was only low-quality evidence that melatonin increases sleep length slightly and no evidence that it improved other sleep parameters. Thus, there is insufficient evidence to recommend use of melatonin for shift-work–related sleep disturbances.

Seasonal affective disorder

Seasonal affective disorder is characterized by recurring episodes of major depression typically during the autumn or winter when daylight periods are shorter, with improvement or resolution during the spring or summer when daylight periods are longer.[8] During the periods of depression, patients often experience atypical symptoms, such as excessive daytime sleepiness, craving for carbohydrates with increased appetite, weight gain and extreme fatigue.[9]

Because seasonal affective disorder appears to involve sleep-wake cycle disruption, melatonin and other related substances have been used to prevent the disorder. The authors of a 2019 Cochrane systematic review searched the medical literature for any randomized, placebo-controlled clinical trials that evaluated the use of melatonin for the prevention of seasonal affective disorder.[10] They found no such trials. Thus, there is insufficient evidence to support such use of melatonin.

Dementia

Nighttime melatonin production decreases as people get older, and this decline is more pronounced in patients with dementia.[11] Therefore, it has been hypothesized that decreased melatonin production may play a role in age-related cognitive decline and dementia.

The authors of a 2006 Cochrane systematic review analyzed data from five randomized, placebo-controlled clinical trials that examined the use of melatonin for treatment of dementia.[12] Three of the trials assessed the cognitive effects of melatonin and showed no significant difference in the progression of cognitive impairment between subjects receiving melatonin and those receiving a placebo.

Two of the five trials evaluated the effects of melatonin on mood (such as depression, anxiety and apathy) and disruptive behaviors (such as hallucinations, delusions, agitation and irritability) and found significant improvements on some behavioral measures but not on several others.[13] Because the trials were small, they fail to provide sufficient evidence of benefit. Importantly, one of the trials showed a significant worsening of mood after one year of melatonin use compared with use of a placebo.[14]

Finally, a separate 2016 Cochrane systematic review analyzed data from two randomized, placebo-controlled clinical trials that tested the use of melatonin for sleep disturbances in dementia patients and found no evidence that it was effective.[15]

Epilepsy

Despite the availability of a wide range of drugs for treating seizures, 30% of epilepsy patients continue to have seizures. There have been reports suggesting that melatonin may be useful for treating seizures.

The authors of a 2016 Cochrane systematic review evaluated data from six randomized, placebo-controlled clinical trials that assessed adding melatonin to prescription seizure medications in epilepsy patients.[16] They found that the trials were small (enrolling a combined total of 125 subjects) and poorly designed. As a result, the authors were unable to draw any conclusions about the use of melatonin for epilepsy. Thus, there is insufficient evidence to support the use of melatonin for seizures.

Protection of the fetal brain

Injury to the fetal brain, often due to inadequate delivery of oxygen to the fetus, is a common cause of death and health problems in infants and children born prematurely. In animal studies, melatonin, which is an antioxidant, has been shown to protect the fetal brain from damage due to insufficient oxygen delivery.[17] A 2016 Cochrane systematic review found no randomized clinical trials that evaluated the use of melatonin in pregnant women for the prevention of fetal brain injury. Thus, there is insufficient evidence to support such use of melatonin.

Adverse effects

Short-term use of melatonin at typically recommended dosages is generally considered safe. Melatonin is a prescription drug in France, so there is more robust monitoring for adverse reactions related to melatonin use in France. More than 200 adverse reactions associated with melatonin use were reported to French drug regulators from 1985 to 2016.[18] Reported adverse events included fainting, drowsiness, headache, seizures, anxiety, depression, rashes, vomiting, constipation and acute pancreatitis.[19]

There have been reports of heart rhythm disorders and palpitations associated with use of melatonin.[20]

Three cases of melatonin-associated hallucinations have been reported in New Zealand.[21]

Melatonin can have clinically important adverse interactions with the following prescription medications:

• Concomitant use of the antidepressant fluvoxamine (LUVOX) with melatonin can increase blood levels of melatonin by more than 20-fold, which may cause central nervous system depression and markedly increased drowsiness.
• Concomitant use of the anticoagulant (blood thinner) warfarin (COUMADIN, JANTOVEN) with melatonin can increase blood warfarin levels and increase the risk of bleeding complications. Patients using warfarin should avoid melatonin.

What You Can Do

To treat jet lag after an airline flight crossing several time zones, you should consider taking a melatonin supplement on a short-term basis before going to bed between 10 p.m. and midnight after you arrive at your destination.

We recommend against using melatonin for any other disorders and conditions because of the lack of good-quality clinical trials supporting such uses and the risk of adverse effects. Without any documented benefit for any of these other uses, avoiding such risks is a healthy choice.

References

[1] Melatonin for jet lag. Drug and Therapeutics Bulletin. 2020;58:21-240.

[2] Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;2:CD00152.

[3] Ibid.

[4] Ibid.

[5] Liira J, Verbeek JH, Costa G, et al. Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. Cochrane Database Syst Rev. 2014;8:CD009776.

[6] Straif K, Baan R, Grosse Y, et al. Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 2007;8(12):1065-1066.

[7] Liira J, Verbeek JH, Costa G, et al. Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. Cochrane Database Syst Rev. 2014;8:CD009776.

[8] Nussbaumer-Streit B, Greenblatt A, Kaminski-Hartenthaler A, et al. Melatonin and agomelatine for preventing seasonal affective disorder. Cochrane Database Syst Rev. 2019;6:CD011271.

[9] Ibid.

[10] Ibid.

[11] Ferrari E, Arcaini A, Gornati R, et al. Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia. Exp Gerontol. 2000 Dec;35(9-10):1239-1250.

[12] Jansen SL, Forbes D, Duncan V, et al. Melatonin for the treatment of dementia. Cochrane Database Syst Rev. 2006;1:CD003802.

[13] Ibid.

[14] Ibid.

[15] McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev. 2016;11:CD009178.

[16] Brigo F, Igwe SC, Del Felice A. Melatonin as an add-on treatment for epilepsy. Cochrane Database Syst Rev. 2016;8:CD006967.

[17] Wilkinson D, Shepherd E, Wallace EM. Melatonin for women in pregnancy for neuroprotection of the fetus. Cochrane Database Syst Rev. 2016;3:CD010527.

[18] Melatonin: a review of adverse effects reported in France. Prescrire Int. 2019;28(202):72-73.

[19] Ibid.

[20] De Vries LJ, Geczy T, Szili-Torok T. Sleep medications containing melatonin can potentially induce ventricular arrhythmias in structurally normal hearts: A 2-patient report. J Cardiovasc Pharmacol 2017;70(4):267-270.

[21] Medsafe, New Zealand Medicines and Medical Devices Safety Authority. Early warning system - monitoring communication: Melatonin and the possible risk of hallucinations added to the medicines monitoring scheme. July 20, 2015. https://www.medsafe.govt.nz/safety/EWS/2015/melatonin-hallucinations.asp. Accessed April 16, 2020.

[22] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “melatonin.” Accessed April 16, 2020.