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Melatonin

  • Vitamins & Supplements
  • Updated November 2, 2023

Melatonin is a hormone produced by the pineal gland that regulates sleep-wake cycles, also called circadian rhythms. As we age, our bodies make less melatonin, and melatonin production is particularly impaired in those with Alzheimer’s disease and other dementias. Melatonin is mainly used to treat sleep problems such as insomnia. Although numerous clinical trials have tested the effects of melatonin on cognitive function, the results have been mixed and inconsistent. Melatonin is generally safe in healthy adults, but experts do not recommend melatonin for elderly people with dementia due to risks of falls and other adverse events.

Evidence

Numerous meta-analyses have examined the short-term effects of melatonin on cognitive function, but results have been mixed and inconsistent. Our search identified: 

• 8 meta-analyses or systematic reviews of clinical trials testing melatonin treatment
• 2 reviews/guidelines on sleep impairment from the US Department of Health & Human Services and the American Academy of Sleep Medicine
• 1 meta-analysis of studies in animals
• Numerous preclinical studies on possible mechanisms of action

Potential Benefit

Clinical trials in humans have reported mixed findings with regards to the effects of melatonin on short-term cognitive functions. In one trial, melatonin improved verbal memory, with slight improvements in other cognitive tests [1]. Another trial showed that a single dose of melatonin enhanced memory functions while under stress, but not after stress [2]. However, in a third trial, melatonin cream did not result in significant effects on cognition [3]. The effects of melatonin on cognitive function may also depend on what time of the day it is administered. In a meta-analysis of 11 randomized controlled trials in healthy people, melatonin treatment during the daytime worsened performance on attention tasks [4]. In general, melatonin treatment is recommended at night, before bedtime. Thus, it is not unusual for melatonin treatment during the day to cause fatigue and sleepiness, contributing to reduced cognitive performance.

In models of Alzheimer’s disease, melatonin has been shown to ameliorate cognitive dysfunction and decrease biological markers of the disease [5], but no clinical research has confirmed these effects.

APOE4 Carriers:

No clinical studies have tested whether melatonin effects are different in APOE4 carriers. One preclinical study tentatively reported that melatonin could protect from possible toxicity from APOE4 [6] but the findings have not yet been replicated. For more information on what the APOE4 gene allele means for your health, read our APOE4 information page.

For Dementia Patients

Results have been mixed and inconsistent with regards to the effects of melatonin in dementia patients. A 2021 meta-analysis of randomized controlled trials in people with Alzheimer’s disease reported that melatonin treatment improved cognitive function in some people but not others and suggested that benefits may depend on the stage of disease and duration of treatment [4]. A high quality meta-analysis from 2020 reported that melatonin treatment may have little or no effect on sleep outcomes or cognition in people with Alzheimer’s disease and sleep disturbances [7]. A randomized controlled study suggested that the combined use of light therapy in the morning and melatonin in the evening may be a possible approach in addressing circadian dysregulation in Alzheimer’s patients [8; 9]. In the 2015 American Academy of Sleep Medicine Clinical Practice Guideline, recommendations were made against the use of melatonin and sleep-promoting medications for elderly people with dementia due to increased risks of falls and other adverse events [10]. Thus, the benefit to risk ratio of melatonin use needs to be carefully evaluated with healthcare providers, particularly in dementia patients.

Safety

Clinical evidence suggests that melatonin supplementation is generally safe for short-term use by most healthy people [11; 12; 13]. The American Academy of Sleep Medicine, however, recommends against the use of melatonin and sleep-promoting medications for demented elderly patients due to increased risks of falls and other adverse events [10]. Although many healthy people have used it for periods longer than two years, the risks or benefits from long-term use have not been well studied. 

Reports of serious adverse effects of melatonin supplementation are rare but include nausea, drowsiness, decreased blood-flow, and lower body temperature (hypothermia) [14]. Melatonin may also be unsafe in people with orthostatic hypotension, bleeding disorders, diabetes, depression, autoimmune diseases, seizure disorders, and transplant recipients [15]. In elderly patients with dementia, melatonin treatment has been shown to worsen caregiver ratings of patient mood [16]. Melatonin may also interfere with the action of other drugs. 

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

How to Use

Melatonin is available over-the-counter in the US as a liquid, pill, and transdermal patch. In the EU, UK, Australia, and Canada, melatonin is available with prescription [17]. As a sleep aid, melatonin is often taken orally in doses of 0.3 to 5.0 mg/day before bedtime. The most effective dose and length of treatment vary by individual. Treatment can range from a few days (for jet lag) to nine months (for trouble falling asleep) and should be overseen by a physician. 

Melatonin was once derived from bovine pineal glands, which carried the risk of viral contamination [18]. But melatonin supplements are now made synthetically and do not carry this risk. As with most supplements, melatonin quality can be uncertain. Several organizations offer independent testing of supplement quality to earn “seals-of-approval” [19]. 

Learn More

Full scientific report (PDF) on Cognitive Vitality Reports

Check for drug-drug and drug-supplement interactions on Drugs.com

References

  1. Peck JS, LeGoff DB, Ahmed I et al. (2004) Cognitive effects of exogenous melatonin administration in elderly persons: a pilot study. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 12, 432-436.
  2. Rimmele U, Spillmann M, Bartschi C et al. (2009) Melatonin improves memory acquisition under stress independent of stress hormone release. Psychopharmacology 202, 663-672.
  3. Scheuer C, Pommergaard HC, Rosenberg J et al. (2016) Effect of topical application of melatonin cream 12.5% on cognitive parameters: A randomized, placebo-controlled, double-blind crossover study in healthy volunteers. J Dermatolog Treat, 1-7.
  4. Sumsuzzman DM, Choi J, Jin Y et al. (2021) Neurocognitive effects of melatonin treatment in healthy adults and individuals with Alzheimer's disease and insomnia: A systematic review and meta-analysis of randomized controlled trials. Neuroscience and biobehavioral reviews 127, 459-473.
  5. Zhai Z, Xie D, Qin T et al. (2022) Effect and Mechanism of Exogenous Melatonin on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-analysis. Neuroscience 505, 91-110.http://www.ncbi.nlm.nih.gov/pubmed/36116555
  6. Poeggeler B, Miravalle L, Zagorski MG et al. (2001) Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide. Biochemistry 40, 14995-15001.
  7. McCleery J, Sharpley AL (2020) Pharmacotherapies for sleep disturbances in dementia. The Cochrane database of systematic reviews 11, CD009178.
  8. Dowling GA, Burr RL, Van Someren EJ et al. (2008) Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease. Journal of the American Geriatrics Society 56, 239-246.
  9. Steele TA, St Louis EK, Videnovic A et al. (2021) Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 18, 53-74.
  10. Auger RR, Burgess HJ, Emens JS et al. (2015) Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 11, 1199-1236.
  11. McCleery J, Cohen DA, Sharpley AL (2014) Pharmacotherapies for sleep disturbances in Alzheimer's disease. The Cochrane database of systematic reviews, Cd009178.
  12. Schutte-Rodin S, Broch L, Buysse D et al. (2008) Clinical guideline for the evaluation and management of chronic insomnia in adults. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 4, 487-504.
  13. Xu J, Wang LL, Dammer EB et al. (2015) Melatonin for sleep disorders and cognition in dementia: a meta-analysis of randomized controlled trials. American journal of Alzheimer's disease and other dementias 30, 439-447.http://www.ncbi.nlm.nih.gov/pubmed/25614508
  14. Buscemi N, Vandermeer B, Hooton N et al. (2006) Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ (Clinical research ed) 332, 385-393.
  15. Ray CA (2003) Melatonin attenuates the sympathetic nerve responses to orthostatic stress in humans. The Journal of physiology 551, 1043-1048.
  16. Riemersma-van der Lek RF, Swaab DF, Twisk J et al. (2008) Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 299, 2642-2655.
  17. Grigg-Damberger MM, Ianakieva D (2017) Poor Quality Control of Over-the-Counter Melatonin: What They Say Is Often Not What You Get. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 13, 163-165.
  18. Altun A, Ugur-Altun B (2007) Melatonin: therapeutic and clinical utilization. International journal of clinical practice 61, 835-845.
  19. (2023) Dietary Supplements: What You Need to Know (NIH Office of Dietary Supplements).