Melatonin

Last updated on September 26, 2023

Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug

Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-in-

development, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic

interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain

health, as well as for age-related health concerns that can affect brain health (e.g.,

cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports

include evaluation of safety data, from clinical trials if available, and from preclinical models.

Melatonin

Evidence Summary

Melatonin may improve sleep onset, blood pressure, lipid profile, metabolic profile, and antioxidant

defenses. It is not recommended for dementia patients due to risks of falls and other adverse events.

Neuroprotective Benefit: A meta-analysis reported melatonin improved cognitive function in

mild AD patients. But melatonin and other sleep medications increase risks of falls and other

adverse events and are not recommended for dementia patients.

Aging and related health concerns: Aside from its effect on sleep onset, melatonin treatment

has shown benefits in preventing delirium, reducing blood pressure, reducing cholesterol and

triglycerides, and improving metabolic and antioxidant biomarkers.

Safety: Melatonin is considered safe for most healthy adults but a few contraindications are

known and long-term use has not been extensively studied. The use of melatonin is not

recommended for elderly patients with dementia due to increased risks of falls.

Last updated on September 26, 2023

Availability: OTC in the US; Rx

in EU, UK, and other countries.

Dose: As a sleep-aid, melatonin is

often taken orally in doses of 1-5

mg per day before bed.

Chemical formula: C

MW: 232.2783

Source: PubChem

Common brand: Circadin®

(prolonged release form)

Half-life: ~45 minutes;

prolonged release forms have

elimination terminal half-life

of 3.5-4.0 hours

BBB: penetrant

Clinical trials: Meta-analyses

of randomized controlled trials

have examined the effects of

melatonin in thousands of

patients with various

conditions.

Observational studies: Small

studies have examined the

relationship between melatonin

levels and aging/dementia.

What is it?

In humans and other animals, melatonin is a hormone produced by the pineal gland located in the brain.

It acts in various ways throughout the body and regulates sleep-wake cycles, also known as circadian

rhythms. As we age, we produce less melatonin, which is thought to account for disrupted and

disordered sleep in older adults. Melatonin is commonly used to treat sleep disorders such as insomnia.

Melatonin treatment is also effective in alleviating symptoms of jet lag after travel across time zones

[Miyamoto et al., 2009].

In the US, melatonin is available as a dietary supplement. In Europe, a sustained-release form of

melatonin is licensed as a medicine for short-term treatment of primary insomnia in adults aged 55

years and older. Melatonin treatment has also been tested extensively in various conditions, including

metabolic diseases, liver conditions, surgery patients, cancer patients, prevention of delirium, and

others. Several melatonin receptor agonists have also been developed and are marketed for insomnia

and other conditions (described in the Sources & Dosing section).

Last updated on September 26, 2023

Neuroprotective Benefit: A meta-analysis reported melatonin improved cognitive function in mild AD

patients. But melatonin and other sleep medications increase risks of falls and other adverse events and

are not recommended for dementia patients.

Types of evidence:

• 8 meta-analyses or systematic reviews of clinical trials testing melatonin treatment

• 1 meta-analysis of animal studies

• Numerous observational studies examining melatonin levels/production

• 2 reviews/guidelines from the US Department of Health & Human Services and the American

Academy of Sleep Medicine

• Numerous preclinical studies on possible mechanisms of action.

Human research to suggest prevention of dementia, prevention of decline, or improved cognitive

function:

A 2021 meta-analyses of up to 11 randomized controlled trials in healthy people reported that

melatonin treatment (ranging from 0.1 mg to 80 mg daily) during the daytime did not slow reaction time

scores or reduce memory function, but significantly decreased accuracy on attention tasks (standardized

mean difference=-0.74; p<0.00001)[Sumsuzzman et al., 2021]. A subgroup analysis showed that

melatonin treatment at noon significantly reduced memory (p<0.00001), while melatonin treatment in

the afternoon did not. Subgroup analyses regarding reaction time demonstrated that a melatonin dose

of 5 mg did not affect reaction time, while doses of 10 mg or higher slowed reaction time (p<0.00001

and 0.0002, respectively). 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 a double-blind randomized controlled trial enrolling 26 healthy older adults, 1 mg of melatonin daily

for 4 weeks improved feelings of restedness and verbal fluency scores [Peck et al., 2004]. A single-blind

placebo-controlled trial of 50 healthy young men showed that a single oral dose of 3 mg melatonin

enhanced recognition memory of objects encoded under stress, but not of objects encoded in the

absence of stress [Rimmele et al., 2009]. In another randomized controlled trial of 10 healthy

volunteers, application of melatonin cream did not result in significant effects on cognitive parameters

[Scheuer et al., 2016].

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Human research to suggest benefits to patients with dementia:

Elderly people with Alzheimer’s disease typically exhibit sleep disturbance, including shorter sleep

duration, fragmented sleep, and a disrupted circadian rhythm. These disturbances in sleep and circadian

rhythm are associated with cognitive decline and memory impairment [Srinivasan et al., 2010]. People

with Alzheimer’s disease and other dementias often experience “sundowning”, which refers to

increased confusion occurring from dusk through the night, with symptoms including disorganized

thinking, reduced attention to external stimuli, agitation, and emotional disturbances. Several studies

have shown that melatonin levels in the cerebral spinal fluid are lower in Alzheimer’s patients compared

to age-matched control subjects, and an impairment in melatonin production at night correlates with

cognitive impairment [Liu et al., 1999; Magri et al., 1997].

Numerous meta-analyses and systematic reviews have evaluated whether melatonin treatment benefits

patients with dementia, with some positive findings, but overall the results are mixed and inconclusive.

A 2015 meta-analysis of 7 studies including 520 patients with dementia concluded that melatonin

therapy improved sleep efficacy and extended total sleep time. However, there was no evidence that

these improvements impacted cognitive function [Xu, 2015]. A smaller 2016 meta-analysis of patients

with Alzheimer’s and other dementias (including 176-279 patients, depending on the outcome measure

of interest) also concluded that melatonin did not improve cognitive scores (MMSE and ADAS-Cog) or

the majority of measures of sleep [Trotti and Karroum, 2016].

A more recent 2021 meta-analysis and systematic review of up to 9 randomized controlled trials in

people with Alzheimer’s disease reported that melatonin treatment (0.15 to 6 mg before bed) for over

12 weeks improved cognitive function, as measured by the Mini-Mental State Examination (MMSE;

mean difference=1.82, p<0.0001)[Sumsuzzman et al., 2021]. Melatonin treatment significantly improved

global cognition in people with mild Alzheimer’s disease (MMSE at or above 20; mean difference-1.89;

p<0.0001), but not in people with moderate Alzheimer’s disease (MMSE above 10, below 20; p=0.98).

When examining the duration of melatonin treatment, long-term treatment over 12 weeks significantly

improved global cognitive function (mean difference=1.82; p<0.0001), but short-term treatment failed

to improve cognitive function (p=0.33).

A 2020 Cochrane meta-analysis of 4 types of sleep medications for dementia patients reported that

there was low-certainty evidence that melatonin treatment (2-10 mg/night) may have little or no effect

Last updated on September 26, 2023

on sleep outcomes (total nocturnal sleep time and ratio of daytime to night-time sleep) over 8 to 10

weeks of treatment in people with Alzheimer’s disease and sleep disturbances [McCleery and Sharpley,

2020]. This meta-analysis included up to 5 randomized controlled trials that tested melatonin treatment

against placebo, with a total of 253 participants. Three studies reported cognitive outcomes and a meta-

analysis found that there may be little or no effect of melatonin on cognition assessed with change from

baseline in either MMSE (mean difference=0.09; 95% CI, –0.85 to 1.03) or ADAS-Cog (mean difference=-

1.03; 95% CI, -2.70 to 0.65). Based on the inconsistency across studies and the low sample size, the

evidence was deemed to be of low certainty. Three studies reported outcomes on activities of daily

living (e.g., ADCS-ADL), and the meta-analysis found moderate-certainty evidence that melatonin

probably has little or no effect on activities of daily living (standardized mean difference=-0.04; 95% CI, -

0.34 to 0.26).

A 2022 network meta-analysis of 50 randomized controlled trials in Alzheimer’s disease patients

(including a total of 19,704 patients) compared melatonin treatment against FDA-approved medications

for Alzheimer’s disease (donepezil, galantamine, rivastigmine, memantine, and Namzaric) [Tseng et al.,

2022]. This network meta-analysis found that medium-term (at least 6 months but <1 year) low-dose

melatonin treatment (less than or equal to 3 mg per night) is associated with the highest post-treatment

cognitive score, measured by MMSE (mean difference=1.48; 95% Cis, 0.51 to 2.46), among all

investigated medications. Medium-term high-dose donepezil was associated with the second highest

post-treatment MMSE score. Melatonin treatment was also associated with the highest post-treatment

quality of life compared to other treatments. However, the authors note that future large-scale, long-

term treatment studies are needed to focus on the efficacy of different dosages and treatment

durations of melatonin supplementation.

In 2015, the American Academy of Sleep Medicine recommended against the use of melatonin and

discrete sleep-promoting medications for elderly people with dementia due to increased risks of falls

and other adverse events [Auger et al., 2015]. However, disrupted or fragmented sleep can worsen the

pathology of dementia by impairing clearance of toxic proteins from the brain. A randomized controlled

study suggested that the combined use of light therapy in the morning and melatonin in the evening (5

mg) may be a possible approach in addressing circadian dysregulation in Alzheimer’s patients [Dowling

et al., 2008; Steele et al., 2021]. The benefit to risk ratio of melatonin use needs to be carefully

evaluated with healthcare providers, especially in dementia patients.

Last updated on September 26, 2023

Mechanisms of action for neuroprotection identified from laboratory and clinical research:

Results from multiple studies suggest that melatonin can reduce neurodegenerative processes and

improve cognitive function through various mechanisms.

Mouse models of Alzheimer’s disease: In a meta-analysis of 9 studies using mouse models of

Alzheimer’s disease, melatonin treatment ameliorated learning and memory (measured by the Morris

water maze) and reduced Aβ40 and Aβ42 deposition in the cortex [Zhai et al., 2022].

Neurogenesis: Neurogenesis is the growth and proliferation of new neurons in the hippocampus, an

area of the brain responsible for learning and memory. Neurogenesis decreases with age and is reduced

in disorders like depression and Alzheimer’s disease. In animal studies, melatonin supplementation

stimulated the creation of new neurons and promoted cell survival in the hippocampus of aged mice.

However, after 12 months of melatonin treatment, there was no effect in cell proliferation or survival,

indicating that melatonin may delay, but not stop the decline of neurogenesis [Ramirez-Rodriguez,

2012].

Mitochondria function: Mitochondria are organelles that are essential for generating energy in a cell. In

Alzheimer’s disease, mitochondrial dysfunction is an early event and triggers cell degradation and death.

In pre-clinical animal studies, it is suggested that melatonin helps in cell energy production by improving

signaling in the mitochondria [Acuna-Castroviejo, 2001; Dragicevic, 2012]. Melatonin is also an

antioxidant with the ability to scavenge “free radicals” and prevent DNA and protein damage. In animal

studies, melatonin treatment inhibited neuronal damage and counteracted neurodegenerative

conditions like oxidative stress [Feng, 2006].

Circadian rhythm and sleep: Circadian rhythms regulate human sleep-wake patterns through hormonal

release and other bodily functions. Disturbances in sleep-wake cycles have been associated with an

increased risk of dementia [Gehrman, 2005]. Melatonin is a hormone that is directly involved in the

regulation of circadian rhythm that has been shown to decrease with age. Animal studies suggest that

melatonin may significantly improve circadian rhythm dysfunction and sleep impairment. In small

clinical trials, some modest benefits of melatonin in sleep and circadian rhythm have been reported, but

overall, the evidence is limited [Auger et al., 2015].

APOE4 interactions: In a test tube experiment, melatonin treatment in the presence of ApoE4 resulted

in the inhibition of amyloid-β fibril formation, a component of Alzheimer’s pathology. In addition,

Last updated on September 26, 2023

melatonin prevented the neurotoxicity mediated by amyloid-β and ApoE4 [Poeggeler, 2001]. However,

no other studies have confirmed this initial finding and no clinical studies in humans have reported that

melatonin may have different effects in APOE4 carriers versus non-carriers.

Aging and related health concerns: Aside from its effect on sleep onset, melatonin treatment has

shown benefits in preventing delirium, reducing blood pressure, reducing cholesterol and triglycerides,

and improving metabolic and antioxidant biomarkers.

Types of evidence:

• 17 meta-analyses or systematic reviews of clinical trials testing melatonin treatment

• Several review articles

• Numerous preclinical studies

Longevity: UNKNOWN

Some evidence from test tube experiments suggests that melatonin may influence the activity of

telomerase, an enzyme responsible for regulating cellular aging [Leon-Blanco, 2003; Rastmanesh,

2011]. However, the impact of this influence on life span in humans still needs to be

researched. Researchers are also exploring whether melatonin and/or light entrainment of circadian

rhythm [Cajochen, 2003] can improve outcomes in critically ill patients [Madrid-Navarro, 2015] and

reduce the need for sedation [Mistraletti, 2015].

Insomnia: PROLONGED-RELEASE MELATONIN MAY IMPROVE SLEEP ONSET LATENCY

Sleep is critically important for long-term health [Hublin, 2007]. Consequences of insomnia can include

reduced productivity, higher health care costs, increased accident risk, and risks of diabetes, obesity,

hypertension, coronary heart disease, and depression [CDC.gov/sleep].

The first-generation drugs for insomnia were barbiturates, including pentobarbital and phenobarbital,

which have a high abuse potential and significant risks of overdose and respiratory suppression

[reviewed in Miyamoto et al., 2009]. The second-generation insomnia drugs were benzodiazepines, such

as lorazepam, triazolam, and estazolam. While benzodiazepines have a lower potential for abuse and

risk of overdose, they are associated with side effects including cognitive impairment, psychomotor

impairment, dependence, tolerance, rebound insomnia, and others. Third-generation drugs were

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benzodiazepine receptor agonists with non-benzodiazepine chemical structures: zolpidem, zopiclone,

zaleplon, and others. These benzodiazepine receptor agonists were aimed to induce sleep while

reducing the cognitive and motor side effects. However, these agonists still have abuse and dependence

potential. It is worth noting that sleep induced by benzodiazepines and benzodiazepine receptor

agonists is electrophysiologically distinct from naturally occurring sleep [Borbely et al., 1985; Brunner et

al., 1991]. For example, these drugs decrease REM sleep and increase stage 2 sleep. More recently,

direct administration of exogenous melatonin and/or melatonin receptor agonists has garnered interest

and attention.

In a 2023 meta-analysis of 22 randomized controlled trials (total of 4,875 participants) testing melatonin

or ramelteon (melatonin receptor agonist) in adults with insomnia disorder, treatment with prolonged

release melatonin showed efficacy with small to medium effect sizes on subjective sleep onset latency

(weighted difference= -6.30 min; p=0.031) and objective sleep onset latency (weighted difference=-5.05

min; p<0.001)[Maruani et al., 2023]. In a subgroup analysis, prolonged release melatonin was efficacious

in improving objective sleep efficiency in people at or over 55 years old (weighted difference=2.95%;

p<0.001). No significant effects of melatonin treatment (prolonged release or immediate release) were

found on subjective or objective total sleep time or on wakefulness after sleep onset compared to

placebo. Melatonin treatment was also not effective in reducing the number of awakenings or

improving sleep quality compared to placebo. Immediate release melatonin treatment did not

significantly reduce sleep onset latency compared with placebo when administered for 4 weeks or less.

Authors of this meta-analysis noted that a first-line therapy for insomnia is typically cognitive behavioral

treatment (CBT), which has shown larger effects than melatonin treatment. However, in cases where

CBT is not possible or only partially effective, benefits may be derived from the addition of prolonged

release melatonin.

In a 2022 network meta-analysis of 170 trials testing 30 interventions for insomnia disorder in a total of

44,089 adults, benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than

melatonin, ramelteon, and zaleplon with regards to acute treatment [De Crescenzo et al., 2022].

However, benzodiazepines are associated with poor tolerability, risk of cognitive impairment, delirium,

falls, and motor accidents, and therefore, are not ideal for long-term use [American Geriatrics Society

2015 Beers Criteria update]. Other benzodiazepine receptor agonists have also been associated with

emergency department visits. When considering all outcomes at different time points, lemborexant and

eszopiclone had the best profile in terms of efficacy, acceptability, and tolerability [De Crescenzo et al.,

2022]. Overall, melatonin and the melatonin receptor agonist, ramelteon, had poor efficacy compared

to other classes of insomnia medications. The authors of this meta-analysis emphasize the importance

Last updated on September 26, 2023

of considering non-pharmacological treatments for insomnia disorder, as they are supported by high-

quality evidence and recommended as first-line treatment by guidelines [Riemann et al., 2017].

In a 2017 Clinical Practice Guideline for the pharmacologic treatment of chronic insomnia in adults by

the American Academy of Sleep Medicine, melatonin is recommended against for the treatment of sleep

onset or sleep maintenance insomnia [Sateia et al., 2017]. For sleep onset insomnia, eszopiclone,

zaleplon, zolpidem, triazolam, and ramelteon are recommended. For sleep maintenance insomnia,

suvorexant, zolpidem, temazepam, and doxepin are recommended. However, all of these

recommendations are weak recommendations (based on the GRADE process) reflecting a lower degree

of certainty in the outcome and appropriateness of the patient-care strategy for all patients.

Delirium: MAY DECREASE DELIRIUM INCIDENCE AND DURATION BUT FINDINGS ARE MIXED

Delirium is characterized by disturbance in attention, awareness, and cognition. Delirium is a common

complication in hospitalized patients, especially in older patients, and it is associated with a longer

hospital stay, increased risk of functional and cognitive decline, increased dementia risk, and increased

mortality risk [Pereira et al., 2021; Inouye et al., 2023]. Other predisposing factors of delirium include

medical comorbidities (e.g., pre-existing cognitive impairment, atherosclerosis, etc.), medication use,

intraoperative factors (e.g., use of benzodiazepines, highly invasive surgery), postoperative factors (e.g.,

pain), and circadian rhythm disturbance [Barnes et al., 2023]. Sleep deprivation and delirium share

behavioral and biological similarities, including disturbances in the sleep-wake cycle and abnormal

melatonin secretion [Weinhouse et al., 2009; Yoshitaka et al., 2013]. Observational studies have

reported lower plasma melatonin levels in people with delirium compared to those without delirium

[Yoshitaka et al., 2013]. While the causes of delirium are not clearly defined and likely vary across

people, several potential causes are modulated by melatonin, including diurnal sleep disturbance,

melatonin dysregulation, neuroinflammation, oxidative stress, and neurotransmitter dysregulation

[Maldonado, 2013].

In a 2023 meta-analysis of 8 randomized controlled trials in ICU patients, melatonin treatment did not

significantly reduce delirium incidence (RR=0.76; 95% CI, 0.54 to 1.07; p=0.12), based on 6 randomized

controlled trials that included a total of 1,625 patients [Aiello et al., 2023]. However, a sensitivity

analysis that added 4 studies (2 retrospective studies and 2 randomized controlled trials) showed that

melatonin/ramelteon reduced delirium risk (RR=0.67; 95% CI, 0.48 to 0.92; p=0.01). Of secondary

outcomes, there was a trend towards a reduction in the duration of mechanical ventilation (mean

difference, -2.80; p=0.09), but no significant effects in the ICU length of stay (mean difference, -0.26;

Last updated on September 26, 2023

p=0.42) or mortality (RR=0.85; p=0.30). The GRADE of evidence suggests a very low certainty of evidence

due to the risk of bias in several studies (ranging from low to high risk). The trial sequential analysis

showed that the sample size required was far from sufficient, with only 1,625 patients enrolled in the

included randomized controlled trials versus the 13,699 patients needed. The authors concluded that

the results are not yet robust, and more studies are needed to validate these findings.

In a 2023 meta-analysis of 4 randomized controlled trials and 2 cohort studies including a total of 2,374

ICU patients, melatonin treatment (3-5 mg) did not reduce the incidence of delirium (OR=0.71; 95% CI,

0.46 to 1.12; p=0.14) [Duan et al., 2023]. However, subgroup analysis showed that melatonin treatment

reduced the incidence of delirium in the cardiovascular care unit (OR=0.52; 95% CI, 0.37 to 0.73;

p=0.0001), but not in the general ICU (OR=1.14; 95% CI, 0.86 to 1.50; p=0.35). There were no significant

melatonin treatment effects on all-cause mortality (OR=0.85; 95% CI, 0.66 to 1.09; p=0.20), length of ICU

stay (mean difference=0.33; p=0.45) or length of hospital stay (mean difference=0.51; p=0.55). The

authors speculate that the preferential benefit of melatonin in the cardiovascular care unit patients may

be related to improved vascular endothelial cell function, anti-vasospasmic effects, anti-apoptotic

effects, improved cerebral perfusion, and reduced microthrombosis.

In a 2023 systematic review and meta-analysis of 11 randomized controlled trials including a total of

1,244 surgery patients, melatonin (3-5 mg or 50 mg/kg per day) or ramelteon treatment (melatonin

agonist; 8 mg per day) resulted in a significantly lower odds of developing postoperative delirium

(OR=0.41; 95% CI, 0.21 to 0.80; p=0.01)[Barnes et al., 2023]. The incidence of delirium ranged from 0-

42% in the intervention groups and 4-92% in the control groups. Because of the lack of reported data,

meta-analyses could not be performed for secondary outcomes or complications. Caveats include the

heterogeneity of the published clinical trials, varied outcome measures across studies, and the highly

variable populations, dosing, and melatonin administration regimens.

In a 2023 meta-analysis of 3 randomized controlled trials and 6 observational studies in a total of 1,211

patients with delirium, melatonin treatment reduced the duration of delirium (-1.72 days, 95% CI, -2.66

to -0.77; p=0.0004) based on 2 randomized controlled trials [Beaucage-Charron et al., 2023]. Melatonin

treatment did not significantly improve hospital length of stay compared to antipsychotics. The authors

noted that the current data is limited for melatonin as the majority of included studies were at high risk

of bias due to limited availability of information regarding study methods. Ongoing studies will likely

provide better insight.

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Prior meta-analyses have found that dexmedetomidine, a selective α2-adrenergic receptor agonist, is

effective in reducing the incidence of delirium by about 50%. A 2020 review that explored different

preventive interventions for delirium noted that ramelteon and dexmedetomidine appear to have the

best supporting evidence thus far [Fontaine et al., 2020]. There is a lack of studies comparing

melatonergic agents with dexmedetomidine and other agents thought to prevent delirium.

Dexmedetomidine is associated with a high dropout rate and adverse events such as bradycardia and

hypotension. It is also worth noting that the route of administration for dexmedetomidine (continuous

intravenous infusion) precludes at-home use of dexmedetomidine.

Prevention and management of delirium involve many non-pharmacological interventions, such as

overnight eye masks, ear plugs, early mobilization, limiting the use of sedative drugs, and strategies to

improve the quality of sleep.

Hypertension: REDUCES BLOOD PRESSURE

Hypertension is a major cause of cardiovascular events and deaths, yet proper blood pressure control is

not achieved by many patients. In a 2022 meta-analysis of 4 randomized controlled trials in people with

hypertension or nocturnal hypertension, controlled release melatonin treatment for 3-4 weeks

significantly reduced nocturnal systolic blood pressure by 3.57 mmHg (95% CI, -7.88 to 0.73)[Lee et al.,

2022]. Melatonin treatment also lowered nocturnal and awake diastolic blood pressure, but these

changes were not statistically significant. Immediate release melatonin treatment had a lack of effect on

blood pressure measures, likely due to the short half-life of around 45 minutes. The overall certainty of

the evidence was low for all blood pressure outcomes because there were only a few included studies to

assess publication bias, and most randomized controlled trials had an unclear risk of bias or imprecision

in outcomes. Melatonin treatment may reduce blood pressure by vasodilation (via inhibition of calcium

channels and enhancement of nitric oxide and cGMP production in the endothelium), antioxidation, and

inhibition of the sympathetic nervous system (reduction of noradrenaline).

In a meta-analysis of 5 randomized controlled trials in people with metabolic impairment (metabolic

syndrome, diabetes, coronary heart disease, and NAFLD), melatonin treatment significantly reduced

systolic blood pressure (mean difference=-3.43 mmHg; 95% CI, -5.76 to -1.09; p=0.004) and diastolic

blood pressure (mean difference=-3.33 mmHg; 95% CI, -4.57 to -2.08; p<0.001) compared with control

treatment [Hadi et al., 2019]. Sensitivity analysis indicated that the results were robust and there was no

evidence regarding publication bias.

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Cardiovascular disease: MAY PROTECT AGAINST ISCHEMIC-REPURFUSION INJURY

Ischemic-reperfusion injury during coronary artery bypass graft (CABG) is associated with increased

oxidative stress, inflammation, and apoptosis, and it can lead to serious complications such as

arrhythmia and myocardial injury. Numerous studies have examined the efficacies of antioxidant

interventions before or during CABG surgery. In a 2023 meta-analysis of 6 randomized controlled trials

with a total of 342 CABG surgery patients, melatonin treatment (3-20 mg per day) led to a significant

reduction in a cardiac injury marker, cardiac troponin I (weighted mean difference [WMD]=-2.28 ng/ml;

95% CI, -2.87 to -1.69; p<0.01) and high sensitivity CRP levels (WMD=-0.62 mg/L; 95% CI, -0.73 to -0.5;

p<0.01)[Farshidianfar et al., 2023]. There was a non-significant decrease in creatine kinase isozyme

muscle/brain (CK-MB) levels (WMD=-2.87 ng/ml; 95% CI, -5.97 to 0.23; p=0.07) with melatonin

treatment. Melatonin treatment schedules varied from just 2 doses to over 1 month. Based on the

Egger’s test, no publication bias was found.

In a 2021 meta-analysis of 7 randomized controlled trials including a total of 426 patients who

underwent myocardial revascularization, melatonin treatment (orally or i.v. or i.c.) resulted in a higher

left ventricular ejection fraction (LVEF) than placebo treatment (WMD=3.1%; 95% CI, 0.6 to 5.5; p=0.01)

[Dominguez-Rodriguez et al., 2021]. Melatonin-treated patients also had lower levels of troponin

(standardized mean difference=-1.76; 95% CI, -2.85 to -0.67; p=0.002). Because only two randomized

controlled trials reported the myocardial infarct size, a meta-analysis could not be performed on this

measure.

Hyperlipidemia: MAY DECREASE LDL-CHOLESTEROL AND TRIGLYCERIDE LEVELS

Dyslipidemia plays an important role in the development of cardiovascular diseases by increasing

atherosclerosis and altering membrane integrity. Melatonin plays a role in the regulation of lipid

metabolism [Mohammadi-Sartang et al., 2018].

In a 2019 meta-analysis of 12 clinical trials including a total of 641 people with various conditions

(metabolic syndrome, obesity, menopause, chronic kidney disease, diabetes, NAFLD, etc.), melatonin

treatment (0.8 mg to 10 mg per day) for 4-56 weeks reduced LDL-cholesterol (SMD=-0.31 mmol/L, 95%

CI, -0.61 to 0.01; p=0.049) and triglyceride levels (SMD=-0.45 mmol/L; 95% CI, -0.77 to -0.13;

p=0.006)[Loloei et al., 2019]. In a subgroup analysis, melatonin treatment for more than 8 weeks

showed significant lowering of LDL-cholesterol (SMD=-0.48 mmol/L; 95% CI, -0.90 to -0.07; p=0.02), but

not in studies where melatonin treatment was less than 8 weeks. A significant effect of melatonin on

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LDL cholesterol was observed in a subset of trials administering melatonin at doses lower than 8 mg

(SMD-=-0.35 mmol/L; 95% CI, -0.70 to −0.01, p=0.05), but not in the subset of trials administering doses

higher than 8 mg (SMD=-0.25 mmol/L; 95% CI, -0.82 to 0.31, p=0.96). With regards to triglyceride levels,

melatonin treatment durations shorter than 8 weeks significantly decreased triglyceride levels (SMD=-

0.69 mmol/L; 95% CI, -1.08 to −0.29; p<0.001), but longer treatment had no significant effect (SMD=-

0.31 mmol/L; 95% CI, -0.75 to 0.12; p=0.16). A significant effect of melatonin on triglyceride levels was

observed at doses higher than 8 mg daily (SMD=-0.45; 95% CI, -0.89 to −0.01; p=0.049), but not when

doses lower than 8 mg were used (SMD=-0.46; 95% CI, -1.04 to 0.12; p=0.12). No effects of melatonin

treatment were seen on HDL cholesterol. Most of the included studies were of small size, and there was

a high heterogeneity likely due to the wide range of health conditions studied.

In a 2018 meta-analysis of 8 randomized controlled trials of people with various conditions (non-

alcoholic steatohepatitis, metabolic syndrome, schizophrenia, hypercholesterolemia), melatonin

treatment (0.3 to 10 mg daily) for 4-24 weeks significantly reduced triglyceride levels (WMD=-31.54

mg/dL; 95% CI, -50.71 to -12.38; p=0.001) and total cholesterol levels (WMD=-18.48 mg/dL; 95% CI, -

35.33 to -1.63; p=0.032)[Mohammadi-Sartang et al., 2018]. There were no significant effects of

melatonin treatment on LDL-cholesterol (WMD=-2.37 mg/dL; 95% CI, -11.61 to -6.86; p=0.615) or HDL-

cholesterol (WMD=1.28 mg/dL; 95% CI, -0.66 to 3.23; p=0.197). In subgroup analyses, melatonin

treatment significantly decreased triglyceride levels at doses ≥8 mg/day (WMD=−42.82 mg/dL; 95% CI,

−69.61 to −16.04; p=0.002) and when trials lasted ≥8 weeks (WMD=−32.25 mg/dL; 95% CI, -51.21 to

−13.28; p=0.001), but not with lower doses or shorter durations. In addition, a significant decrease of

total cholesterol was found with melatonin doses of ≥8 mg/day (WMD=−39.56 mg/dL; 95% CI, −54.13 to

−25.00; p<0.001) and when baseline total cholesterol levels were ≥200 mg/dL.

Cancer: MAY IMPROVE SURVIVAL AND CANCER THERAPY-RELATED SIDE EFFECTS

Melatonin has been investigated for cancer treatment and prevention. For example, the use of

melatonin as an addition to standard cancer treatments was reported in a meta-analysis to reduce the

risk of mortality by 40% (RR=0.60; 95% CI, 0.54 to 0.73) [Mills, 2005]. In a 2012 meta-analysis, melatonin

improved complete and partial remission and the one-year survival rate in patients with solid tumor

cancers, while concurrently alleviating radio/chemotherapy-related side effects [Wang et al., 2012].

In a 2022 meta-analysis of 19 randomized controlled trials including a total of 2,101 patients with

cancer, melatonin treatment (3-20 mg per night) did not significantly affect sleep quality, quality of life,

fatigue, pain, or severity of stomatitis (inflammation of oral mucosa)[Fan et al., 2022]. However,

Last updated on September 26, 2023

melatonin treatment significantly reduced stomatitis rate (RR=0.47; 95% CI, 0.26 to 0.88; p=0.02), except

in people with head and neck cancer (RR=1.09; 95% CI, 0.92 to 1.29; p=0.35). In studies where melatonin

treatment was administered for more than 14 days, melatonin treatment significantly eased depression

(standardized mean difference [SMD]=-0.14; 95% CI, -0.27 to -0.01; p=0.03). Further clinical trials are

needed to determine whether specific dosages or durations may offer benefit in specific types of cancer.

Type 2 diabetes and metabolic diseases: MAY IMPROVE METABOLIC INDICES

In a 2021 meta-analysis of 12 randomized controlled trials enrolling healthy adults and people with

metabolic diseases (diabetes, metabolic syndrome, NAFLD, osteopenia, polycystic ovary syndrome),

melatonin treatment (1-10 mg nightly) for 2-56 weeks significantly reduced fasting insulin levels, and

showed a trend towards reduced insulin resistance measured by HOMA-IR, but did not significantly alter

fasting glucose or hemoglobin A1c (HbA1c) levels compared with placebo [Lauritzen et al., 2021].

In another 2021 meta-analysis of 16 randomized controlled trials enrolling healthy people or those with

metabolic diseases (diabetes, metabolic syndrome, NAFLD, bipolar disorder, schizophrenia), melatonin

treatment (3-10 mg per day) for 4-24 weeks significantly reduced fasting blood glucose (mean

difference=-4.65; 95% CI, -8.06 to -1.23; p<0.01), but not HbA1c or insulin resistance [Delpino et al.,

2021].

In a 2019 meta-analysis of 12 clinical trials including a total of 641 people with various conditions

(metabolic syndrome, obesity, menopause, chronic kidney disease, diabetes, NAFLD, etc.), melatonin

treatment (0.8 mg to 10 mg per day) for 4-56 weeks did not significantly lower body weight, BMI, or

waist circumference [Loloei et al., 2019].

Paradoxically, melatonin may also increase blood sugar in certain situations, and therefore decrease the

effectiveness of medications to lower blood sugar in people with diabetes [WebMD]. Over 100 genetic

variants are associated with type 2 diabetes, including a common variant of the melatonin receptor 1B

gene (MTNR1B). In people with a specific variant (GG) of the MTNR1B gene, melatonin can inhibit insulin

secretion [Tuomi et al., 2016]. Thus, people with this GG variant can have lower insulin and higher

glucose levels in response to melatonin treatment.

Last updated on September 26, 2023

Liver disease: POTENTIAL BENEFIT

Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in hepatocytes, which can

progress to steatohepatitis, fibrosis, cirrhosis, and liver cancer. In a pilot clinical study of patients with

nonalcoholic steatohepatitis, melatonin treatment (5 mg twice daily, orally) for 3 months significantly

improved liver function [Gonciarz et al., 2010]. In a double-blind randomized controlled trial in 45

patients with NAFLD, melatonin treatment (6 mg daily) for 3 months improved liver enzymes (ALT and

AST), the grade of fatty liver, systolic and diastolic blood pressure, and the inflammation biomarker hs-

CRP [Bahrami et al., 2020]. Longer and larger clinical trials are needed to validate these findings.

Oxidative stress: INCREASED ANTIOXIDANT CAPACITY, DECREASED OXIDATIVE STRESS

High oxidative stress is associated with cardiovascular disease, diabetes, metabolic syndrome, and other

age-related conditions. Melatonin can reduce oxidative stress by scavenging free radicals and activating

antioxidant enzymes [Jomova et al., 2023]. In a 2020 meta-analysis of 15 randomized controlled trials in

people with various conditions (cystic fibrosis, obesity, cardiovascular disease, cancer, diabetes, multiple

sclerosis, polycystic ovary syndrome, methadone maintenance, transplant patients) as well as in healthy

people, melatonin treatment (3-100 mg/day) for 14-180 days significantly increased total antioxidant

capacity level (standardized mean difference[SMD]=1.03; 95% CI, 0.24 to 1.81; p=0.011) and reduced

oxidative stress markers including protein carbonyl (SMD=-1.78; 95% CI, -2.97 to -0.58; p=0.004) and

malondialdehyde levels (SMD=-0.94; 95% CI, -1.48 to -0.40; p=0.001) [Ghorbaninejad et al., 2020]. The

effects on total antioxidant capacity was greatest when melatonin doses at or over 20 mg/day were

used and in people under 35 years old. A significant increase in total antioxidant capacity was observed

in studies where the treatment duration was at or over 60 days (SMD=1.31; 95% CI, 0.10 to 2.51;

p=0.033), but not in those with study durations under 60 days. Malondialdehyde levels were also

decreased with melatonin doses below 20 mg/day in people over 35 years old. Subgroup analyses found

that melatonin treatment significantly reduced malondialdehyde in women (SMD=−1.94; 95% CI, −3.68

to −0.19; p=0.029) but not in men. However, the Egger test showed significant evidence of publication

bias for meta-analyses assessing the effect of melatonin on protein carbonyl and malondialdehyde

levels. No effects of melatonin treatment were seen on nitric oxide (modulator of endothelial function)

or antioxidant enzymes: glutathione reductase, superoxide dismutase, or glutathione peroxidase.

However, in studies using melatonin doses at or above 20 mg/day, there was a significant decrease in

nitric oxide levels (SMD=−3.16; 95% CI, −4.26 to −2.07; p<0.001).

Last updated on September 26, 2023

In another 2020 meta-analysis of 12 randomized controlled trials in people with various conditions (neck

cancer, diabetes, diabetic hemodialysis, Parkinson’s disease, obesity, polycystic ovary syndrome,

methadone maintenance, orthognathic patients, epileptic children), melatonin treatment (3-250 mg) for

2-12 weeks significantly increased total antioxidant capacity (SMD=0.76; 95% CI, 0.30 to 1.21),

glutathione levels (SMD=0.57; 95% CI, 0.32 to 0.83), and activities of superoxide dismutase (SMD=1.38;

95% CI, 0.13 to 2.62), glutathione peroxidase (SMD=1.36; 95% CI, 0.46 to 2.30), and glutathione

reductase (SMD=1.21; 95% CI, 0.65 to 1.77), while significantly decreasing malondialdehyde levels

(SMD=-0.79; 95% CI, -1.19 to -0.39) [Morvaridzadeh et al., 2020]. Melatonin treatment duration of at

least 10 weeks increased total antioxidant capacity more efficiently than in studies where melatonin

treatment lasted less than 10 weeks. A subgroup analysis by disease type showed that melatonin

treatment reduced malondialdehyde levels in people with metabolic diseases more than in non-

metabolic diseases. Melatonin treatment did not significantly affect nitric oxide or catalase activity.

Melatonin exerts anti-oxidative effects through direct scavenging of reactive oxygen species and

reactive nitrogen species, stimulation of antioxidative enzymes (glutathione reductase, glutathione

peroxidase), and upregulating the endogenous antioxidant, glutathione [reviewed in Leelaviwat et al.,

2022].

Safety: Melatonin is considered safe for most healthy adults but a few contraindications are known and

long-term use has not been extensively studied. The use of melatonin is not recommended for elderly

patients with dementia due to increased risks of falls.

Types of evidence:

• 9 meta-analyses or systematic reviews of clinical trials testing melatonin treatment

• Numerous reviews, guidelines, and observational studies

• Several preclinical studies

General safety:

Evidence reviews by the AHRQ (Agency for Healthcare Research and Quality), the American Academy of

Sleep Medicine and numerous clinical trials suggests that melatonin supplementation is safe for most

healthy people for short-term use (up to 2 years) [McCleery, 2014; Xu, 2015; Schutte-Rodin,

2008]. Although many healthy people have used it for periods longer than 2 years, the risks or benefits

Last updated on September 26, 2023

from long-term use have not been well-studied. Melatonin derived from animal pineal glands should be

avoided as it may be contaminated with viruses [Altun, 2007].

Reports of serious adverse effects of melatonin supplementation are rare. Common adverse effects

include nausea, drowsiness, dizziness, hypotension, nightmares, abdominal pain, and decreased blood-

flow leading to lower body temperature (hypothermia) [Buscemi, 2006; Leelaviwat et al.,

2022]. Melatonin is best taken before bed, to align with the circadian rhythm. Melatonin may worsen

symptoms of “orthostatic hypotension”, a blood-pressure condition common in older adults [Ray, 2003].

Melatonin may also be unsafe in people with the following conditions: bleeding disorders, diabetes,

depression, autoimmune diseases, seizure disorders, and transplant recipients [WebMD].

People with dementia:

The American Academy of Sleep Medicine recommends against the use of melatonin and discrete sleep-

promoting medications for elderly patients with dementia due to increased risks of falls and other

adverse events [Auger et al., 2015]. In elderly patients with dementia, melatonin treatment has also

been shown to worsen caregiver ratings of patient mood [Riemersma-van der Lek et al., 2008].

A 2022 network meta-analysis of 50 randomized controlled trials in Alzheimer’s disease patients

(including a total of 19,704 patients) compared melatonin treatment against FDA-approved medications

for Alzheimer’s disease (donepezil, galantamine, rivastigmine, memantine, and Namzaric) and found

that melatonin treatment was associated with a similar drop-out rate and adverse events as compared

with placebo [Tseng et al., 2022].

In a 2020 Cochrane meta-analysis of 9 randomized controlled trials testing pharmacotherapies for sleep

disturbances in Alzheimer’s dementia, 5 trials tested melatonin treatment (2-10 mg per night) and there

was low-certainty evidence that melatonin and placebo groups did not differ in the number of adverse

events per person, in the severity of adverse events, or the likelihood of reporting any adverse event

[McCleery and Sharpley, 2020].

People with or at risk of delirium:

In a 2023 meta-analysis of clinical trials and observational studies examining delirium treatments,

melatonin treatment did not cause adverse events such as falls, nausea, rash, neurologic deterioration,

Last updated on September 26, 2023

or oversedation [Beaucage-Charron et al., 2023]. In one of the included studies, one participant

receiving melatonin had increased alanine aminotransferase (ALT) levels but recovered 15 days later.

Drug interactions:

Melatonin may reduce the effects of nifedipine and increase the effects of sedatives (clonazepam,

lorazepam, phenobarbital, zolpidem) and warfarin [Drugs.com, WebMD]. Caffeine and fluvoxamine may

increase the effects of melatonin. On the other hand, melatonin may alleviate the sleep disruption

caused by drugs like beta-blockers and benzodiazepines that alter melatonin production [Wright, 2015;

Stoschitzky, 1999; Scheer, 2012].

Sources and Dosing:

Melatonin is found in small concentrations in foods, such as meats, grains, fruits and vegetables. Since

melatonin regulates sleep cycles in humans it is most commonly marketed as a sleep aid dietary

supplement. It is available over-the-counter in the US as a liquid, tablet, pill, and transdermal patch. In

the EU, UK, Australia, and Canada, melatonin is available with prescription [Grigg-Damberger and

Ianakieva, 2017]. In the UK and Australia, melatonin is approved for the short-term treatment (<13

weeks) of primary insomnia in people over the age of 55 years old. In the UK, melatonin is also

prescribed for treatment of some sleep disorders in children with neurological disorders (2-10 mg

doses).

Melatonin was once derived from bovine pineal glands, which carried the risk of it being contaminated

with viruses [Altun, 2007]. Currently, melatonin supplements are made synthetically so they do not carry

the risk of being contaminated with infectious material. However, over-the-counter melatonin is not

regulated by the FDA, so several organizations offer independent testing of supplement quality to earn

“seals-of-approval.” Quality testing and important facts about supplements are offered by the NIH

Office of Dietary Supplements .

As a sleep-aid, melatonin is often taken orally in doses of 1-5 mg per day before bed. The most effective

dose will vary from person to person and should only be taken as advised by a physician.

Supraphysiological serum levels are expected with melatonin doses over 0.5 mg [Lee et al., 2022].

Length of treatment is also variable depending on the condition it is used to treat, but can range from a

few days (for jet lag) to 9 months (for trouble falling asleep) [WebMD].

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Bioavailability of melatonin can vary depending on whether it is ingested orally or sublingually. With oral

tablets, it is estimated that about 33% is absorbed through the gastrointestinal tract, though

bioavailability varies widely across people [Di et al., 1997]. Melatonin taken sublingually may have

higher bioavailability (50% or higher) and faster effects compared to oral tablets, though it is unlikely to

follow natural physiological trajectories of melatonin levels in the body. There have not been any studies

that directly compared the effectiveness of melatonin delivered orally versus sublingually.

Other formulations/drugs:

Circadin® and other prolonged-release forms of melatonin

Prolonged-release melatonin is designed to mimic the pharmacokinetics of endogenously produced

melatonin. Daily Circadin® (2 mg) consistently improved sleep quality, sleep latency (- 9 min), and next-

morning alertness in middle aged people with insomnia [Luthringer et al., 2009; Lemoine et al., 2012;

Hajak et al., 2015], middle-aged healthy people [Otmani et al., 2008], middle aged and elderly

insomniacs with hypertension [Lemoine et al., 2012], and in perimenopausal women with insomnia

[Dolev, 2011]. In mild to moderate AD patients taking AChE inhibitors and/or mementine, prolonged-

release melatonin (2 mg) improved cognitive performance (IADL and MMSE) in addition to sleep quality

[Wade et al., 2014]. Some of these clinical trials also showed improvement in quality of life with

Circadin® [Dolev, 2011; Lemoine et al., 2012]. Prolonged-release melatonin does not cause negative

effects on daytime psychomotor, driving, or memory performance [Otmani et al., 2008; Luthringer et al.,

2009] and is well-tolerated with no withdrawals or “rebound insomnia” upon discontinuation of the

drug [Lemoine et al., 2007, 2012; Luthringer et al., 2009; Wade et al., 2011, 2014]. Side effects with

Circadin® are not common but include irritability, nervousness, restlessness, and others. Circadin®

should not be taken if you have diabetes, depression, bleeding/clotting disorders, high/low blood

pressure, or epilepsy/seizure disorders. Drugs that may interact with melatonin include antibiotics,

aspirin/acetoaminophen, birth control pills, insulin (and other diabetes medicine), narcotics, antacids

(Prevacid, Prilosec, Zofran), ADHD medication, heart medicine (mexiletine, propranolol, verapamil),

anticoagulant/antiplatelet drugs (Plavix, warfarin), NSAIDs, and steroids (prednisone, etc.). Other safety

information can be found at drugs.com.

Piromelatine® (Neu-P11)

Piromelatine® is a melatonin receptor (MT1/2/3) and serotonin receptor (5HT-1A/D) agonist. Neurim

Pharmaceuticals Ltd has shown positive phase II RCT results for the treatment of primary and comorbid

insomnia [link]. Piromelatine® 20/50 mg treatment for 4 weeks resulted in significant and clinically

meaningful improvements in polysomnographic parameters (Wake After Sleep Onset; WASO), sleep

Last updated on September 26, 2023

efficiency, total sleep time, time in NREM sleep, as well as subjective sleep duration/quality.

Piromelatine® is generally safe and well-tolerated, with no negative effects on next-day psychomotor

performance. See full Piromelatine report for details and updates.

Ramelteon (Rozerem®)

Ramelteon, marketed as Rozerem® by Takeda Pharmaceuticals, is a synthetic drug that acts on

melatonin receptors (MT1/2) and is approved for insomnia related to difficulty of sleep onset. Meta-

analyses have shown that Ramelteon is associated with reduced sleep latency (-4.3 min), shorter latency

to persistent sleep (-9.36 min), improved sleep quality and efficiency, and longer total sleep time (+7.26

min) [Liu and Wang, 2012; Kuriyama et al., 2014]. However, no improvement in the percentage of REM

sleep has been observed. Subjective sleep latency is reduced with 4 and 8 mg doses, sleep quality is

increased with the 8 mg dose, and latency to persistent sleep is reduced in all doses studied (4, 8, 16, 32

mg). Side effects include diarrhea, dizziness, drowsiness, fatigue, and tiredness. The occurrence of

somnolence, but not other adverse events reported, was significantly higher in people taking Ramelteon

than placebo [Kuriyama et al., 2014]. Next-day residual effects were not significantly different between

Ramelteon and placebo groups [Liu and Wang, 2012]. Ramelteon should not be taken if you have severe

liver problems, sleep apnea, COPD, or mental or mood problems. Ramelteon interacts with azole

antifungals, donepezil, doxeparin, and fluvoxamine. Other safety information can be found here.

Ramelteon has also been shown to reduce the incidence of delirium. See full Ramelteon report for

details and updates.

Research underway:

There are over 100 clinical studies testing melatonin, based on ClinicalTrials.gov. Aside from studies of

sleep, melatonin is studied in various conditions, including acute/ischemic stroke, concussion, brain

injury, coronary artery bypass grafting surgery, hypertension, cardiovascular diseases, osteoarthritis,

postoperative delirium, autism spectrum disorder, schizophrenia, epilepsy, kidney injury prevention, and

others. One randomized controlled study is testing melatonin (5 mg) on cognition and brain health in

people with mild cognitive impairment (NCT03954899).

Last updated on September 26, 2023

Search terms:

PubMed, Google, Cinicaltrials.gov:

• Melatonin, Ramelteon, Rozerem, Piromelatine, MEL, MLT, Pineal, hormone, Circadin, prolonged-

release melatonin, PRM, amyloid, blood pressure, cancer, hypertension, dementia, Alzheimer’s,

aging, mortality, cognitive function, telomere, gait, lifespan, ApoE4, sleep deprivation, delirium, and

USP certified supplements.

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