Melatonin for Cognitive Impairment

Overseen By Natalie Denburg, Ph.D

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Nazan Aksan

Must not be taking: Antidepressants, Blood pressure, Anticoagulants, others

Disqualifiers: OSA, COPD, Psychiatric, Neurodegenerative, others

Compensation: Varies

Number of Visits: 5

Duration: 36 weeks

230 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether taking 5mg of melatonin daily for nine months can improve brain health in individuals with mild cognitive issues, such as forgetfulness, often early signs of Alzheimer's. Researchers are studying two groups: one with mild cognitive impairment and one without. Participants will receive either melatonin or a placebo (a pill resembling melatonin but without active ingredients) to compare results. Ideal participants have noticeable memory problems but no serious mental or neurological illnesses and are willing to stop using other sleep aids. As an unphased trial, this study allows participants to contribute to groundbreaking research on melatonin's potential benefits for brain health.

Will I have to stop taking my current medications?

You will need to stop using any prescription or non-prescription sleep aids for the duration of the study, except for the study-issued medications. If you are taking certain medications like Fluvoxamine, Nifedipine, anti-coagulants, anti-seizure drugs, muscle relaxants, or narcotic pain relievers, you will not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that melatonin, especially in low to moderate doses like the 5 mg used in this study, is generally safe. In one study with nearly 2,000 participants, researchers found no serious side effects linked to melatonin. Another study found that doses between 3 to 24 mg per day were well-tolerated by individuals with mild memory problems.

Additionally, long-term use of melatonin at doses around 5-6 mg has proven safe. This finding reassures those considering joining the trial, as the dosage aligns with those shown to be safe in past research.

Overall, people have used melatonin without major issues, making it a promising option for further study in brain health. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using melatonin for cognitive impairment because it presents a natural alternative to traditional treatments like acetylcholinesterase inhibitors. Unlike these standard drugs, melatonin is a hormone that helps regulate sleep-wake cycles, potentially offering cognitive benefits with fewer side effects. Additionally, since melatonin is available over-the-counter and has a well-established safety profile, it could offer a more accessible and less costly option for individuals experiencing cognitive issues. This approach provides a fresh angle by targeting the sleep-related aspects of cognitive impairment, which are often overlooked in conventional treatments.

What evidence suggests that melatonin might be an effective treatment for cognitive impairment?

Research shows that melatonin might improve brain function. Studies have found that taking 3-9 mg of melatonin daily can enhance thinking and emotional well-being over time. In this trial, some participants will receive 5 mg of melatonin daily to evaluate its effects on cognitive impairment. Long-term melatonin use has been linked to better brain health. It may also help with sleep problems, indirectly benefiting the brain. While most research focuses on Alzheimer's and sleep issues, these findings suggest possible benefits for people with mild memory or thinking problems. ^{1 2 3 5 6}

Who Is on the Research Team?

Natalie Denburg, Ph.D.

Principal Investigator

University of Iowa

Are You a Good Fit for This Trial?

This trial is for adults aged 56-85 with mild cognitive impairment or healthy aging, who score at least 18 on the MoCA test and have a CDR Sum of boxes <1. Participants must not use sleep aids other than study medications, be willing to undergo two lumbar punctures, and bring a study partner to visits. Exclusions include certain medical conditions like obstructive sleep apnea without CPAP, major psychiatric diseases, neurodegenerative diseases, recent hospitalizations or chemotherapy.

Inclusion Criteria

All participants must score 18 or above on Montreal Cognitive Assessment (MoCA)

I am willing to have two spinal taps during the study.

I can stop using any sleep aids not provided by the study.

Exclusion Criteria

I am not taking specific medications like Fluvoxamine, Nifedipine, blood thinners, anti-seizure drugs, muscle relaxants, or narcotic pain relievers.

Individuals with any of the following conditions/diseases will be excluded: Obstructive sleep apnea (OSA) without CPAP use, chronic obstructive pulmonary disease, emphysema, major psychiatric disease (bipolar, schizophrenia), history of alcohol/drug abuse, neurodegenerative disease diagnosis (e.g. Parkinson's, Lewy body, ALS, MS), prior history of stroke or traumatic brain injury, have undergone chemotherapy in the past 2 years, have been hospitalized for injury/surgery in the past three-months

CDR>=1, clinically significant depression/anxiety (GDS>=9; GAI>=9)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline

Participants complete a baseline visit with tests to measure motor, affective, and cognitive function

1 visit

1 visit (in-person)

Wash-out

Participants wear actigraphy watches for 8 weeks to monitor sleep and circadian rhythm

8 weeks

1 visit (in-person) at the end of 8 weeks

Treatment

Participants receive study medication (5mg melatonin or placebo) and continue monitoring with actigraphy watches

36 weeks

3 visits (in-person) at weeks 16, 30, and 44; phone calls at weeks 9 and 30

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Melatonin
• Placebo

Trial Overview The trial tests if taking 5mg of melatonin daily for nine months can improve Alzheimer's disease biomarkers and cognitive function in people with mild cognitive impairment (MCI+) compared to those without (MCI-). It involves measuring AD biomarkers from spinal fluid and assessing cognition through neuropsychological tests.

How Is the Trial Designed?

Group I: MCI- Melatonin 5mg Experimental Treatment 1 Intervention

MCI- individuals receiving 5mg of melatonin-OTC for a period of 9 months

Group II: MCI+ Melatonin 5mg Experimental Treatment 1 Intervention

MCI+ individuals receiving 5mg of melatonin-OTC for a period of 9 months

Group III: MCI+ placebo Placebo Group 1 Intervention

MCI+ individuals receiving placebo for a period of 9 months

Group IV: MCI- placebo Placebo Group 1 Intervention

MCI- individuals receiving placebo for a period of 9 months

Melatonin is already approved in European Union, United States for the following indications:

Approved in European Union as Circadin for:

• Insomnia in adults aged 55 and over
• Sleep disorders in children with autism spectrum disorder

Approved in European Union as Slenyto for:

• Insomnia in children and adolescents aged 2-18 with autism spectrum disorder

Approved in United States as Melatonin for:

• Sleep disorders in children with autism spectrum disorder
• Insomnia in adults

Who Is Running the Clinical Trial?

Nazan Aksan

Lead Sponsor

Trials

1

Recruited

230+

Natalie Denburg

Lead Sponsor

Trials

1

Recruited

230+

Published Research Related to This Trial

This study will assess the feasibility and acceptability of using a higher dose (25 mg) of melatonin in 40 older adults with mild cognitive impairment (MCI) over 12 weeks, focusing on its potential to reduce brain oxidative stress and improve sleep disturbances.

The trial is designed as a randomized, double-blind, placebo-controlled study, which will provide valuable insights into the effects of melatonin on cognitive function and may inform future research aimed at preventing dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of 3-month melatonin supplementation for brain oxidative stress and sleep in mild cognitive impairment: protocol for a randomised, placebo-controlled study. Menczel Schrire, Z., Phillips, CL., Duffy, SL., et al.[2021]

A review of six clinical trials on melatonin receptor agonists for preventing delirium showed mixed results, with some trials indicating a reduction in delirium incidence by 12% to 30%, while the largest trial found no benefit.

Due to the conflicting evidence and limited safety evaluations, the routine use of melatonin receptor agonists for delirium prevention is not currently recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin Receptor Agonists for Delirium Prevention. Walker, CK., Gales, MA.[2022]

A systematic review of 50 studies on oral melatonin supplementation found that 26 studies reported no significant adverse events, indicating a generally favorable safety profile for melatonin, especially when used according to natural circadian rhythms.

While most adverse events were minor and manageable, some studies noted potential impacts on endocrine and cardiovascular functions, suggesting that dosage and timing are important factors to consider in melatonin use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Foley, HM., Steel, AE.[2019]

In a study involving 16 healthy young adults, taking 5 mg of melatonin during the day significantly impaired neurobehavioral performance, particularly in tasks requiring tracking and reaction times.

The performance decrements observed closely correlated with the levels of melatonin in saliva, indicating that melatonin can negatively affect cognitive functions when taken at inappropriate times, such as during the day.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of daytime oral melatonin administration on neurobehavioral performance in humans. Rogers, NL., Phan, O., Kennaway, DJ., et al.[2019]

In a double-blind, placebo-controlled study with police officers working night shifts, melatonin (5 mg) significantly improved sleep quality and increased alertness during working hours, particularly in the early morning.

While melatonin showed benefits for sleep and alertness, it had mixed effects on cognitive performance, with some tests showing unchanged or slightly improved results, but others indicating a negative impact on memory scanning speed and mental load perception.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Folkard, S., Arendt, J., Clark, M.[2019]

In a study of 96 outpatients with mild cognitive impairment (MCI), those treated with melatonin (3-24 mg) for 15 to 60 months showed significant improvements in cognitive performance, as measured by various tests including the Mini-Mental State Examination.

Melatonin treatment also led to reduced depression scores and improved sleep quality, suggesting it can be an effective add-on therapy for MCI patients, especially as it reduced the need for benzodiazepines compared to those not receiving melatonin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic application of melatonin in mild cognitive impairment. Cardinali, DP., Vigo, DE., Olivar, N., et al.[2021]

Melatonin treatment for over 12 weeks significantly improved cognitive function in Alzheimer's disease patients, particularly in the mild stage, as indicated by an increase in mini-mental state examination (MMSE) scores.

In healthy subjects, while daytime melatonin treatment decreased accuracy in responses, it did not negatively impact memory function, suggesting that melatonin may be a safer alternative to traditional sleep medications for managing insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Sumsuzzman, DM., Choi, J., Jin, Y., et al.[2022]

In a study of 50 MCI outpatients, those who received melatonin (3-9 mg daily for 9-18 months) showed significant improvements in cognitive performance compared to those who did not, as measured by various neuropsychological tests.

Melatonin treatment also led to reduced depression scores and improved sleep quality, suggesting it may be a beneficial add-on therapy for managing mild cognitive impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study. Furio, AM., Brusco, LI., Cardinali, DP.[2013]

Melatonin, a chronobiotic agent, has been shown to improve sleep quality and cognitive performance in patients with mild cognitive impairment (MCI), based on a review of six clinical studies involving 651 participants.

The findings suggest that melatonin could be an effective adjunct therapy in the early stages of Alzheimer's disease, potentially addressing sleep-wake cycle disruptions commonly seen in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of chronobiotics in the resynchronization of the sleep/wake cycle. Therapeutical application in the early phases of Alzheimer's disease. Cardinali, DP., Furio, AM., Brusco, LI.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3560473/

Therapeutic application of melatonin in mild cognitive ... Daily 3 - 9 mg of a fast-release melatonin preparation given po at bedtime for up to 3 years significantly improved cognitive and emotional performance and ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0149763421001974

Neurocognitive effects of melatonin treatment in healthy ... This study examined cognitive outcomes from randomized trials of melatonin treatment for Alzheimer's disease (AD), insomnia, and healthy-subjects.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10053496/

Chronic Administration of Melatonin - PubMed Central - NIH Melatonin seems to be effective in ameliorating sleep disturbances ... Long-term melatonin use is associated with positive cognitive outcomes ...

4. nature.com nature.com/articles/s41380-024-02691-6

Melatonin: A potential nighttime guardian against Alzheimer's Melatonin alleviates cognition impairment by antagonizing brain insulin resistance in aged rats fed a high-fat diet. J Pineal Res. 2019;67 ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03954899

NCT03954899 | Disease Modifying Potential of 5mg ... The study will examine whether 5mg melatonin (over the counter, OTC) over a 9-month period improves Alzheimer's disease (AD) biomarkers and cognitive function.

6. ema.europa.eu ema.europa.eu/en/documents/rmp/slenyto-epar-risk-management-plan_en.pdf

Slenyto, INN-melatonin - European Medicines Agency Neurim-pooled clinical safety data containing nearly 2000 patients on the reference product Circadin does not contain any cases of retinal ...