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

Trial Summary

What is the purpose of this trial?

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 in two groups of individuals: those with mild cognitive impairment (MCI+) and those who are not (MCI-). AD biomarkers will be measured from cerebrospinal fluid (CSF) obtained from lumbar punctures. Cognitive function will be evaluated with routine neuropsychological tests. AS OF AUGUST 2024, THE LUMBAR PUNCTURE PROCEDURES FOR THIS CLINICAL TRIAL HAVE BEEN ELIMINATED. THAT IS, PARTICIPANTS ARE NO LONGER RECEIVING A LUMBER PUNCTURE. BUT ARE CONTINUING TO RECEIVE TWO SEPARATE BLOOD DRAWS FOR BIOMARKER TESTING.

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.

What data supports the effectiveness of the drug melatonin for cognitive impairment?

Research suggests that melatonin can improve cognitive performance and emotional well-being in patients with mild cognitive impairment (MCI), as shown by better scores on cognitive tests and improved sleep quality. Studies also indicate that melatonin may help enhance cognitive function in Alzheimer's disease patients. ^{1 2 3 4 5}

Is melatonin generally safe for humans?

Melatonin is generally considered safe for humans, with most studies reporting only minor and short-lived side effects like fatigue and mood changes. Some studies noted effects on heart rate and blood pressure, which can be managed by proper dosing and timing. ^{1 4 6 7 8}

How does the drug melatonin differ from other treatments for cognitive impairment?

Melatonin is unique because it helps regulate the sleep-wake cycle, which can be disrupted in people with cognitive impairment, and it may improve sleep quality and cognitive performance. Unlike other treatments, melatonin is a natural hormone that decreases with age and can be used as an add-on therapy to enhance the effects of standard medications. ^{1 2 3 4 9}

Research Team

Natalie Denburg, Ph.D.

Principal Investigator

University of Iowa

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Therapeutic application of melatonin in mild cognitive impairment. [2021]

4. England 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. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Melatonin Receptor Agonists for Delirium Prevention. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Effect of daytime oral melatonin administration on neurobehavioral performance in humans. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. [2019]

8. Scotland pubmed.ncbi.nlm.nih.gov

Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. [2019]

9. United Arab Emirates 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. [2019]