Melatonin for Cognitive Impairment
Recruiting in Palo Alto (17 mi)
Overseen ByNatalie Denburg, Ph.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Nazan Aksan
Must not be taking: Antidepressants, Blood pressure, Anticoagulants, others
Disqualifiers: OSA, COPD, Psychiatric, Neurodegenerative, others
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.
12345Is 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.
14678How 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.
12349Eligibility 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.
+11 more
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)
Trial 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
Participant Groups
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.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: MCI- Melatonin 5mgExperimental Treatment1 Intervention
MCI- individuals receiving 5mg of melatonin-OTC for a period of 9 months
Group II: MCI+ Melatonin 5mgExperimental Treatment1 Intervention
MCI+ individuals receiving 5mg of melatonin-OTC for a period of 9 months
Group III: MCI+ placeboPlacebo Group1 Intervention
MCI+ individuals receiving placebo for a period of 9 months
Group IV: MCI- placeboPlacebo Group1 Intervention
MCI- individuals receiving placebo for a period of 9 months
Melatonin is already approved in European Union, 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Iowa Hospitals & ClinicsIowa City, IA
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Who Is Running the Clinical Trial?
Nazan AksanLead Sponsor
Natalie DenburgLead Sponsor
References
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]Endogenous melatonin levels are inversely associated with age and cognitive deficits. Although melatonin can improve psychopathological behavior disturbances in clinical trials, whether melatonin may also enhance cognitive function remains elusive. This study examined cognitive outcomes from randomized trials of melatonin treatment for Alzheimer's disease (AD), insomnia, and healthy-subjects. Twenty-two studies met the inclusion criteria (AD = 9, insomnia = 2, healthy-subjects = 11). AD patients receiving >12 weeks of melatonin treatment improved mini-mental state examination (MMSE) score [MD: 1.82 (1.01; 2.63) p
Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study. [2013]Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome characterized by cognitive impairment preceding dementia. Approximately 12% of MCI patients convert to Alzheimer's disease (AD) or other dementia disorders every year. In the present report we retrospectively examined the initial and final neuropsychological assessment of 50 MCI outpatients, 25 of whom had received daily 3-9 mg of a fast-release melatonin preparation p.o. at bedtime for 9-18 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin showed significantly better performance in Mini Mental State Examination and the cognitive subscale of the Alzheimer's Disease Assessment Scale. After application of a battery of neuropsychological tests including Mattis' test, Digit-symbol test, Trail A and B tasks and the Rey's verbal test, better performance was found in melatonin-treated patients, except for the Digit-symbol test score which remained unchanged. Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with an improvement in wakefulness and sleep quality. The results suggest that melatonin can be a useful add-on drug for treating MCI in a clinical setting.
Therapeutic application of melatonin in mild cognitive impairment. [2021]Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome defined by cognitive impairment in advance of dementia. We previously reported in a retrospective analysis that daily 3 - 9 mg of a fast-release melatonin preparation given p. o. at bedtime for up to 3 years significantly improved cognitive and emotional performance and daily sleep/wake cycle in MCI patients. In a follow up of that study we now report data from another series of 96 MCI outpatients, 61 of who had received daily 3 - 24 mg of a fast-release melatonin preparation p. o. at bedtime for 15 to 60 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin exhibited significantly better performance in Mini-Mental State Examination and the cognitive subscale of the Alzheimer's disease Assessment Scale. After application of a neuropsychological battery comprising a Mattis´ test, Digit-symbol test, Trail A and B tasks and the Rey´s verbal test, better performance was found in melatonin-treated patients for every parameter tested. Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with the improvement in the quality of sleep and wakefulness. The comparison of the medication profile in both groups of MCI patients indicated that 9.8% in the melatonin group received benzodiazepines vs. 62.8% in the non-melatonin group. The results further support that melatonin can be a useful add-on drug for treating MCI in a clinic environment.
Feasibility of 3-month melatonin supplementation for brain oxidative stress and sleep in mild cognitive impairment: protocol for a randomised, placebo-controlled study. [2021]Melatonin has multiple proposed therapeutic benefits including antioxidant properties, synchronisation of the circadian system and lowering of blood pressure. In this protocol, we outline a randomised controlled trial to assess the feasibility, acceptability and tolerability of higher dose (25 mg) melatonin to target brain oxidative stress and sleep disturbance in older adults with mild cognitive impairment (MCI).
Melatonin Receptor Agonists for Delirium Prevention. [2022]To review the prospective controlled trials available for the use of melatonin receptor agonists for delirium prevention.
Effect of daytime oral melatonin administration on neurobehavioral performance in humans. [2019]The pineal hormone melatonin has been proposed as a potential treatment for insomnia and circadian rhythm disorders, as experienced by shiftworkers and transmeridian travellers. If melatonin is to be used in a clinical setting, it is important that the neurobehavioral performance effects associated with its administration be identified. As with other drugs that increase sleepiness, e.g., sedatives and antihistamines, inappropriate effects on neurobehavioral performance could result in a corresponding increase in side effects and potential risk to users. The aim of this study was to investigate the effects of 5 mg oral melatonin, administered at 12.30 hr to 16 young (22.4 +/- 1.8 years), healthy subjects (ten males and six females), on the following neurobehavioral performance tasks: two-choice visual reaction and response time, unpredictable tracking, extended two-choice visual reaction and response time, and simple auditory response and reaction time, in a randomised, double-blind crossover protocol. Following melatonin administration, significant decrements in performance on the tracking task and on response and reaction time scores for the visual choice and extended two-choice visual tasks were observed. The profile of these performance decrements across the experimental sessions were found to closely map the profile of salivary melatonin levels. The findings of the present study highlight the significant neurobehavioral performance effects associated with the daytime administration of melatonin.
Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. [2019]The pineal hormone melatonin is potentially useful in the treatment of disorders, especially sleep disorders, associated with circadian rhythm disturbance. We have examined its effects on sleep, mood, and behaviour in a double-blind, placebo-controlled study of a small group of police officers working spans of seven successive night shifts. Compared to placebo, and to no treatment, melatonin (5 mg) taken at the desired bedtime improved problems related to sleep and increased alertness during working hours, especially during the early morning. In letter-target performance tests visual search speed and accuracy were either unchanged or slightly improved. Memory scanning speed and perception of mental load were adversely affected. This preliminary study suggests that melatonin has beneficial effects on sleep and alertness, but that its effects on performance need careful evaluation.
Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. [2019]While melatonin was once thought of simply as a sleep-inducing hormone, recent research has resulted in development of a deeper understanding of the complex physiological activity of melatonin in the human body. Along with this understanding has come widespread, increasing use of melatonin supplementation, extending beyond its traditional use as a sleep aid into novel fields of application. This increased use often involves off-label and self-prescription, escalating the importance of safety data. In order to examine the current knowledge relating to safety of the exogenous neurohormone, we conducted a comprehensive, critical systematic review of clinical evidence. We examined controlled studies of oral melatonin supplementation in humans when they presented any statistical analysis of adverse events. Of the fifty articles identified, twenty-six found no statistically significant adverse events, while twenty-four articles reported on at least one statistically significant adverse event. Adverse events were generally minor, short-lived and easily managed, with the most commonly reported adverse events relating to fatigue, mood, or psychomotor and neurocognitive performance. A few studies noted adverse events relating to endocrine (e.g. reproductive parameters, glucose metabolism) and cardiovascular (e.g. blood pressure, heart rate) function, which appear to be influenced by dosage, dose timing and potential interactions with antihypertensive drugs. Oral melatonin supplementation in humans has a generally favourable safety profile with some exceptions. Most adverse effects can likely be easily avoided or managed by dosing in accordance with natural circadian rhythms. Further research is required to explore the potential for melatonin to interact with endogenous hormones and pharmaceuticals.
The use of chronobiotics in the resynchronization of the sleep/wake cycle. Therapeutical application in the early phases of Alzheimer's disease. [2019]Treatment of circadian rhythm disorders, whether precipitated by intrinsic factors (e.g., sleep disorders, blindness, mental disorders, aging) or by extrinsic factors (e.g., shift work, jet-lag) has led to the development of a new type of agents called "chronobiotics". The term "chronobiotic" defines a substance displaying the therapeutic activity of shifting the phase or increasing the amplitude of the circadian rhythms. The prototype of this therapeutic group is melatonin, whose administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from circadian rhythm sleep disorders, like delayed sleep phase syndrome, jet lag or shift-work. Daily melatonin production decreases with age, and in several pathologies, attaining its lowest values in Alzheimer's disease (AD) patients. About half of dementia patients have severe disruptions in their sleep-wakefulness cycle. Melatonin replacement is effective to treat sundowning and other sleep wake disorders in fully developed AD, although controversial data on this point exist. Indeed, large interindividual differences between patients suffering from AD exist and can explain these erratic results. Theoretically the effect of melatonin could be more consistent at an earlier stage of the disease, i.e., mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. PubMed was searched using Entrez for articles including clinical trials. Search terms were "Alzheimer" "mild cognitive impairment" and "melatonin". Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. Five double blind, randomized placebo-controlled trials and 1 open-label retrospective study (N = 651) all agree in indicating that treatment with daily evening melatonin improves sleep quality and cognitive performance in MCI. The analysis of published evidence and patents indicates that melatonin can be a useful ad-on therapeutic tool in the early phases of AD.