Melatonin for Cardiovascular Response to Stress

Overseen By Jeremy M Kellawan, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Oklahoma

Must not be taking: Melatonin, Cardiometabolic, Sex hormones

Disqualifiers: Cardiovascular diseases, Diabetes, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2 visits

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether melatonin can alter how the heart and blood vessels respond to stress from cold and exercise. Participants will receive either melatonin or a placebo (a mint-flavored spray with no active ingredients) to compare effects. It suits healthy men and women who do not regularly use melatonin and have no history of heart issues or conditions like diabetes. Women should have a regular menstrual cycle and not use hormone replacement therapies. As a Phase 4 trial, melatonin is already FDA-approved and proven effective; this research aims to understand how it benefits more patients.

Will I have to stop taking my current medications?

If you are taking cardiometabolic medications (like blood pressure or cholesterol meds) or sex hormone replacements, you will need to stop taking them to join this trial.

What is the safety track record for melatonin?

Research has shown that melatonin is usually safe for use. Studies have found that it can help control heart rate and lower blood pressure at night, suggesting potential benefits for heart health. Melatonin is often used to aid sleep and is available over the counter, supporting its safety profile. Other studies report no major serious side effects, making it a promising option for those considering participation in clinical trials. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about using melatonin for addressing cardiovascular stress because it offers a novel approach compared to traditional treatments like beta-blockers and ACE inhibitors. Unlike these medications that typically modulate blood pressure and heart rate directly, melatonin works by potentially enhancing the body's natural circadian rhythms and reducing oxidative stress, which can indirectly support cardiovascular health. Additionally, the sublingual delivery method of melatonin allows for quick absorption, which might provide faster stress relief than standard oral medications.

What evidence suggests that melatonin might be an effective treatment for cardiovascular response to stress?

This trial will compare the effects of melatonin with a placebo on cardiovascular response to stress. Research has shown that melatonin benefits heart health. Studies have found that melatonin helps control heart rate and can lower nighttime blood pressure, especially in individuals with high blood pressure. As a natural antioxidant, it reduces damage to blood vessels and the heart. By improving the function of the inner lining of blood vessels, melatonin protects the heart and blood vessels. Overall, melatonin supports better heart function and reduces heart-related risks. ^{1 6 7 8 9}

Who Is on the Research Team?

Jeremy M Kellawan

Principal Investigator

University of Oklahoma

Are You a Good Fit for This Trial?

This trial is for healthy men and women, specifically premenopausal women with regular menstrual cycles. It excludes those on cardiometabolic meds, with high blood pressure or diabetes, using sex hormone replacements or tobacco products, pregnant individuals, people with a history of autonomic dysfunction, cardiovascular diseases, allergies to melatonin or regular users of melatonin.

Inclusion Criteria

I am a healthy man or woman.

I am a premenopausal woman with a regular menstrual cycle.

Exclusion Criteria

You use tobacco or nicotine products.

I am using sex hormone replacement therapy.

You are allergic to melatonin.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Treatment

Participants complete placebo and melatonin treatments in a single-blind, counter-balanced design

2 visits

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

What Are the Treatments Tested in This Trial?

Interventions

• Melatonin

Trial Overview

The study aims to see if taking melatonin once can change how the heart and blood vessels respond to stress from cold exposure at rest and during exercise. Participants will be randomly given either melatonin or a placebo (a dummy pill) to compare effects.

How Is the Trial Designed?

Group I: Melatonin Experimental Treatment 1 Intervention

5mg commercially available melatonin (MEL) spray will be given sublingually.

Group II: Placebo Placebo Group 1 Intervention

Placebo (PLA) is 10 sublingual sprays of a diluted (1 microliter/29ml filtered water) mint extract.

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?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Published Research Related to This Trial

Young men with polymorbid cardiovascular pathology (PCVP) showed lower levels of nocturnal melatonin excretion, which correlated with more severe depressive and anxiety symptoms, indicating a potential link between melatonin levels and mental health in these patients.

Comprehensive treatment that included psychotherapy and psychophysiological sessions led to greater improvements in melatonin levels and overall health indicators compared to standard therapy alone, suggesting that a multi-faceted approach may be more effective for managing PCVP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin: Manager of psychosomatic and metabolic disorders in polymorbid cardiovascular pathology. Partsernyak, AS., Polyakova, VO., Trufanov, AG., et al.[2022]

Melatonin is a safe and effective treatment for sleep disturbances in the elderly, helping to restore circadian rhythms that are often disrupted with aging.

In addition to improving sleep, melatonin also acts as an anti-inflammatory agent, which may help mitigate low-grade inflammation associated with aging and reduce the risk of chronic illnesses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin's Benefits and Risks as a Therapy for Sleep Disturbances in the Elderly: Current Insights. Cardinali, DP., Brown, GM., Pandi-Perumal, SR.[2022]

Melatonin plays a crucial role in regulating daily rhythms in mammals by acting as a hormonal signal from the master clock in the SCN to synchronize various tissues, helping maintain proper circadian rhythms.

Pharmacological treatments with melatonin or melatonin agonists can effectively synchronize the SCN clock and improve circadian timing, especially when light exposure at night is avoided.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The internal time-giver role of melatonin. A key for our health. Pévet, P.[2022]

In a postmarketing surveillance study of 653 patients aged 55 and older, prolonged-release melatonin (PRM) significantly improved sleep quality from an average score of 4.2 to 2.6 and morning alertness from 4.0 to 2.5 over three weeks of treatment.

PRM demonstrated a low incidence of rebound insomnia (3.2% early withdrawal, 2.0% late withdrawal) and was well tolerated, with minimal adverse effects, suggesting it is a safe and effective alternative to traditional hypnotics for managing insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin. Hajak, G., Lemme, K., Zisapel, N.[2021]

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 can effectively improve sleep and adjust circadian rhythms when taken at the right times, helping with issues like jet lag and shift work, but its effectiveness is closely related to the timing and dosage.

While melatonin is generally safe for short-term use in healthy adults, there is a lack of long-term safety data, and its use should be carefully managed to avoid potential negative effects, especially with unregulated preparations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of circadian rhythm disorders--melatonin. Arendt, J., Deacon, S.[2019]

Timed melatonin administration may offer a new treatment approach for cardiac ischemia and hypertension that does not respond to traditional medications, suggesting its potential efficacy in managing these conditions.

The study builds on previous research linking melatonin to blood pressure regulation and circadian rhythms, indicating that timing of melatonin could be crucial for optimizing its therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin, refractory hypertension, myocardial ischemia and other challenges in nightly blood pressure lowering. Zaslavskaya, RM., Lilitsa, GV., Dilmagambetova, GS., et al.[2019]

Chronic administration of melatonin has been shown to significantly lower nighttime blood pressure in individuals with hypertension, suggesting its potential as an anti-hypertensive agent.

The effectiveness of melatonin in reducing blood pressure is linked to its levels in the body, with higher nighttime melatonin correlating with greater reductions in arterial blood pressure, indicating a possible mechanism involving melatonin receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anti-hypertensive action of melatoninergic compounds]. Inoue, Y.[2014]

In a study involving 16 men with untreated essential hypertension, repeated nighttime intake of melatonin (2.5 mg daily for 3 weeks) significantly reduced nocturnal blood pressure by 6 mm Hg systolic and 4 mm Hg diastolic, without affecting heart rate.

The study suggests that enhancing circadian rhythm function through melatonin may offer a new treatment strategy for essential hypertension, as improvements in blood pressure were statistically unrelated to sleep quality enhancements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Scheer, FA., Van Montfrans, GA., van Someren, EJ., et al.[2016]

Exogenous melatonin has been shown to lower nighttime blood pressure and improve overall blood pressure readings, which could be beneficial for individuals with coronary artery disorder (CAD).

Low levels of melatonin are associated with CAD and related conditions, suggesting that melatonin supplementation may be a promising area for future clinical trials targeting cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and Human Cardiovascular Disease. Pandi-Perumal, SR., BaHammam, AS., Ojike, NI., et al.[2019]

Melatonin can help adults with delayed sleep phase disorder fall asleep earlier, but its use in children is concerning because it is not officially approved for them and lacks formal safety testing.

There are significant safety concerns regarding melatonin's effects on children's reproductive, cardiovascular, immune, and metabolic systems, as well as potential drug interactions, which have not been adequately studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential safety issues in the use of the hormone melatonin in paediatrics. Kennaway, DJ.[2015]

Melatonin significantly influences circadian rhythms through its action on the suprachiasmatic nucleus (SCN), which is the brain's biological clock.

While the exact site for melatonin's photoperiodic effects is still unclear, evidence suggests it may act in or near the medial hypothalamus, with melatonin receptors found in various brain regions and peripheral tissues, indicating a complex mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central melatonin receptors: implications for a mode of action. Morgan, PJ., Williams, LM.[2019]

Diurnal rhythms significantly influence cardiovascular health, affecting heart rate, blood pressure, and the occurrence of serious cardiac events, with molecular changes in gene expression also playing a role.

Melatonin, which varies throughout the day, is crucial for cardiovascular functions and may help synchronize internal biological clocks, offering potential benefits through its antioxidant and anti-inflammatory properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and circadian biology in human cardiovascular disease. Dominguez-Rodriguez, A., Abreu-Gonzalez, P., Sanchez-Sanchez, JJ., et al.[2013]

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