Optimization of Melatonin Administration in Healthy Adults (MelOpt)

Optimizing Timing and Dose of Melatonin Administration: a Randomized, Double-blind Controlled Trial in Healthy Adults

The goal of this clinical trial is to evaluate whether the timing and dosage of exogenous melatonin can improve sleep onset and maintenance in healthy adults aged 18-45 years (50% female) with no history of sleep disorders.

The main questions it aims to answer is whether an optimized melatonin administration schedule (4 mg, 3 hours before bedtime) will be more effective in improving sleep initiation and maintenance than an administration schedule more commonly advised (2 mg, 30 minutes before bedtime).

Researchers will compare five conditions involving different combinations of melatonin or placebo administered 30 minutes or 3 hours before bedtime to see if earlier timing and/or higher dosage produces better sleep outcomes.

Participants will:

• Complete a habituation night without any intervention.

• Undergo five randomized, double-blind experimental sleep conditions including:

  2 mg melatonin 30 minutes before bedtime 2 mg melatonin 3 hours before bedtime 4 mg melatonin 30 minutes before bedtime 4 mg melatonin 3 hours before bedtime Placebo at both time points

• Be monitored via polysomnography to measure sleep parameters

Study Overview

• Status: Not yet recruiting
• Conditions: Sleep Disorders
• Intervention / Treatment: Dietary supplement: Mel 2 mg 30 min; Dietary supplement: Mel 2 mg 3 h; Dietary supplement: Mel 4 mg 30 min; Dietary supplement: Mel 4 mg 3 h; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 14
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ugo Faraguna, MD, PhD; Phone Number: +39 050 2213470; Email: ugo.faraguna@unipi.it

Study Locations

• Italy
  • PI
    • Pisa, PI, Italy, 56126
      • University of Pisa, Institute of Physiology, Sonnolab
      • Contact: Ugo Faraguna, MD, PhD; Phone Number: +39 050 2213470; Email: ugo.faraguna@unipi.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age between 18 and 45 years of age
• Fluent knowledge of Italian language
• Review and signing of the informed consent form

Exclusion Criteria:

• Diagnosis of sleep or circadian rhythm disorder
• Diagnosis of neurological, psychiatric or medical condition that may interfere with sleep
• Ongoing treatment with medications that may affect sleep, including hypnotics and other types of melatonin
• Travel to a country with a time zone difference of at least two hours within the two months prior to or during the study
• Shift work
• Confirmed pregnancy
• Breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo administered 30 minutes before bedtime, placebo administered 3 hours before bedtime
Active Comparator: 2mg 30min	Dietary supplement: Mel 2 mg 30 min; Melatonin 2 mg 30 minutes before bedtime, placebo 3 hours before bedtime
Experimental: 2mg 3h	Dietary supplement: Mel 2 mg 3 h; Placebo administered 30 minutes before bedtime, melatonin 2 mg administered 3 hours before bedtime
Experimental: 4mg 30min	Dietary supplement: Mel 4 mg 30 min; Melatonin 4 mg administered 30 minutes before bedtime, placebo administered 3 hours before bedtime
Experimental: 4mg 3h	Dietary supplement: Mel 4 mg 3 h; Placebo administered 30 minutes before bedtime, melatonin 4 mg administered 3 hours before bedtime

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Onset Latency	Time required to fall asleep assessed using polisomnography	First night following administration of the drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Sleep Time	Night sleep duration assessed using polisomnography	First night following administration of the drug
Sleep Efficiency	Ratio between total sleep time and time in bed	First night following administration of the drug
Wake After Sleep Onset	Minutes spent awake between the sleep onset and morning awakening	First night following administration of the drug

Collaborators and Investigators

• Sponsor: IRCCS Fondazione Stella Maris

Publications and helpful links

General Publications

• Bruno S, Cenerini G, Lo Giudice L, Cruz-Sanabria F, Benedetti D, Crippa A, Fiori S, Ferri R, Masi G, Faraguna U. Optimizing timing and dose of exogenous melatonin administration in neuropsychiatric pediatric populations: a meta-analysis on sleep outcomes. Sleep Med Rev. 2025 Dec;84:102158. doi: 10.1016/j.smrv.2025.102158. Epub 2025 Aug 30.
• Cruz-Sanabria F, Bruno S, Crippa A, Frumento P, Scarselli M, Skene DJ, Faraguna U. Optimizing the Time and Dose of Melatonin as a Sleep-Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose-Response Meta-Analysis. J Pineal Res. 2024 Aug;76(5):e12985. doi: 10.1111/jpi.12985.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: December 22, 2025
• First Submitted That Met QC Criteria: March 31, 2026
• First Posted (Actual): April 7, 2026

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: melatonin; hypnotics and sedatives; drug administration schedule; sleep health; sleep drugs
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Sleep Wake Disorders; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Honey
• Other Study ID Numbers: 0043072/2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The data cannot be shared publicly for the privacy of individuals who participated in the study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No