Time to Onset for Melatonin
Endogenous melatonin levels begin to rise 1-3 hours before habitual sleep onset time, with the dim light melatonin onset (DLMO) typically occurring approximately 2-3 hours before sleep. 1, 2
Endogenous Melatonin Timing
The natural onset of melatonin production occurs 1-3 hours before habitual bedtime, marking the start of the biological night as regulated by the suprachiasmatic nucleus (SCN). 1
- The DLMO represents the approximation of melatonin synthesis onset and is tightly associated with other physiological changes including core body temperature changes, sleepiness, and EEG activity. 1
- Melatonin levels remain elevated throughout the night and return to low daytime levels typically within 1 hour of habitual wake time. 1
Exogenous Melatonin Pharmacokinetics
Immediate-Release Formulations
Immediate-release melatonin reaches peak plasma concentrations within 30-60 minutes after oral ingestion, regardless of nutritional status. 3
- Peak concentration (Tmax) occurs at approximately 0.6 hours (36 minutes) after administration. 4
- Plasma melatonin remains at or above endogenous nighttime levels for 3-4 hours. 3
- The elimination half-life ranges from 0.54 to 0.95 hours. 4, 3
- Maximum concentration for a 4 mg dose reaches approximately 13,120 pg/mL. 4
Extended-Release Formulations
Extended-release melatonin formulations raise melatonin levels within 15 minutes and reach peak concentrations at approximately 1.5-1.6 hours after administration. 4, 5
- Time to peak concentration (Tmax) is 1.56 hours for extended-release versus 0.6 hours for immediate-release. 4
- Extended-release formulations sustain elevated melatonin levels (>300 pg/mL) for approximately 6 hours. 4
- The elimination half-life is longer at 1.63-2.1 hours compared to immediate-release. 4, 5
- Maximum concentration for a 4 mg extended-release dose is approximately 7,581 pg/mL, lower than immediate-release but sustained longer. 4
Clinical Timing Recommendations
For optimal circadian rhythm regulation, melatonin should be administered 1-2 hours before desired bedtime (approximately 6 PM for typical sleep schedules). 6
- In pediatric/adolescent populations with delayed sleep-wake phase disorder and psychiatric comorbidities, fast-release melatonin at 3-5 mg administered between 18:00-19:00 advanced sleep onset time by approximately 37 minutes. 1
- This timing aligns with the natural DLMO occurring 2-3 hours before sleep onset. 2
Important Caveats
Multiple factors can significantly interfere with melatonin levels and timing:
- Light exposure, even at levels lower than typical room illumination (<5 lux required for accurate measurement), suppresses melatonin production. 1, 2
- NSAIDs require a 72-hour washout period, while caffeine and alcohol require 24 hours before melatonin assessment. 1, 2
- Beta-blockers and alcohol suppress endogenous melatonin levels. 1, 2
- Postural changes and exercise can artificially increase melatonin levels. 1, 2