Melatonin

Melatonin is not a first-line, proven treatment for narcolepsy (stimulants, sodium oxybate, pitolisant/solriamfetol are recommended by major guidelines). However, melatonin can help improve nocturnal sleep timing/continuity and modify REM sleep, so some clinicians use it as an adjunct to stabilise night sleep (which can indirectly help daytime sleepiness and REM-related phenomena).

Melatonin is the body’s nocturnal “circadian” hormone acting on MT1 and MT2 receptors in the brain; it shifts/synchronises circadian timing and promotes sleep onset. McGill University

Recent mechanistic work shows the MT1 receptor plays an important role in regulating REM sleep, which is directly relevant to narcolepsy (narcolepsy involves REM intrusions, cataplexy, sleep paralysis). This provides a plausible mechanism for melatonin to modify REM architecture in narcolepsy. ScienceDaily

Clinical reviews and sleep physiology papers note melatonin can increase REM continuity or percentage in people with reduced REM and can improve aspects of nocturnal sleep continuity — a potential way to reduce overnight fragmentation that aggravates daytime sleepiness. (That is, melatonin is helpful for nocturnal sleep regulation, and better nocturnal sleep sometimes improves daytime symptoms.) Oxford Academic

Important: there is no single universally accepted melatonin dosing protocol for narcolepsy — most guidance and clinical practice use melatonin to improve nighttime sleep (not to treat core excessive daytime sleepiness or cataplexy). Typical approaches used in studies/clinical practice:

• Timing: take melatonin in the evening, usually 30–90 minutes before desired bedtime for immediate-release formulations; 1–2 hours before bedtime for prolonged-release formulations (PR melatonin is designed to mimic natural overnight secretion). NICE
• Common doses (examples from clinical guidance):
• Immediate-release: low doses such as 0.5–3 mg by mouth at bedtime are commonly used for sleep onset problems; some clinicians use up to 5 mg depending on tolerance and effect. Sleep Foundation
• Prolonged-release (licensed for older adults with insomnia): 2 mg PR once nightly (1–2 hours before bedtime) is the licensed dose for insomnia in some countries and is commonly referenced in practice guidance. (Noting licensing is for insomnia and older adults; clinicians extrapolate in other contexts.) NICE
• Duration: many formularies/guidelines recommend reviewing response and considering short-to-medium term use (weeks to a few months). Long-term safety data are less robust and ongoing prescribing is often periodically reviewed. northoftyneapc.nhs.uk
• Use in narcolepsy: when used for narcolepsy it is generally adjunctive — aim is to regularise nighttime sleep (which may reduce daytime sleepiness and reduce REM fragmentation). There is no guideline endorsement of melatonin as first-line monotherapy for narcolepsy; decisions should be individualised and done under specialist supervision. JCSM

• Randomized trial(s) showing REM/subjective benefit: an early randomized study reported melatonin increased REM percentage and improved subjective daytime function in patients with reduced REM sleep duration (melatonin vs placebo; clinical measures improved). This is evidence that melatonin can change REM architecture and may affect daytime functioning in selected patients. (Example: J Clin Endocrinol Metab study reporting REM increases with melatonin). Oxford Academic
• Mechanistic / recent preclinical work: the McGill/MUHC research identifying MT1 receptor’s role in REM sleep strengthens the biological rationale for using melatonin or MT1-targeting agents to influence REM-related symptoms in disorders like narcolepsy. ScienceDaily+1
• Reviews / narrative evidence base: systematic reviews and narrative reviews of melatonin for sleep disorders conclude melatonin is effective for certain sleep problems (delayed sleep phase, some insomnia subtypes) but the evidence for narcolepsy specifically is limited — most data are small trials, case reports and physiologic studies rather than large-scale randomized trials showing clear, durable benefit for core narcolepsy symptoms. Taylor & Francis Online
• Guideline position: major clinical practice guidelines for narcolepsy (AASM 2021; European Academy/ESRS/EUNN guideline) do not list melatonin as a recommended first-line pharmacologic treatment for narcolepsy (they recommend modafinil, solriamfetol, pitolisant, sodium oxybate, etc.). This demonstrates the relative lack of high-quality evidence to support melatonin as a primary therapy. JCSM

Summary: there are plausible mechanisms and small trials/case reports showing melatonin changes REM and helps nightly sleep — but high-quality randomized evidence supporting melatonin as an effective treatment for the core daytime symptoms of narcolepsy is limited. Melatonin is therefore used as an adjunct to stabilise sleep timing/architecture rather than as a proven primary therapy. Oxford Academic