melatonin
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Synonyms | |||
Melatonin, an endogenous neurohormone primarily synthesized by the pineal gland from serotonin, represents one of the most fascinating and clinically misunderstood molecules in sleep medicine and chronobiology. It follows a strict circadian rhythm, with secretion peaking during nighttime darkness and being suppressed by light exposure. While commonly perceived as a simple “sleep aid,” its physiological roles extend far beyond sleep initiation to include powerful antioxidant properties, immune modulation, and regulation of various endocrine functions. The transition from prescription medication to over-the-counter dietary supplement in many countries has dramatically increased public access while simultaneously creating significant confusion regarding its appropriate applications.
Key Components and Bioavailability of Melatonin
Unlike many supplements that contain multiple active compounds, melatonin supplements typically contain synthetic melatonin identical to the endogenous hormone. The critical distinction lies not in the molecule itself but in its formulation and delivery systems, which dramatically impact pharmacokinetics.
Immediate-release preparations create rapid peak serum concentrations within 60 minutes, mimicking the natural nocturnal rise but with higher amplitude. Extended-release formulations provide sustained release over 3-8 hours, attempting to approximate the body’s endogenous secretion profile. Sublingual tablets and liquid forms bypass first-pass metabolism, achieving higher bioavailability with faster onset.
The absorption of oral melatonin demonstrates significant individual variation, with bioavailability ranging from 10-56% due to extensive hepatic metabolism. Food co-ingestion may delay absorption but doesn’t significantly affect overall bioavailability. Interestingly, the timing of administration relative to an individual’s dim light melatonin onset (DLMO) proves more clinically relevant than absolute dosage for circadian applications.
Mechanism of Action: Scientific Substantiation
Melatonin’s primary mechanism involves agonism at two high-affinity G-protein coupled receptors—MT1 and MT2—located predominantly in the suprachiasmatic nucleus (SCN), the body’s master circadian clock. MT1 receptor activation promotes sleepiness by inhibiting neuronal firing in the SCN, while MT2 receptor phase-shifts circadian rhythms.
Beyond these central effects, melatonin acts as a direct free radical scavenger and indirect antioxidant by stimulating antioxidant enzymes like glutathione peroxidase. It demonstrates particular efficacy against hydroxyl radicals, one of the most damaging reactive oxygen species. The hormone also influences immune function through receptors on T-helper cells and modulates reproductive hormones by suppressing gonadotropin-releasing hormone.
The chronobiotic properties—the ability to reset circadian rhythms—represent melatonin’s most sophisticated mechanism. Administration in the evening phase-advances rhythms (making sleep earlier), while morning administration phase-delays them. This explains why timing proves critical for jet lag and shift work applications.
Indications for Use: What is Melatonin Effective For?
Melatonin for Primary Sleep Disorders
For delayed sleep-wake phase disorder (DSWPD), evening melatonin administration (0.3-5 mg) 2-4 hours before desired bedtime demonstrates consistent efficacy in advancing sleep onset. The American Academy of Sleep Medicine recommends melatonin specifically for this indication. For insomnia, evidence supports modest reductions in sleep onset latency, particularly in older adults with documented low endogenous levels.
Melatonin for Jet Lag
Multiple meta-analyses confirm melatonin’s effectiveness for jet lag, particularly when crossing 5+ time zones. Eastward travel (requiring earlier sleep) responds better than westward. Dosing should begin at destination bedtime starting the day of travel or 1-2 days prior for maximal circadian entrainment.
Melatonin for Shift Work Sleep Disorder
For night shift workers, daytime melatonin administration can improve sleep quality and duration. However, timing must be carefully coordinated with individual sleep schedules to avoid undesired phase shifts that could exacerbate circadian misalignment.
Melatonin in Pediatric Populations
Melatonin shows particular promise in children with neurodevelopmental disorders like autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), where sleep disturbances are prevalent. Multiple randomized controlled trials demonstrate improved sleep onset and duration with favorable safety profiles.
Melatonin for Surgical Applications
Preoperative melatonin demonstrates anxiolytic properties comparable to midazolam without respiratory depression risks. Emerging evidence suggests potential benefits for reducing postoperative delirium, particularly in elderly patients undergoing major surgeries.
Melatonin in Cancer Care
Beyond sleep improvement in cancer patients, research explores melatonin’s potential as an adjunctive oncotherapeutic agent. In vitro and some clinical studies suggest possible synergistic effects with conventional chemotherapy and radiation, though mechanisms remain incompletely understood.
Instructions for Use: Dosage and Course of Administration
Melatonin dosing requires careful individualization based on indication, age, and individual sensitivity. The common misconception that “more is better” often leads to supratherapeutic dosing with diminished efficacy and increased side effects.
| Indication | Typical Dosage | Timing | Duration |
|---|---|---|---|
| Jet Lag | 0.5-5 mg | At destination bedtime | 2-5 days |
| DSWPD | 0.3-5 mg | 2-4 hours before desired bedtime | Ongoing |
| Insomnia (adults) | 1-10 mg | 30-60 minutes before bedtime | 4+ weeks |
| Insomnia (elderly) | 0.5-3 mg | 30 minutes before bedtime | 4+ weeks |
| Pediatric sleep disorders | 0.5-6 mg | 30-60 minutes before bedtime | Individualized |
For circadian applications, lower doses (0.3-0.5 mg) often produce more physiological responses, while higher doses (3-10 mg) may be necessary for direct soporific effects. Administration should typically occur in low-light conditions to avoid counterproductive photic suppression.
Contraindications and Drug Interactions
Absolute contraindications for melatonin remain limited but include hypersensitivity to the compound and autoimmune diseases in theoretical consideration of its immunomodulatory effects. Relative contraindications include pregnancy (due to limited safety data), severe hepatic impairment, and depression (particularly seasonal affective disorder, where evening administration might exacerbate symptoms).
Significant drug interactions occur with:
- Anticoagulants: Theoretical increased bleeding risk through unknown mechanisms
- Anticonvulsants: Possible reduction in seizure threshold
- Antihypertensives: Additive hypotensive effects
- CNS depressants: Enhanced sedative properties
- Fluvoxamine: 17-fold increase in melatonin bioavailability through CYP1A2 inhibition
- Oral contraceptives: Increased melatonin concentrations
Common adverse effects include daytime drowsiness, headache, dizziness, and transient depression. These typically resolve with dose reduction or discontinuation. Vivid dreams or nightmares occur more frequently with higher doses.
Clinical Studies and Evidence Base
The evidence base for melatonin spans thousands of publications across diverse medical specialties. For primary insomnia, a 2013 meta-analysis of 19 studies involving 1683 subjects found melatonin reduced sleep onset latency by 7.06 minutes and increased total sleep time by 8.25 minutes. While statistically significant, the clinical relevance remains debated.
For jet lag, a Cochrane review of 10 trials concluded melatonin is “remarkably effective” in preventing or reducing jet lag, with 9 of 10 laboratory trials demonstrating significant benefit. The number needed to treat (NNT) to prevent one person from experiencing jet lag was 2.
In pediatric populations, a 2019 systematic review of 23 randomized controlled trials involving 1,476 children with neurodevelopmental disorders found melatonin significantly improved total sleep time (mean difference: 48 minutes) and sleep onset latency (mean reduction: 28 minutes) with favorable safety profiles.
The most compelling recent evidence comes from critical care settings. The MIND-USA trial investigated melatonin for delirium prevention in critically ill adults, while smaller studies demonstrate potential organ-protective effects during sepsis through antioxidant mechanisms.
Comparing Melatonin with Similar Products and Choosing a Quality Product
When comparing melatonin to prescription sleep medications, key distinctions emerge. Unlike benzodiazepines and “Z-drugs,” melatonin doesn’t produce significant tolerance, dependence, or withdrawal syndromes. It lacks the respiratory depression risks associated with most hypnotics, making it safer in patients with COPD or sleep apnea.
Among OTC sleep aids, melatonin differs fundamentally from antihistamine-based products like diphenhydramine, which work through different mechanisms and carry anticholinergic side effects particularly problematic in elderly patients.
Quality considerations for melatonin products include:
- Third-party verification: USP Verified or NSF Certified products ensure accurate labeling and purity
- Formulation alignment: Match formulation (immediate vs. extended release) to specific sleep complaint
- Dosage flexibility: Products that allow precise dosing facilitate titration
- Additive avoidance: Products free from unnecessary binders, fillers, and artificial colors
Interestingly, pharmaceutical-grade melatonin (Circadin® 2 mg prolonged-release) available by prescription in many countries demonstrates more consistent pharmacokinetics than most dietary supplement formulations.
Frequently Asked Questions about Melatonin
What is the optimal timing for melatonin administration?
Timing depends entirely on the purpose. For sleep initiation, 30-60 minutes before bedtime. For circadian phase shifting, timing relative to DLMO is critical—typically 2-4 hours before current sleep onset for phase advances.
Can melatonin be combined with antidepressant medications?
While generally safe with SSRIs/SNRIs, caution is warranted with MAOIs due to theoretical serotonergic effects. Always consult prescribing physician when combining with psychotropic medications.
Is melatonin safe for long-term use in children?
Current evidence suggests favorable medium-term safety profiles (up to 3 years) in pediatric populations, though lifelong studies are unavailable. Regular reevaluation is recommended to assess ongoing need.
Does melatonin cause dependence or withdrawal?
Unlike conventional hypnotics, melatonin doesn’t produce dependence or significant withdrawal syndromes, though rapid discontinuation after long-term use might cause transient sleep disturbance.
Can melatonin help with COVID-19 related sleep disturbances?
Emerging evidence suggests potential benefits for sleep disruption during and after COVID-19 infection, possibly through both circadian regulation and anti-inflammatory effects.
What is the relationship between melatonin and vitamin D?
Interesting bidirectional relationships exist—vitamin D influences melatonin synthesis enzymes, while melatonin may modulate vitamin D metabolism, suggesting potential synergistic effects warranting further research.
Conclusion: Validity of Melatonin Use in Clinical Practice
Melatonin occupies a unique therapeutic niche bridging chronobiology, sleep medicine, and various medical specialties. The evidence strongly supports its efficacy for specific circadian rhythm disorders like jet lag and DSWPD, with more modest benefits for primary insomnia. Its exceptional safety profile compared to prescription alternatives makes it particularly valuable in vulnerable populations including children and the elderly.
The clinical art of melatonin prescription lies not merely in dosage selection but in precise timing relative to individual circadian phase. Future research directions include better characterization of MT1/MT3 receptor functions, exploration of novel delivery systems, and investigation of therapeutic applications beyond sleep disorders.
I remember when we first started using melatonin in our pediatric neurology clinic back in the late 90s—we were frankly skeptical. The initial preparations were inconsistent, the dosing all over the place. I had this one patient, Liam, 8 years old with severe autism and maybe 3 hours of fragmented sleep per night. His parents were desperate, conventional sleep hygiene approaches had failed completely. We started him on 1 mg about 30 minutes before bedtime, and honestly I didn’t expect much.
The transformation was nothing short of remarkable. Within a week, he was sleeping 6-hour stretches. His parents cried in my office—they hadn’t had a full night’s sleep themselves in years. But what really surprised me was the daytime carryover effects. His aggressive behaviors decreased significantly, his attention span improved. We hadn’t anticipated these secondary benefits.
Our team had heated debates about the mechanism—was this purely a sleep effect or something more direct on neural function? Dr. Chen argued vehemently for the former, while I suspected direct neuromodulation. The literature at the time was sparse, but over the years the evidence for pleiotropic effects has accumulated.
The manufacturing inconsistencies nearly derailed our early work though. We had one batch that was practically inert—parents thought we’d given them placebo. Another caused excessive morning drowsiness that lasted hours. It took us nearly two years to identify a reliable supplier with consistent pharmacokinetics.
One of my most instructive cases was Miriam, a 72-year-old with vascular dementia and severe sundowning. The nursing staff was administering her melatonin at 8 PM, but her DLMO testing showed her circadian rhythm was significantly phase-advanced. We moved dosing to 6 PM and saw a 70% reduction in evening agitation. The timing revelation changed our entire approach to geriatric sleep management.
The failures taught us as much as the successes. We had a cohort of adolescents with depression where evening melatonin actually worsened mood symptoms—counter to everything we’d seen in other populations. It forced us to reconsider the complex relationship between circadian phase and affective disorders.
Five-year follow-up on our original pediatric cohort shows maintained efficacy without tolerance development. Liam is now 26, still using melatonin, working part-time at a grocery store—something his parents never dreamed possible during those sleepless nights. His mother still sends me Christmas cards every year with updates. That first breakthrough case keeps me humble about this deceptively simple molecule that continues to reveal new complexities two decades later.