Melatonin: The Complete Scientific Guide

🧬 What is Melatonin? Complete Identification

Melatonin is an endogenous chronobiotic hormone produced nightly by the pineal gland and is chemically identified as N‑[2-(5‑methoxy‑1H‑indol‑3‑yl)ethyl]acetamide (CAS 73‑31‑4).

Medical definition: Melatonin is a pleiotropic indoleamine that conveys the biological signal of darkness to the central circadian pacemaker (the suprachiasmatic nucleus, SCN) and to peripheral tissues via receptor‑mediated and receptor‑independent actions.

Alternative names: N‑Acetyl‑5‑methoxytryptamine, MLT, Melatonina, and proprietary names for prolonged‑release formulations such as Circadin.

Classification: hormone / chronobiotic; used as a dietary supplement in the US under DSHEA and as a prescription prolonged‑release drug in some countries.

Chemical formula: C13H16N2O2.

Origin and production: Endogenously synthesized from tryptophan via serotonin and N‑acetylserotonin in the pineal gland under SCN control; commercial melatonin is synthetically manufactured and is chemically identical to human melatonin.

📜 History and Discovery

Melatonin was first isolated and named in 1958 by Lerner and colleagues from bovine pineal extracts.

• 1958 — Lerner et al. isolate melatonin from bovine pineal tissue (Aaron B. Lerner and colleagues).
• 1960s–1970s — Early physiological effects characterized; link established between darkness and pineal secretion.
• 1972 — Demonstration of a clear circadian rhythm of melatonin in humans, tightly suppressed by light exposure.
• 1980s — Biosynthetic pathway clarified (tryptophan → serotonin → N‑acetylserotonin → melatonin) and AANAT regulation described.
• 1990s — Cloning and mapping of MT1 and MT2 receptors.
• 2000s–2020s — Widespread OTC use in the US; clinical research expands to neuroprotection, immunomodulation, and adjunctive roles in diverse conditions including COVID‑19.

Traditional vs modern use: Melatonin is endogenous; traditional herbal uses relied on plant materials containing indoles. Modern use is pharmacologic and chronobiologic, with prescription prolonged‑release formulations authorized in some jurisdictions.

Fascinating facts: nocturnal peak declines with age; blue light (~460–480 nm) rapidly suppresses secretion; melatonin has both receptor‑dependent and receptor‑independent antioxidant effects.

⚗️ Chemistry and Biochemistry

Melatonin's structure contains a 5‑methoxyindole core with a flexible N‑acetyl‑ethyl side chain enabling both hydrophobic and polar interactions with receptor binding pockets.

• Molecular formula: C13H16N2O2
• Molar mass: 232.278 g/mol
• Appearance: white to off‑white crystalline powder
• Solubility: poorly soluble in water (~≤2 mg/mL), soluble in ethanol and DMSO; lipophilic enough to cross the blood–brain barrier
• logP: ≈ 1.5–2.7 (enables CNS penetration)
• Melting point: ~116–118 °C
• Stability: light‑ and heat‑sensitive; store protected from light in cool, dry conditions

Galenic forms

Common oral formulations include immediate‑release tablets/capsules, prolonged‑release tablets (e.g., Circadin), sublingual/orodispersible forms, liquids, and experimental transdermal systems.

💊 Pharmacokinetics: The Journey in Your Body

Oral melatonin is rapidly absorbed from the small intestine and subject to substantial first‑pass hepatic metabolism; reported absolute oral bioavailability varies widely across studies from ~10% to 56%, with a commonly cited mean around ~15%.

Absorption and Bioavailability

Mechanism: passive diffusion across enterocytes driven by lipophilicity; sublingual forms allow partial buccal uptake and reduced first‑pass loss.

• Immediate‑release Tmax: ~30–60 minutes (range 20 min–2 h)
• Effect of food: high‑fat meals can delay Tmax and alter Cmax; clinical impact is formulation‑dependent
• Variability: smokers and CYP1A2 inducers lower exposure; CYP1A2 inhibitors (e.g., fluvoxamine) markedly raise plasma levels

Distribution and Metabolism

Distribution: melatonin crosses the blood–brain barrier and distributes into the CNS and peripheral tissues including retina, gut, vasculature, immune cells and mitochondria.

Metabolism: primarily hepatic via CYP1A2 to 6‑hydroxymelatonin followed by sulfation/glucuronidation; minor CYP2C19/2C9/2D6 contributions reported.

Elimination

Route: renal excretion of conjugated metabolites (predominant urinary metabolite: 6‑sulfatoxymelatonin).

Terminal half‑life: immediate‑release formulations typically show elimination half‑life ~30–60 minutes in young healthy adults; most systemic melatonin is cleared within 4–8 hours.

🔬 Molecular Mechanisms of Action

Melatonin acts via high‑affinity G protein‑coupled receptors MT1 (MTNR1A) and MT2 (MTNR1B) in the SCN and peripheral tissues and via receptor‑independent antioxidant and mitochondrial mechanisms.

• MT1: inhibits SCN neuronal firing; associated with sleep‑promoting effects.
• MT2: mediates phase‑shifting of the circadian clock.
• MT3 / quinone reductase 2: may contribute to redox modulation.
• Intracellular signaling: Gi/o coupling → ↓cAMP, modulation of cGMP and ion channels, downstream changes in PER/CRY clock gene timing.
• Antioxidant actions: direct free‑radical scavenging and upregulation of SOD, catalase, GPx; supports mitochondrial electron transport integrity.

✨ Science‑Backed Benefits

Melatonin has reproducible benefits for circadian alignment and sleep‑initiation; secondary evidence supports adjunctive uses with variable certainty.

🎯 Reduction of Sleep Latency

Evidence Level: High

Physiology: exogenous melatonin signals biological night to the SCN and lowers physiological arousal to permit earlier sleep onset.

Molecular mechanism: MT1/MT2 activation reduces SCN firing and modulates sleep‑related neurotransmission.

Target populations: adults with sleep‑onset insomnia, jet lag, shift workers.

Onset: often within the first night; benefit typically accrues over days.

Clinical Study: Ferracioli‑Oda et al. (2013). PLoS ONE. [PMID: 23620827] — meta‑analysis found that melatonin significantly reduced sleep latency versus placebo across randomized trials (pooled effect significant; see PMID: 23620827 for pooled estimates and subgroup details).

🎯 Improved Sleep Maintenance and Quality (Older Adults)

Evidence Level: High (prolonged‑release 2 mg in ≥55 years)

Physiology: sustained melatonergic signaling throughout the night supports consolidated sleep and morning alertness.

Target populations: adults ≥55 years with insomnia.

Clinical Study: Circadin pivotal trials (2 mg prolonged‑release). EMA assessment (2007). [EMA EPAR Circadin; clinical trial reports summarized online]

🎯 Circadian Phase Shifting (Jet Lag, DSPS)

Evidence Level: High

Physiology: melatonin acts as a chronobiotic: timed dosing produces predictable phase advances or delays of the circadian clock.

Clinical Study: Multiple RCTs summarized in reviews show melatonin (0.5–5 mg) given at destination local bedtime reduces subjective jet‑lag symptoms within 1–3 nights; see Ferracioli‑Oda et al. (2013) for pooled data. [PMID: 23620827]

🎯 Children with Neurodevelopmental Disorders (ASD, ADHD)

Evidence Level: High

Physiology: many children with neurodevelopmental disorders have abnormal melatonin rhythms; supplementation corrects or compensates for this deficit and improves sleep onset and duration.

Clinical Study: Multiple pediatric RCTs and meta‑analyses (e.g., Braam et al.; Gringras et al.) report significant reductions in sleep‑onset latency and increases in total sleep time versus placebo in children with ASD/ND. [PMID: 29427092; PMIDs for individual RCTs summarized in that review]

🎯 Preoperative Anxiolysis and Perioperative Sleep

Evidence Level: Medium

Physiology: melatonin produces sedative and anxiolytic effects through melatonergic and indirect GABAergic modulation, improving preoperative calm and postoperative sleep quality.

Clinical Study: Multiple RCTs show preoperative melatonin (0.5–5 mg) reduces self‑reported anxiety scores and may lower anesthetic requirements compared with placebo; see perioperative meta‑analyses (peer‑reviewed anesthesiology literature) for pooled effect sizes. [PMID: 33338293]

🎯 Antioxidant and Mitochondrial Protection (Preclinical/Translational)

Evidence Level: Low–Medium (strong preclinical data)

Mechanism: direct scavenging of ROS/RNS, upregulation of antioxidant enzymes, stabilization of mitochondrial membranes and inhibition of apoptosis.

Clinical Study: Translational and early clinical studies summarize mitochondrial protective effects; comprehensive reviews (e.g., Cardinali et al.) discuss mechanisms and translational potential. [DOI: 10.1016/j.lfs.2020.117716]

🎯 Immunomodulation and Anti‑inflammatory Adjunct (Investigational)

Evidence Level: Low–Medium

Mechanism: suppression of NF‑κB signaling, modulation of cytokine profiles (IL‑6, TNF‑α), and attenuation of NLRP3 inflammasome activation in preclinical models.

Clinical Study: Reviews and observational studies during COVID‑19 hypothesized adjunctive benefits; RCTs are limited and heterogeneous. [DOI: 10.1016/j.lfs.2020.117716]

🎯 Adjunctive Use in Oncology (Supportive Care)

Evidence Level: Low–Medium

Possible benefits: improved sleep, quality of life and reduced chemotherapy‑related symptoms reported in small trials; anti‑proliferative effects seen in preclinical models.

Clinical Study: Small randomized and controlled trials in cancer patients report symptomatic benefit; larger confirmatory trials are lacking (see systematic reviews summarizing small RCTs).

📊 Current Research (2020–2026)

Research in the 2020s intensified on melatonin's immunomodulatory and antioxidant roles and on optimizing formulations for sleep maintenance and circadian therapeutics.

📄 Melatonin and COVID‑19: Potential Use as Adjuvant Treatment

• Authors: Cardinali et al.
• Year: 2020
• Study type: Review / hypothesis
• Participants: N/A (preclinical and clinical summaries)
• Results: Biological plausibility for anti‑inflammatory and antioxidant benefit; clinical evidence limited to observational reports and small studies.

Conclusion: melatonin is a biologically plausible adjunct in COVID‑19 but RCT data were lacking at time of publication. [DOI: 10.1016/j.lfs.2020.117716]

📄 Systematic Review and Meta‑analysis of Melatonin for Primary Sleep Disorders

• Authors: Ferracioli‑Oda et al.
• Year: 2013
• Study type: Systematic review & meta‑analysis (RCTs)
• Participants: pooled RCT populations (varied)
• Results: melatonin reduced sleep latency and modestly increased total sleep time compared with placebo; heterogeneity depended on dose and population.

Conclusion: melatonin is efficacious for sleep latency reduction and has modest benefit for total sleep time in pooled RCT data. [PMID: 23620827]

💊 Optimal Dosage and Usage

Typical OTC adult starting doses commonly recommended are 0.3 mg to 3 mg depending on goal; many clinicians start at 0.3–1 mg for circadian entrainment and 2 mg prolonged‑release for older adults with maintenance insomnia.

Recommended Daily Dose (NIH/ODS Reference)

• Standard OTC range: 0.3–10 mg nightly in adults (most common: 0.5–5 mg)
• Physiologic replacement / chronobiotic: 0.1–0.5 mg (microdoses for phase shifting)
• Prolonged‑release for older adults: 2 mg PR at bedtime (evidence‑based formulation)
• Pediatric: weight‑adjusted dosing frequently 0.5–3 mg for young children; up to 3–6 mg in older children under supervision

Timing

Immediate‑release: take 30–60 minutes before desired bedtime for sleep latency benefit.

Chronobiotic phase‑shifting: timing relative to the dim light melatonin onset (DLMO) is critical; evening dosing prior to habitual DLMO advances phase, morning dosing can delay phase — ideally guided by circadian assessment in clinical practice.

With food: taking with a heavy meal may delay Tmax and blunt rapid onset; take on an empty or light stomach for prompt effect.

Forms and Bioavailability

• Immediate‑release: bioavailability commonly cited ~~10–56% (mean ~15% in many studies).
• Prolonged‑release: similar total exposure with extended Tmax and flatter overnight profile.
• Sublingual/orodispersible: may provide faster rise and reduced first‑pass loss (product‑specific).

🤝 Synergies and Combinations

Melatonin works best when combined with behavioral circadian strategies (light management, sleep hygiene) and can be safely combined with non‑sedating adjuncts like magnesium for sleep quality.

• Evening light management + melatonin: reduce blue light 2–3 hours before bedtime to avoid endogenous suppression and potentiate supplement effect.
• Melatonin + CBT‑I: pharmacologic chronobiotic support plus behavioral therapy often yields superior outcomes for chronic insomnia.
• Melatonin + magnesium glycinate: may improve subjective sleep depth (typical combo: melatonin 0.5–3 mg with magnesium 100–300 mg elemental at bedtime).

⚠️ Safety and Side Effects

At common doses (0.3–5 mg), melatonin is generally well tolerated; adverse events are usually mild and transient.

Side Effect Profile

• Daytime sleepiness / somnolence: ~1–10% depending on dose and population
• Dizziness: ~1–5%
• Headache: ~1–5%
• Nausea / GI upset: ~1–3%
• Vivid dreams / nightmares: ~1–3%

Overdose

No precise human LD50 is established; clinically significant toxicity is uncommon.

Symptoms of excessive dosing: pronounced drowsiness, confusion, hypotension (rare), GI upset, altered mood or paradoxical agitation.

Management: supportive care, monitor airway/vitals; no specific antidote.

💊 Drug Interactions

Melatonin undergoes CYP1A2 metabolism; drugs that strongly inhibit or induce CYP1A2 have clinically meaningful effects on melatonin exposure.

⚕️ CYP1A2 inhibitors

• Medications: fluvoxamine (Luvox), ciprofloxacin (Cipro)
• Interaction type: metabolism inhibition → increased melatonin levels
• Severity: high
• Recommendation: consider marked dose reduction or avoid standard dosing; monitor for excess sedation. [Case reports and PK studies]

⚕️ CYP1A2 inducers

• Medications/substances: rifampin, carbamazepine, chronic tobacco smoking
• Interaction: increased clearance → reduced efficacy
• Severity: medium
• Recommendation: may require dose increase under clinician supervision.

⚕️ Anticoagulants

• Medications: warfarin (Coumadin)
• Interaction: theoretical pharmacodynamic effect on coagulation; isolated reports exist
• Severity: low–medium
• Recommendation: monitor INR when initiating or stopping melatonin.

⚕️ CNS depressants

• Medications: zolpidem (Ambien), benzodiazepines, opioids
• Interaction: additive sedation and respiratory depression risk
• Severity: medium–high
• Recommendation: use caution, consider dose reductions and avoid driving until effects known.

⚕️ Oral hormonal contraceptives / estrogens

• Medications: combined OCPs (ethinyl estradiol)
• Interaction: reduced melatonin clearance → increased exposure
• Severity: low–medium
• Recommendation: monitor for daytime sleepiness; adjust dose if needed.

⚕️ Antidepressants / MAOIs

• Medications: SSRIs (fluoxetine), MAOIs (tranylcypromine)
• Interaction: complex; monitor sleep and mood when coadministered
• Severity: low–medium
• Recommendation: clinician oversight advised.

🚫 Contraindications

Absolute Contraindications

• Known hypersensitivity to melatonin or excipients

Relative Contraindications

• Severe hepatic impairment (reduced clearance)
• Concurrent potent CYP1A2 inhibitors (e.g., fluvoxamine) without dose adjustment
• Autoimmune disease (theoretical immunomodulation)
• Concurrent warfarin therapy without INR monitoring

Special Populations

• Pregnancy: insufficient data; generally avoid unless benefits justify risks.
• Breastfeeding: limited data on transfer to milk; use with caution.
• Children: widely used under pediatric supervision; weight‑based dosing advised.
• Elderly: increased sensitivity; consider 2 mg prolonged‑release where indicated and monitor for daytime somnolence and falls.

🔄 Comparison with Alternatives

Melatonin differs from prescription melatonin receptor agonists (e.g., ramelteon) by being an endogenous, multi‑mechanistic molecule available OTC with broader receptor‑independent effects but greater variability in product quality.

• Ramelteon: selective MT1/MT2 agonist, prescription, predictable PK.
• Benzodiazepines / Z‑drugs: stronger hypnotic effect but higher risk (abuse, next‑day cognition, respiratory depression).
• Natural alternatives: tart cherry, valerian — evidence weaker and inconsistent.

✅ Quality Criteria and Product Selection (US Market)

Because melatonin supplements vary in content and purity, select products with third‑party verification (USP, NSF, ConsumerLab) and from reputable manufacturers.

• Look for USP or NSF verification and GMP declarations.
• Prefer batch‑tested brands and transparent COAs (certificate of analysis).
• Avoid products with large labeling discrepancies or undeclared actives.
• US reputable brands: Natrol, Thorne, Life Extension, Pure Encapsulations, NOW Foods (brand quality varies; prefer third‑party tested lines).

📝 Practical Tips

• Start low: 0.3–1 mg for circadian phase shifting; titrate up for sleep latency if needed.
• Time doses 30–60 minutes before bedtime for immediate‑release products.
• Use prolonged‑release 2 mg PR for older adults with sleep maintenance problems when available.
• Limit evening blue‑light exposure to potentiate melatonin’s effect.
• Discuss with a clinician if pregnant, breastfeeding, on warfarin, or taking potent CYP1A2 inhibitors.

🎯 Conclusion: Who Should Take Melatonin?

Melatonin is appropriate for adults and children with circadian‑related sleep problems (jet lag, delayed sleep phase) and for sleep‑onset insomnia; prolonged‑release formulations are preferable for older adults with sleep maintenance issues; selection and dose should be individualized and products chosen for verified quality.

References and further reading: NIH/ODS fact sheet on melatonin; Ferracioli‑Oda et al. (2013) PLoS ONE [PMID: 23620827]; Braam et al. (2018) pediatric reviews [PMID: 29427092]; Cardinali et al. (2020) Life Sciences [DOI: 10.1016/j.lfs.2020.117716]; EMA Circadin EPAR (2007); RCTs and meta‑analyses summarized in PubMed (see cited PMIDs above).