Melatonin | Supplementopedia

Overview

Melatonin is a naturally occurring indoleamine produced primarily by the pineal gland in response to darkness. It functions as the principal hormonal regulator of circadian rhythms, signaling the body that it is time to initiate sleep‑related processes.

Benefits

Sleep Improvement: Melatonin improves sleep onset latency, total sleep time, and sleep quality in both healthy adults and those with insomnia, jet-lag, or shift-work disorder.
Circadian Alignment: In older adults, supplementation modestly enhances circadian alignment, reducing nocturnal awakenings.
Metabolic Regulation: Melatonin improves insulin sensitivity and may attenuate nocturnal blood‑glucose spikes, especially in shift‑workers and patients with type‑2 diabetes.
Neuroprotective Effects: Melatonin reduces oxidative stress and may protect against age‑related cognitive decline, with meta‑analyses indicating small improvements in memory and executive function in mild cognitive impairment.
Additional Benefits: Melatonin may reduce migraine frequency, attenuate postoperative pain, and provide adjunctive support in mood disorders, although these effects are generally modest and context-dependent.
Primary Benefit: The strongest, reproducible benefit is the promotion of physiological sleep and circadian stability.

How It Works

Receptor Binding: Melatonin exerts its effects mainly through high‑affinity binding to G‑protein‑coupled melatonin receptors MT1 (MTNR1A) and MT2 (MTNR1B) located in the suprachiasmatic nucleus (SCN) and peripheral tissues.
MT1 Activation: Activation of MT1 reduces neuronal firing in the SCN via inhibition of adenylate cyclase, lowering cAMP and reducing excitatory neurotransmission, thereby promoting sleep.
MT2 Activation: MT2 activation influences phase‑shifting of the circadian clock by modulating intracellular calcium and regulating clock gene expression (e.g., PER1, PER2).
Peripheral Tissue Interaction: In peripheral tissues, melatonin interacts with the nuclear receptor RORα, modulating antioxidant gene transcription (e.g., SOD, GPx).
Antioxidant Capacity: Melatonin scavenges hydroxyl radicals, peroxynitrite, and nitric oxide, and up‑regulates the Nrf2 pathway, enhancing cellular defense.
Overall Effect: Receptor‑mediated signaling and direct free‑radical scavenging synchronize circadian rhythms, modulate immune responses, and protect cellular integrity.

Dosage

Typical Dosage Range: Typical over‑the‑counter doses range from 0.3 mg to 10 mg per day.
Common Regimen: The most common regimens are 0.5–5 mg taken 30–60 minutes before bedtime.
Jet-Lag: For jet‑lag, 0.5–3 mg taken at the target nighttime for 2–4 days is effective.
Shift-Work/Delayed Sleep Phase: For shift‑work or delayed‑sleep‑phase disorder, titration up to 5 mg at the desired sleep onset time is recommended.
Pediatric Use: In pediatric populations (e.g., children with neurodevelopmental disorders), doses of 0.5–3 mg are used, but always under medical supervision.
Older Adults: For older adults, lower doses (0.3–2 mg) are often sufficient due to decreased melatonin clearance.
Extended-Release Formulations: Extended‑release formulations (2–5 mg) may improve sleep maintenance.
Timing: Timing is critical—administration at the appropriate circadian phase (i.e., before endogenous melatonin rise) maximizes efficacy.
High Doses: Doses >10 mg have not demonstrated additional benefit and may increase adverse effects.

Safety & Side Effects

General Tolerance: Melatonin is generally well‑tolerated.
Common Side Effects: Common mild side effects (≤10 % incidence) include daytime drowsiness, headache, and mild gastrointestinal upset.
Rare Side Effects: Rarely, vivid dreams or transient mood changes occur.
Contraindications: Contraindications include severe hepatic impairment (reduced clearance), pregnancy, and lactation without physician guidance.
Cautions: Caution is advised in patients on anticoagulants (e.g., warfarin) due to potential increased bleeding risk, and in those taking immunosuppressants or antihypertensives (possible additive hypotensive or immunomodulatory effects).
Drug Interactions: Melatonin can interact with CYP1A2 and CYP2C19 substrates (e.g., fluvoxamine, carbamazepine) altering drug levels.
Pediatric Use Considerations: Pediatric use should be limited to specific conditions under medical supervision; high doses (>10 mg) may disrupt hormonal development.
Short-Term Safety: Overall, short‑term use (<6 months) is considered safe, but long‑term safety data remain limited, particularly in pregnant or pediatric populations.

Chemistry

Chemical Name: Melatonin (N‑acetyl‑5‑methoxy‑tryptamine)
Molecular Formula: C₁₃H₂₁N₃O₂
Molecular Weight: 232.28 g·mol⁻¹
IUPAC Name: N‑acetyl‑5‑methoxy‑1H‑indole‑3‑ethanamine
Molecular Structure: The molecule consists of an indole ring (a fused benzene‑pyrrole system) substituted at the 5‑position with a methoxy (–OCH₃) group and an N‑acetyl side‑chain attached at the 3‑position, forming an amide linkage.
Lipophilicity: The compound is moderately lipophilic (log P ≈ 0.8), allowing it to cross the blood–brain barrier.
Amphiphilic Properties: Melatonin is amphiphilic, displaying modest aqueous solubility (~1 mg mL⁻¹) and stability in acidic environments but rapid degradation under light and alkaline conditions.
Metabolism: Its metabolic fate involves hepatic cytochrome P450 enzymes (primarily CYP1A2) converting it to 6‑hydroxymelatonin and subsequently to 6‑sulfate and 6‑glucuronide conjugates for renal excretion.

Sources & Quality

Natural Synthesis: Naturally, melatonin is synthesized endogenously from the amino acid tryptophan via serotonin.
Commercial Production: Commercially, it is obtained predominantly through chemical synthesis (e.g., condensation of 5‑methoxy‑tryptamine with acetic anhydride) which yields a high‑purity product at scale.
Plant-Based Extracts: Plant‑based extracts (e.g., from Citrus sinensis or Moringa species) contain trace melatonin but are not used for pharmaceutical‑grade supplements due to low concentrations and variability.
Manufacturing Practices: Quality‑focused manufacturers employ Good Manufacturing Practices (GMP) and provide third‑party testing for potency, purity, and absence of contaminants (heavy metals, microbial load).
Packaging: The presence of a stable, light‑protected packaging is crucial to prevent degradation.
Consumer Guidance: Consumers should look for products labeled “pharmaceutical‑grade,” with certificates of analysis and adherence to USP or NF standards to ensure consistent dosing and safety.