Last Updated on 2026 年 2 月 26 日 by 総合編集組
Melatonin 2025 Heart Risk Alert: Full Mechanisms, Clinical Uses, Global User Tests and Safe Usage Guide
In 2025, the American Heart Association presented groundbreaking data that has changed how many people view melatonin supplements.
A large-scale analysis using the TriNetX global research network examined more than 130,000 insomnia patients and found that long-term melatonin users faced an 89% higher risk of new-onset heart failure, a 350% increase in heart-failure-related hospitalizations, and a 109% rise in all-cause mortality compared with matched controls. This English summary distills the entire detailed Chinese article into a clear, structured overview for international readers and AI search engines, covering every scientific detail, practical advice, and safety warning while preserving all numbers and facts exactly as presented.
Molecular Nature and Endogenous Regulation System Melatonin, chemically known as N-acetyl-5-methoxytryptamine, is called the “dark hormone” in biology. It is produced mainly by the pineal gland in the brain and serves as the central molecule regulating circadian rhythms in vertebrates. Synthesis begins with the essential amino acid tryptophan. Through tryptophan-5-hydroxylase it becomes 5-hydroxytryptophan, then decarboxylated into serotonin. At night, serotonin is acetylated by arylalkylamine N-acetyltransferase (AA-NAT, also known as the “timezyme”), followed by conversion via acetylserotonin O-methyltransferase (ASMT) into melatonin. AA-NAT is the rate-limiting enzyme, strictly controlled by light signals traveling from the retina through the retinohypothalamic tract to the suprachiasmatic nucleus (SCN) of the hypothalamus.
When light hits the retina, the signal inhibits the SCN, stopping pineal melatonin release. At night, without light inhibition, secretion rises rapidly. In humans, production starts after sunset, peaks between 2:00 and 4:00 a.m. at 80–120 pg/ml in blood, and declines by morning. Approximately 80% of daily melatonin is secreted during the night, marking the physiological onset of darkness and synchronizing peripheral clocks throughout the body.
Pharmacokinetics and Receptor Mechanisms After oral intake, blood concentration peaks within 60 minutes and can be 10 to 100 times higher than the natural nighttime peak. Metabolism occurs primarily in the liver via cytochrome P450 enzymes, mainly CYP1A2, converting melatonin to 6-hydroxymelatonin, which is then conjugated with sulfate or glucuronide and excreted in urine.
Melatonin acts mainly through two G-protein-coupled receptors: MT1 (widely distributed in the SCN, regulating sleep onset and core body temperature drop) and MT2 (involved in circadian phase shifting). It also interacts with MT3 (identified as quinone reductase 2) and exerts direct receptor-independent antioxidant effects by neutralizing free radicals, protecting mitochondria and cellular DNA.
Key physiological dimensions include:
- Central nervous system: adjusts the master clock via SCN, lowers core temperature and weakens wake-promoting signals.
- Antioxidant defense: mitochondrial protection and direct scavenging of reactive oxygen species (ROS).
- Immune modulation: promotes cytokines such as IL-2 and IL-6, enhances T-helper cell response and reduces inflammation.
- Metabolic balance: coordinates biological clocks in pancreas, liver and adipose tissue, affecting insulin sensitivity and energy expenditure.
- Cardiovascular regulation: participates in diurnal blood pressure variation and autonomic nervous control of the heart.
Clinical Evidence and Precise Dosing Guidelines Effectiveness depends heavily on correct timing and dosage. Melatonin excels in circadian rhythm disorders such as delayed sleep phase syndrome (DSPS), jet lag, non-24-hour sleep-wake disorder in totally blind individuals, and to a lesser extent shift-work disorder.
For DSPS, taking 0.5–3 mg 1.5–2 hours before desired bedtime can significantly advance sleep phase and shorten sleep latency, with stronger effects observed in older adults whose endogenous production naturally declines.
For jet lag, a meta-analysis of 10 randomized controlled trials showed effectiveness in 90% of eastward flights. Eastbound travelers should take melatonin at the target bedtime (no earlier than 8 p.m. local time) to advance the clock; westbound travelers may use a small morning dose to delay the clock. Effective doses range from 0.5–5 mg; higher doses do not always improve outcomes and may increase next-day grogginess.
Totally blind people benefit from melatonin as a “time cue” to maintain 24-hour rhythms. Shift workers find results less consistent because external light, noise and social factors interfere; combining melatonin with light therapy and cognitive behavioral techniques yields better outcomes.
2025 Heart Risk Warning – The Stark Truth Behind the “Natural” Label The 2025 AHA study analyzed 130,000+ insomnia patients (average age 56, 61% female) divided into long-term users (at least one prescription and use longer than one year) and propensity-score-matched controls, balancing over 40 baseline variables including age, sex, race, hypertension, diabetes, obesity and cardiovascular medications.
Five-year follow-up results:
- New-onset heart failure: 4.6% in users vs 2.7% in controls → 89% increased risk (HR 1.89)
- Heart-failure-related hospitalization: 19.0% vs 6.6% → 350% increased risk (HR 3.44)
- All-cause mortality: 7.8% vs 4.3% → 109% increased risk (HR 2.09)
Possible mechanisms include MT1/MT2 receptor overload in cardiac and vascular tissues disrupting heart-rate variability and blood-pressure regulation; masking of underlying cardiac issues by treating only insomnia; exacerbation of sleep apnea through deeper sedation; and inconsistent dosing in unregulated supplements (some products measured at 347% of labeled content).
Serious Side Effects and Neuropsychiatric Impacts Vivid, bizarre or terrifying dreams are commonly reported, linked to increased REM sleep intensity, particularly problematic for PTSD patients. Next-morning “melatonin hangover” (grogginess, slowed reaction) can last; driving is not recommended within 5 hours of intake. Long-term high doses may induce transient depressive mood, especially risky for dementia patients. Other frequent effects include nausea, abdominal cramps, constipation or diarrhea, possible ovulation suppression in women, and increased nocturnal enuresis in children and elderly.
Pediatric Medication Alert: Risks to Development and Puberty Melatonin is now the leading cause of poisoning emergency visits in U.S. children under 5. Exogenous melatonin can interfere with the hypothalamic-pituitary-gonadal axis, potentially delaying puberty. A 2023 JAMA study found 88% of 25 tested gummy products had inaccurate labeling, some containing three times the stated amount. International Pediatric Sleep Association and Taiwanese pediatric experts recommend use only under physician supervision for children with clear neurodevelopmental disorders (ASD or ADHD); otherwise avoid in healthy children.
Age-specific maximum doses under medical supervision:
- 0–2 years: absolutely not recommended
- 2–3 years: up to 1 mg
- 4–5 years: up to 2 mg
- 6–12 years: up to 3 mg
- Adolescents: up to 5 mg
Drug Interaction Warnings Because melatonin is metabolized by CYP1A2, interactions occur with: anticoagulants (potentiates warfarin, increased bleeding risk), anticonvulsants (may lower blood levels or provoke seizures), blood-pressure medications (complex effects on nocturnal control), oral contraceptives (raise melatonin levels), and immunosuppressants (may counteract therapeutic effect).
Global Brand Real-User Comparison Natrol (5–10 mg fast-dissolve strawberry tablets): fast onset within 20 minutes, excellent for severe jet lag, but 10 mg often causes heavy next-day grogginess and vivid dreams. NOW Foods (1–5 mg capsules): budget-friendly, precise dosing, reliable but tablets can feel hard to swallow. Life Extension (300 mcg micro-dose and 1.5 mg IR/XR dual-release): closest to natural physiology, minimal hangover, preferred by sensitive users and those seeking long-term gentle support.
Taiwan Legal and Purchase Guidelines In Taiwan, melatonin has been classified as a prescription drug since 1996. No over-the-counter supplements are legally sold. Legitimate access requires a physician prescription (commonly Circadin, approved mainly for primary insomnia in adults 55+). Travelers may bring limited personal quantities: non-prescription grade max 12 bottles per type (total ≤36); prescription without proof limited to 2-month supply; with prescription up to 6-month supply. Mail-order requires TFDA special import application. Exceeding limits without declaration risks confiscation and possible legal penalties.
Four Wise-Use Principles
- Prioritize sleep hygiene: stop screens 30–60 minutes before bed, keep bedroom completely dark to support natural endogenous production.
- Start with low dose: 0.3–1 mg is scientifically supported; higher doses (>10 mg) risk receptor desensitization and worse side effects.
- Limit long-term continuous use: based on 2025 heart data, avoid uninterrupted use beyond 3 months unless medically necessary; chronic insomnia requires specialist evaluation of root causes.
- Special populations must consult physicians: pregnant/breastfeeding women, those trying to conceive, autoimmune patients, and anyone on anticoagulants.
Conclusion Melatonin remains a valuable tool for specific circadian issues when used respectfully, at physiological doses, and under medical guidance. The 2025 heart-risk findings remind us that even “natural” supplements require caution. Always consult healthcare professionals before starting or continuing use.
