Melatonin

Hypnotics. Melatonin receptor agonists

ATC code: N05CH01 (Melatonin)

Brand names – drugs

Circadin, Slenyto

Brand names – supplements

Natrol Melatonin, Nature Made Melatonin

Supplements are not tested in clinical trials and are not registered as medications.

Mechanism of action

Melatonin is a pineal hormone that synchronises circadian rhythms with the light cycle. It binds MT1 and MT2 receptors in the suprachiasmatic nucleus of the hypothalamus. Reduces sleep latency and shifts the circadian rhythm when correctly timed. Distinct from classical hypnotics (benzodiazepines, Z-drugs) – does not cause dependence, sedative effect is minimal. Efficacy depends on individual receptor sensitivity and timing relative to the individual circadian rhythm.

Indications

Jet lag disorder

First line

Melatonin is first-line for jet lag treatment and prevention. The 2002 Cochrane review (10 RCTs) showed a 50% reduction in jet lag symptoms when crossing 5 or more time zones. Dose: 0.5–5 mg 30 minutes before desired sleep in local time, for 2–5 days after arrival. AASM 2015 recommends melatonin for jet lag with “strong” evidence. Effect is more pronounced with eastward travel.

Doses above 3 mg do not provide additional benefit. In older adults, start at 0.5–1 mg to reduce residual morning sleepiness.

Sources

Delayed sleep phase syndrome

First line

Melatonin in low doses (0.3–0.5 mg) 5–7 hours before desired sleep time is the main pharmacological approach to delayed sleep phase syndrome. AASM 2015 recommends melatonin combined with morning bright-light therapy. Standard hypnotics (Z-drugs, benzodiazepines) do not help in DSPS – the problem is not sleep onset itself but a shifted internal clock. Therapy lasts weeks to months with gradual timing adjustment.

Sources

AASM: Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders (2015)

Insomnia in older adults

Second line

Prolonged-release melatonin (Circadin 2 mg) is EMA-approved for short-term (up to 13 weeks) treatment of chronic insomnia in patients 55 and older. The effect is modest – sleep latency reduction by 9 minutes and improved subjective sleep quality. Used when CBT-I and standard hypnotics are contraindicated. Foundational therapy is CBT-I and sleep hygiene.

Sources

Chronic insomnia in adults under 55

Not recommended

AASM 2017 recommends against melatonin for chronic insomnia in adults under 55 (weak recommendation, low evidence). Systematic reviews showed a clinically insignificant effect – sleep latency reduction by 4 minutes, sleep duration increase by 13 minutes. Foundational therapy is CBT-I; pharmacological options include doxylamine, short-course benzodiazepine receptor agonists, and orexin antagonists.

Sources

AASM: Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults (2017)

Anti-aging and longevity (marketed indication)

Not recommended

Melatonin for slowing ageing, antioxidant protection, or extending lifespan is not mentioned in international guidelines. The antioxidant hypothesis has not been convincingly confirmed in clinical RCTs. The marketing position of “youth hormone” lacks evidence. Long-term high-dose use in older adults has not been studied and is not recommended.

Sources

AASM: Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults (2017)

Practical notes

Timing and administration

Timing is critical. For insomnia and older adults: 30–60 minutes before desired sleep. For DSPS: 5–7 hours before target sleep time. For eastward jet lag: evening local time. For westward: evening local time from day 2–3. Use after midnight in people with normal circadian rhythm shifts the sleep phase and worsens sleep.

Dose titration

Standard supplement dose: 3 mg; pharmaceutical immediate-release: 1.5–3 mg (Melaxen); prolonged-release: 2 mg (Circadin). Optimal dose for most indications: 0.5–3 mg. Doses above 5 mg do not improve sleep onset but increase morning grogginess and nightmare risk. In children with ASD, the dose is individualised in a specialist service.

Monitoring

No specific monitoring is needed with short-term use. With long-term therapy (over 3 months), reassess efficacy and need for continuation. In patients on warfarin, monitor INR when adding melatonin. Individual response varies with baseline endogenous melatonin levels.

Special situations

In children, melatonin is registered in Russia only as Slenyto for children over 2 with autism spectrum disorder. Routine use in healthy children and adolescents is not recommended. In epilepsy, caution is required – seizure threshold reduction has been reported in some patients. In depression, bipolar disorder, or autoimmune disease, use is discussed with the treating clinician.

Common myths

Myth: “melatonin is a safe sleep aid for everyone”. Fact: effect on insomnia in adults under 55 is clinically insignificant. Benefit is established mainly for jet lag and DSPS. In epilepsy, on warfarin, or on immunosuppressive therapy, caution is required.

Myth: “higher dose, better effect”. Fact: doses above 3–5 mg do not improve sleep onset but increase morning grogginess and nightmare risk. Supplements at 10 mg and above are marketing, not science.

Myth: “melatonin is the youth hormone”. Fact: antioxidant and anti-ageing effects are not clinically confirmed. Long-term high-dose use in older adults has not been studied. Age-related decline in melatonin secretion is physiological, not pathological.

Safety

Contraindications

Hypersensitivity to melatonin
Severe hepatic impairment
Autoimmune diseases (relative contraindication)
Pregnancy and breastfeeding
Children under 2 (all forms); under 18 outside paediatric protocols

Serious adverse effects

Paradoxical reactions – worsening of insomnia, increased anxiety (rare)
Allergic reactions (very rare)

Common adverse effects

Headache
Morning sleepiness
Dizziness
Nausea

Uncommon adverse effects

Vivid dreams, nightmares
Irritability, mood changes
Gastrointestinal discomfort

PregnancyFDA C

Data in pregnancy are insufficient. Endogenous melatonin contributes to pregnancy physiology and foetal development. Supplemental melatonin in pregnancy is not recommended.

Breastfeeding

Transfers into breast milk. Use during breastfeeding is not recommended due to possible effects on infant circadian rhythm.