Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone primarily produced by the pineal gland in response to darkness, serving as the body’s signal for nighttime. Research shows melatonin exerts its diverse biological effects through both receptor-mediated and receptor-independent pathways. Its chronobiotic effects occur primarily through activation of two G-protein coupled receptors (MT1 and MT2) in the suprachiasmatic nucleus of the hypothalamus—the body’s master circadian clock. When melatonin binds to MT1 receptors, it inhibits neuronal firing and suppresses the clock’s activity, signaling to the body that it is nighttime and promoting sleep onset. Beyond its sleep-regulating effects, melatonin functions as a potent and unique antioxidant that can easily cross cell membranes and the blood-brain barrier. It directly scavenges reactive oxygen species while also stimulating the expression and activity of antioxidant enzymes including superoxide dismutase and glutathione peroxidase. Melatonin demonstrates immunomodulatory effects through receptors expressed on immune cells and exhibits anti-inflammatory properties by inhibiting NF-κB activation. Clinical studies support its efficacy for sleep onset insomnia, jet lag, and shift work adaptation. Typical supplemental doses range from 0.3-10mg, with lower doses (0.3-1mg) often being as effective as higher doses for sleep improvement.
Alternative Names: N-acetyl-5-methoxytryptamine, Pineal hormone, Sleep hormone, Circadian hormone
Categories: Hormone, Neurohormone, Chronobiotic, Antioxidant
Primary Longevity Benefits
- Sleep quality improvement
- Circadian rhythm regulation
- Antioxidant protection
- Immune modulation
Secondary Benefits
- Jet lag reduction
- Shift work adaptation
- Mood support
- Neuroprotection
- Mitochondrial support
- Gut health
- Anti-inflammatory effects
- Blood pressure regulation
Mechanism of Action
Melatonin exerts its diverse biological effects through multiple mechanisms involving receptor-mediated and receptor-independent pathways. As an endogenous neurohormone primarily produced by the pineal gland, melatonin’s most well-known function is regulating the sleep-wake cycle and other circadian rhythms. This chronobiotic effect is primarily mediated through melatonin’s interaction with two G-protein coupled receptors: MT1 and MT2. These receptors are widely distributed throughout the body but are particularly concentrated in the suprachiasmatic nucleus (SCN) of the hypothalamus, which serves as the body’s master circadian clock.
When melatonin binds to MT1 receptors in the SCN, it inhibits neuronal firing and suppresses the clock’s activity, signaling to the body that it is nighttime and promoting sleep onset. This effect is reinforced by melatonin’s action on MT2 receptors, which helps synchronize the circadian rhythm to the environmental light-dark cycle. The timing of melatonin secretion is crucial for its chronobiotic effects – levels naturally rise in the evening (typically beginning 2-3 hours before habitual bedtime), peak during the night, and decline toward morning. This pattern, often called the ‘darkness hormone’ effect, is controlled by the SCN based on light information received from the retina.
Bright light, particularly blue wavelength light, suppresses melatonin production, while darkness permits its synthesis and release. Beyond its receptor-mediated effects on sleep and circadian rhythms, melatonin functions as a potent antioxidant through several mechanisms. Unlike many other antioxidants, melatonin can easily cross cell membranes and the blood-brain barrier, allowing it to protect both lipid and aqueous cellular components. Melatonin directly scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS), including the highly damaging hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, and peroxynitrite.
Remarkably, melatonin and several of its metabolites formed during this scavenging process (such as cyclic 3-hydroxymelatonin and N1-acetyl-N2-formyl-5-methoxykynuramine) also possess antioxidant properties, creating a cascade of protection against oxidative damage. Beyond direct scavenging, melatonin enhances the body’s endogenous antioxidant defenses by stimulating the expression and activity of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. It also increases cellular glutathione levels and helps maintain mitochondrial homeostasis, protecting these critical cellular powerhouses from oxidative damage. In the immune system, melatonin demonstrates immunomodulatory effects through both receptor-dependent and receptor-independent mechanisms.
Immune cells, including T and B lymphocytes, natural killer cells, and monocytes, express melatonin receptors. Through these receptors, melatonin can influence cytokine production, enhance the activity of natural killer cells, and modulate lymphocyte proliferation. Rather than simply stimulating or suppressing immune function, melatonin appears to normalize immune responses, enhancing activity when needed while preventing excessive inflammation. This balanced immunomodulation may be particularly beneficial during aging, when immune function often becomes dysregulated.
Melatonin also exhibits anti-inflammatory properties through several pathways. It inhibits nuclear factor-kappa B (NF-κB) activation, a key transcription factor in inflammatory responses, thereby reducing the production of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Additionally, melatonin inhibits the activity of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), further reducing inflammatory mediator production. In the brain, melatonin demonstrates neuroprotective effects through multiple mechanisms.
Beyond its antioxidant and anti-inflammatory actions, melatonin modulates various neurotransmitter systems, including gamma-aminobutyric acid (GABA), glutamate, dopamine, and serotonin. It also promotes neurogenesis, enhances brain-derived neurotrophic factor (BDNF) expression, and protects against excitotoxicity. These effects may contribute to melatonin’s potential benefits for cognitive function and protection against neurodegenerative diseases. Melatonin also influences mitochondrial function, enhancing energy production while reducing oxidative damage.
It improves mitochondrial electron transport chain activity, increases ATP production, and maintains mitochondrial membrane potential. These effects on cellular energy metabolism may contribute to melatonin’s protective effects against age-related decline in various tissues. In the cardiovascular system, melatonin demonstrates cardioprotective effects through antioxidant activity, improvement in lipid profiles, and regulation of blood pressure. Melatonin receptors are present in cardiovascular tissues, and their activation can influence vascular tone, cardiac remodeling, and ischemia-reperfusion injury.
For metabolic regulation, melatonin influences glucose metabolism and insulin sensitivity. MT1 and MT2 receptors are expressed in pancreatic islet cells, and melatonin signaling can modulate insulin secretion. Melatonin also affects adipose tissue metabolism and may influence body weight regulation through effects on energy expenditure and food intake. Through these diverse and complementary mechanisms—receptor-mediated chronobiotic effects, potent antioxidant activity, immunomodulation, anti-inflammatory actions, neuroprotection, and metabolic regulation—melatonin influences numerous physiological processes, explaining its wide range of potential health benefits beyond sleep regulation.
Optimal Dosage
Disclaimer: The following dosage information is for educational purposes only. Always consult with a healthcare provider before starting any supplement regimen, especially if you have pre-existing health conditions, are pregnant or nursing, or are taking medications.
No official Recommended Dietary Allowance (RDA) has been established for melatonin, as it is not considered an essential nutrient but rather a hormone that the body naturally produces. The optimal dose varies significantly depending on the specific health goal, individual factors, and formulation used. For sleep improvement in healthy adults, research suggests that lower doses (0.3-1 mg) are often as effective as higher doses for initiating sleep, with some evidence suggesting they may produce more physiological sleep patterns. However, many commercial products contain much higher doses (3-10 mg), which may be beneficial for specific conditions but unnecessary for general sleep support in most individuals.
The timing of melatonin administration is crucial for its effectiveness. For sleep onset issues, taking melatonin 30-60 minutes before desired bedtime is typically recommended. For circadian rhythm adjustment (such as jet lag or shift work), timing should be based on the specific circadian shift desired. Immediate-release formulations are generally preferred for sleep onset difficulties, while extended-release formulations may be more beneficial for sleep maintenance issues.
Individual response to melatonin varies considerably due to factors including age, body weight, metabolism, concurrent medications, and genetic variations in melatonin receptors and metabolizing enzymes.
By Condition
| Condition | Dosage | Notes |
|---|---|---|
| general sleep improvement | 0.3-3 mg, 30-60 minutes before bedtime | Lower doses (0.3-1 mg) often sufficient and may produce more natural sleep patterns; start with lowest effective dose |
| jet lag | 0.5-5 mg, taken at destination bedtime | Begin on day of travel and continue for 2-5 days; timing is crucial for effectiveness |
| delayed sleep phase syndrome | 0.5-5 mg, 3-5 hours before current sleep onset time | Gradually adjust timing as sleep schedule normalizes; combine with morning light therapy for best results |
| shift work sleep disorder | 1-3 mg, taken at desired sleep time | Consistent timing important; may need to be combined with light management strategies |
| insomnia in older adults | 1-2 mg, 1-2 hours before bedtime | May be particularly beneficial due to age-related decline in endogenous melatonin production |
| REM sleep behavior disorder | 3-12 mg, 30-60 minutes before bedtime | Higher doses typically used than for general sleep improvement; extended-release formulations often preferred |
| sleep disturbances in autism spectrum disorders | 1-6 mg, 30-60 minutes before bedtime | Start with lower doses and increase gradually if needed; monitor for daytime sleepiness |
| antioxidant/neuroprotective effects | 3-10 mg daily | Higher doses typically used for non-sleep applications; timing less critical than for sleep effects |
By Age Group
| Age Group | Dosage | Notes |
|---|---|---|
| children (under 12 years) | 0.5-3 mg, only under medical supervision | Limited research in pediatric populations; generally reserved for specific conditions like autism spectrum disorders or circadian rhythm disorders |
| adolescents (12-18 years) | 0.5-5 mg, preferably under medical guidance | May be particularly helpful for delayed sleep phase syndrome common in adolescents; start with lower doses |
| adults (18-55 years) | 0.3-5 mg for most sleep applications | Lower doses (0.3-1 mg) often sufficient for sleep onset; higher doses may be needed for specific conditions |
| older adults (55+ years) | 1-3 mg for sleep improvement | May be more beneficial due to age-related decline in endogenous melatonin production; monitor for morning grogginess |
| pregnant and breastfeeding women | Not recommended without medical supervision | Insufficient safety data; endogenous melatonin plays important roles in pregnancy and fetal development |
Bioavailability
Absorption Rate
Melatonin demonstrates variable oral bioavailability, ranging from approximately 3% to 33% depending on individual factors and formulation. This wide range is primarily due to significant first-pass metabolism in the liver, where melatonin is rapidly metabolized by cytochrome P450 enzymes (primarily CYP1A2) to form 6-hydroxymelatonin, which is then conjugated with sulfate or glucuronic acid for excretion. After oral administration of immediate-release formulations, melatonin is absorbed relatively quickly from the gastrointestinal tract, with peak plasma concentrations typically occurring within 20-60 minutes. However, the presence of food, particularly high-fat meals, can delay absorption by 30-90 minutes and potentially reduce peak concentrations.
Sublingual and transmucosal formulations (such as sublingual tablets and oral sprays) bypass first-pass metabolism, resulting in faster absorption (peak levels within 10-30 minutes) and potentially higher bioavailability compared to traditional oral formulations. Extended-release formulations are designed to release melatonin gradually over 6-8 hours, resulting in lower peak concentrations but more sustained plasma levels throughout the night. This pharmacokinetic profile may better mimic the body’s natural melatonin secretion pattern and be more beneficial for sleep maintenance issues. Once in circulation, melatonin is widely distributed throughout the body and readily crosses the blood-brain barrier due to its lipophilic nature.
The plasma half-life of exogenous melatonin is relatively short, approximately 40-60 minutes for immediate-release formulations, though the physiological effects may persist longer due to receptor binding and downstream signaling cascades. Individual variations in melatonin metabolism, particularly in CYP1A2 activity, can significantly affect bioavailability and response to supplementation. Genetic polymorphisms, age, concurrent medications, and lifestyle factors (such as smoking, which induces CYP1A2) can all influence melatonin metabolism and clearance.
Enhancement Methods
Sublingual or transmucosal administration (bypasses first-pass metabolism), Taking on an empty stomach (food, particularly high-fat meals, can delay and reduce absorption), Liposomal formulations (may enhance absorption and cellular delivery), Transdermal patches (bypass first-pass metabolism and provide sustained delivery), Avoiding grapefruit juice and other CYP1A2 inhibitors before taking (can dramatically increase melatonin levels), Micronized formulations (smaller particle size may improve dissolution and absorption), Cyclodextrin complexes (improve solubility and stability), Avoiding caffeine and smoking (both induce CYP1A2, potentially reducing melatonin levels), Nanoemulsions and nanoparticle formulations (emerging technologies that may enhance bioavailability), Combination with absorption enhancers in some specialized formulations
Timing Recommendations
The timing of melatonin administration is crucial for its effectiveness and varies significantly depending on the intended purpose. For sleep onset difficulties, melatonin is most effective when taken 30-60 minutes before desired bedtime. This timing allows plasma levels to rise as natural melatonin would in individuals with healthy circadian rhythms. Taking melatonin too early (3+ hours before bedtime) may shift the circadian rhythm earlier than desired and potentially cause earlier than desired morning awakening.
Conversely, taking it too late (at or after bedtime) may not provide sufficient time for the hormone to take effect for sleep initiation. For circadian rhythm adjustment, such as managing jet lag or shift work disorder, timing should be based on the specific circadian shift desired. For eastward travel (advancing the clock), melatonin should be taken at the destination bedtime. For westward travel (delaying the clock), melatonin may be taken in the second half of the night according to the destination time zone, though this is practically challenging and often unnecessary as westward travel is generally easier to adjust to.
For delayed sleep phase syndrome (difficulty falling asleep until late hours), melatonin should initially be taken 3-5 hours before the current typical sleep onset time, then gradually adjusted earlier as the sleep schedule normalizes. This approach helps advance the circadian rhythm to an earlier schedule. For shift workers trying to sleep during daylight hours, melatonin should be taken at the desired sleep time, regardless of whether this is morning or afternoon. Combining melatonin with light management (darkness during sleep, bright light during desired wake times) enhances effectiveness.
When using extended-release formulations for sleep maintenance issues, the same timing principles apply – 30-60 minutes before desired bedtime is typically recommended. For individuals using melatonin primarily for its antioxidant or neuroprotective effects rather than sleep regulation, timing is less critical, though evening administration is still generally recommended to align with the body’s natural melatonin rhythm. Consistency in timing from day to day is important for optimal effects, particularly when using melatonin for circadian rhythm regulation. Irregular timing can send conflicting signals to the body’s circadian system and reduce effectiveness.
For individuals taking multiple supplements or medications, separating melatonin from stimulants (like caffeine) and certain medications (particularly those affecting CYP1A2 activity) by at least 2 hours may help maintain consistent absorption and effectiveness.
Safety Profile
Safety Rating
Side Effects
- Morning grogginess or hangover-like effects (particularly with higher doses)
- Headache (typically mild and transient)
- Dizziness
- Nausea
- Vivid dreams or nightmares
- Mild anxiety or irritability in some individuals
- Temporary changes in blood pressure (both increases and decreases have been reported)
- Short-term daytime sleepiness
- Mild depression symptoms in susceptible individuals
- Temporary changes in body temperature (slight reduction)
- Potential for sleep disruption if taken at incorrect timing
- Mild gastrointestinal discomfort
Contraindications
- Autoimmune disorders (theoretical concern due to immunomodulatory effects)
- Pregnancy and breastfeeding (insufficient safety data; melatonin affects reproductive hormones)
- Seizure disorders (may lower seizure threshold in some individuals)
- Severe liver disease (may affect melatonin metabolism)
- Severe kidney disease (limited research on safety)
- Transplant recipients (theoretical concern due to immunomodulatory effects)
- Active bleeding or bleeding disorders (theoretical concern based on potential antiplatelet effects)
- Depression (may worsen symptoms in some individuals)
- Diabetes (may affect blood glucose and insulin sensitivity)
- Caution advised in children except under medical supervision
Drug Interactions
- Anticoagulant and antiplatelet medications (potential additive effects on bleeding risk)
- Antihypertensive medications (may enhance blood pressure-lowering effects)
- Immunosuppressants (theoretical interaction due to melatonin’s immunomodulatory effects)
- Diabetes medications (may affect blood glucose levels and insulin sensitivity)
- Contraceptive drugs (may reduce effectiveness of hormonal contraceptives)
- Fluvoxamine and other CYP1A2 inhibitors (dramatically increase melatonin levels)
- Benzodiazepines and other sedatives (additive sedative effects)
- Caffeine and other stimulants (may reduce melatonin’s effectiveness)
- Nifedipine and other calcium channel blockers (melatonin may reduce their effectiveness)
- Antidepressants (complex interactions depending on specific medication)
- Anti-seizure medications (potential for complex interactions)
- Corticosteroids (may counteract some of melatonin’s immune effects)
Upper Limit
No official Tolerable Upper Intake Level (UL) has been established for melatonin. Based on available research, short-term use of doses up to 10 mg daily appears to be safe for most healthy adults, though such high doses are unnecessary for most sleep applications and may increase the risk of side effects. For long-term use, lower doses (0.5-5 mg) are generally recommended, as there is limited research on the safety of chronic high-dose supplementation. It’s worth noting that many over-the-counter melatonin supplements contain significantly more melatonin than labeled, with some products containing 150-478% of the stated amount, according to independent testing.
This inconsistency makes it difficult to establish precise upper limits and increases the risk of unintentional overdosing. While melatonin appears to have a high margin of safety with no reported cases of fatal overdose from melatonin alone, extremely high doses may potentially disrupt circadian rhythms, hormone balance, and sleep architecture. The principle of using the lowest effective dose is particularly important with melatonin, as higher doses do not necessarily produce better sleep outcomes and may increase the risk of side effects like morning grogginess, headaches, and vivid dreams. For children, even more caution is warranted, with typical therapeutic doses ranging from 0.5-3 mg under medical supervision.
Long-term safety data in pediatric populations is limited, raising concerns about potential effects on development, particularly sexual development given melatonin’s role in reproductive hormone regulation. For older adults, who typically have lower endogenous melatonin production, slightly higher doses may be appropriate (1-3 mg), though starting with the lowest effective dose is still recommended. As with any supplement, those with specific health conditions, on medications, or with known sensitivities should consult healthcare providers before using melatonin, particularly for long-term use or at higher doses.
Regulatory Status
Fda Status
In the United States, melatonin is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under this classification, melatonin can be sold without prescription and without requiring FDA approval for safety and efficacy before marketing, unlike pharmaceutical drugs. As a dietary supplement, manufacturers are responsible for ensuring their products are safe before marketing, though they are not required to provide evidence of safety to the FDA. The FDA can take action against unsafe melatonin products after they reach the market.
Manufacturers are prohibited from making specific disease claims (such as claiming melatonin treats insomnia, which is classified as a disease) but can make structure/function claims (such as ‘helps support normal sleep patterns’ or ‘may help with occasional sleeplessness’). All melatonin supplements must include a disclaimer stating that the product has not been evaluated by the FDA and is not intended to diagnose, treat, cure, or prevent any disease. The FDA does not regulate the quality or purity of melatonin supplements, which has led to significant variability in product content. Independent testing has repeatedly found substantial discrepancies between labeled and actual melatonin content in many supplements, with some products containing significantly more or less melatonin than claimed.
Some products have also been found to contain serotonin, which is not permitted in dietary supplements. The FDA has not established a recommended daily intake for melatonin, as it is not considered an essential nutrient.
International Status
Eu: In the European Union, melatonin is regulated more strictly than in the United States. In most EU countries, melatonin products containing more than 2 mg are classified as medicinal products requiring prescription. A prescription product called Circadin (2 mg prolonged-release melatonin) is approved for short-term treatment of primary insomnia in patients aged 55 years and older. Lower-dose melatonin products (typically ≤1 mg) may be sold as food supplements in some EU countries, though regulations vary between member states. For example, in Germany and Poland, all melatonin products are considered medicines, while in Italy and the Netherlands, low-dose products may be sold as food supplements. The European Food Safety Authority (EFSA) has approved a health claim for melatonin stating that it ‘contributes to the reduction of time taken to fall asleep’ when 1 mg is taken close to bedtime.
Canada: In Canada, melatonin is classified as a natural health product (NHP) rather than a dietary supplement or drug. It is available over-the-counter but is subject to more regulatory oversight than in the United States. Health Canada has approved specific health claims for melatonin related to sleep, including ‘helps increase the total sleep time in people suffering from sleep restriction or altered sleep schedule’ and ‘helps relieve the daytime fatigue associated with jet lag.’ Products must have a Natural Product Number (NPN) issued by Health Canada, indicating they have been assessed for safety, efficacy, and quality. Dosage recommendations and specific indications are more standardized than in the U.S. market.
Australia: In Australia, melatonin was historically available only by prescription. However, in June 2021, the Therapeutic Goods Administration (TGA) reclassified low-dose melatonin (≤2 mg) as a Schedule 3 (Pharmacist Only) medicine, making it available over-the-counter for adults aged 55 and older for the short-term treatment of primary insomnia. Higher doses remain prescription-only. As a registered medicine rather than a supplement, melatonin products in Australia are subject to stricter quality control and standardization requirements than in countries where it is classified as a supplement.
Japan: In Japan, melatonin is not approved as either a drug or a dietary supplement. It cannot be legally sold for human consumption, though it may be available through personal importation channels for individual use. The Japanese regulatory authorities have not recognized melatonin for any health-related uses.
Uk: Following Brexit, the UK has maintained regulations similar to the EU. Melatonin is primarily available as a prescription medicine (Circadin and generic equivalents) for short-term treatment of insomnia in patients aged 55 and older. Some lower-dose products may be available as food supplements, but the regulatory environment remains more restrictive than in the United States.
Synergistic Compounds
| Compound | Synergy Mechanism | Evidence Rating |
|---|---|---|
| Magnesium | Magnesium and melatonin work together to promote relaxation and sleep through complementary mechanisms. Magnesium activates GABA receptors and regulates neurotransmitters involved in sleep, while melatonin regulates circadian rhythm and sleep onset. Magnesium also plays a role in melatonin production by helping convert serotonin to melatonin. Together, they may provide more comprehensive sleep support than either alone – magnesium helping with muscle relaxation and nervous system calming, while melatonin helps regulate sleep timing and initiation. This combination may be particularly beneficial for individuals with both physical tension and circadian rhythm disruptions. | 4 |
| L-Theanine | L-theanine promotes relaxation without sedation by increasing alpha brain waves and GABA, while melatonin regulates sleep-wake cycles and sleep initiation. This combination addresses both the mental relaxation needed to prepare for sleep and the hormonal signaling that initiates sleep. L-theanine may help reduce the mental chatter and anxiety that can interfere with falling asleep, while melatonin helps synchronize the body’s internal clock. Together they provide complementary support for the transition from wakefulness to sleep, potentially improving both sleep onset and quality. | 3 |
| Vitamin B6 (Pyridoxine) | Vitamin B6 is a cofactor in the production of melatonin from serotonin, which itself is produced from tryptophan. By ensuring adequate B6 status, the body can more efficiently convert serotonin to melatonin, potentially enhancing endogenous melatonin production alongside supplemental melatonin. This combination supports the body’s natural melatonin synthesis pathway while providing exogenous melatonin. B6 also supports overall neurotransmitter balance, which may complement melatonin’s sleep-promoting effects. | 3 |
| 5-HTP (5-Hydroxytryptophan) | 5-HTP is a precursor to serotonin, which is subsequently converted to melatonin in the pineal gland. By providing 5-HTP, the serotonin-melatonin pathway receives additional support, potentially enhancing both serotonin (mood) and melatonin (sleep) levels. This combination may be particularly beneficial for individuals with both mood and sleep disturbances, as it addresses both the serotonergic and melatonergic systems. The timing of these supplements can be staggered (5-HTP earlier in the evening, melatonin closer to bedtime) to optimize their respective effects. | 3 |
| GABA (Gamma-Aminobutyric Acid) | GABA is the primary inhibitory neurotransmitter in the brain, promoting relaxation and reducing neuronal excitability. Melatonin has been shown to enhance GABAergic transmission in certain brain regions. Together, they provide complementary calming effects – GABA directly inhibiting neuronal activity and promoting relaxation, while melatonin regulates sleep-wake cycles and sleep initiation. This combination may help address both the neurochemical (GABA) and hormonal (melatonin) aspects of sleep regulation, potentially improving both sleep onset and quality. | 3 |
| Vitamin C | Vitamin C serves as an antioxidant that may help protect melatonin from oxidative degradation, potentially extending its activity. Additionally, vitamin C appears to support the recycling of other antioxidants that work alongside melatonin in neutralizing free radicals. This combination enhances the overall antioxidant network, with melatonin and vitamin C protecting different cellular components through complementary mechanisms. For sleep applications, this synergy may be less relevant than for melatonin’s antioxidant applications. | 2 |
| Valerian Root | Valerian root promotes relaxation and sleep through GABA modulation and other mechanisms, while melatonin regulates sleep-wake cycles. Valerian primarily addresses the relaxation and sedation aspects of sleep, while melatonin addresses the circadian timing aspects. Together they provide complementary support for both sleep initiation and quality. This combination may be particularly beneficial for individuals with both anxiety-related sleep difficulties and circadian rhythm disruptions, though the sedative effects may be additive and should be approached cautiously. | 3 |
| Zinc | Zinc plays a role in melatonin production and receptor function. It is a cofactor for various enzymes involved in neurotransmitter synthesis and regulation, including those in the melatonin production pathway. Zinc also modulates GABA activity, which complements melatonin’s sleep-promoting effects. Additionally, both zinc and melatonin have antioxidant properties, potentially providing enhanced protection against oxidative stress. This combination supports both melatonin’s effectiveness and overall sleep neurochemistry. | 2 |
| Glycine | Glycine promotes sleep by reducing core body temperature and acting as an inhibitory neurotransmitter in the brain stem and spinal cord. Melatonin regulates sleep-wake cycles and also reduces core body temperature as part of its sleep-promoting effects. Together, they may enhance the temperature-dropping effect that facilitates sleep onset and improve sleep quality through complementary mechanisms. Glycine particularly supports deep, slow-wave sleep, while melatonin helps with sleep initiation and timing, potentially providing more comprehensive sleep support than either alone. | 3 |
| Tart Cherry Extract | Tart cherries are one of the few natural food sources containing melatonin, along with other bioactive compounds like anthocyanins that may support sleep and reduce inflammation. Combining tart cherry extract with supplemental melatonin provides both the precise dose of melatonin and the complementary phytochemicals from tart cherry that may enhance overall sleep benefits. The anthocyanins in tart cherry also have antioxidant properties that may work synergistically with melatonin’s antioxidant effects. This combination provides a more food-based approach alongside the standardized melatonin supplement. | 3 |
Antagonistic Compounds
| Compound | Mechanism | Evidence Rating |
|---|---|---|
| Caffeine | Caffeine directly antagonizes melatonin’s effects through multiple mechanisms. It blocks adenosine receptors, which normally promote sleepiness when activated, creating a state of alertness that counteracts melatonin’s sleep-inducing effects. Caffeine also suppresses melatonin production by affecting the activity of enzymes involved in melatonin synthesis. Additionally, caffeine consumption, especially in the afternoon or evening, can delay the natural rise in melatonin levels that typically occurs before bedtime. The combination of supplemental melatonin with caffeine sends contradictory signals to the body’s sleep-wake system, potentially reducing melatonin’s effectiveness for sleep improvement. | 5 |
| Alcohol | While alcohol may initially promote sleepiness, it significantly disrupts sleep architecture and quality, counteracting melatonin’s sleep-enhancing effects. Alcohol suppresses REM sleep and causes sleep fragmentation, leading to less restorative sleep. It also interferes with the body’s natural melatonin production and can alter melatonin’s effectiveness by disrupting circadian signaling pathways. When combined with supplemental melatonin, alcohol may increase sedation initially but ultimately undermines sleep quality and duration. Additionally, both compounds are metabolized by the liver, potentially leading to altered metabolism of either substance when used together. | 4 |
| Bright Light (particularly blue wavelength) | Bright light, especially blue wavelength light from electronic devices, directly suppresses melatonin production by signaling through melanopsin receptors in specialized retinal ganglion cells. This suppression can occur even with relatively low light levels from screens. When supplemental melatonin is taken while simultaneously being exposed to bright light (especially in the evening), the light exposure can counteract melatonin’s circadian signaling effects. This antagonistic relationship is particularly relevant for evening use of electronic devices, which can significantly reduce both endogenous and supplemental melatonin’s effectiveness for promoting sleep onset. | 5 |
| Vitamin B12 (in high doses) | High doses of vitamin B12 may potentially interfere with melatonin’s effects by increasing alertness and energy levels, particularly when taken later in the day. Some research suggests that B12 may affect circadian rhythm regulation in a manner that could counteract melatonin’s circadian-regulating effects. While the evidence for direct antagonism is limited, the opposing effects on alertness and energy levels suggest that high-dose B12 supplementation in the evening may reduce melatonin’s sleep-promoting benefits. This potential interaction is likely dose-dependent and may vary between individuals. | 2 |
| Stimulant Medications | Stimulant medications (including those for ADHD like amphetamine and methylphenidate) promote wakefulness and alertness through mechanisms that directly oppose melatonin’s sleep-promoting effects. These medications increase catecholamine (dopamine, norepinephrine) activity, enhance cortical arousal, and can suppress endogenous melatonin production. When combined with supplemental melatonin, particularly when the stimulant is active in the system, these opposing mechanisms create conflicting signals to the brain’s sleep-wake systems. This antagonism can significantly reduce melatonin’s effectiveness for promoting sleep onset and quality. | 4 |
| Tobacco/Nicotine | Nicotine acts as a stimulant that can interfere with melatonin’s sleep-promoting effects. It increases alertness and arousal through activation of nicotinic acetylcholine receptors and release of excitatory neurotransmitters. Nicotine also appears to suppress endogenous melatonin production and may alter melatonin metabolism. Smoking before bedtime can delay sleep onset and reduce sleep quality, directly counteracting melatonin supplementation goals. Additionally, the withdrawal from nicotine during sleep can cause sleep fragmentation and vivid dreams, further disrupting sleep architecture. | 3 |
| Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) | Some research suggests that NSAIDs like ibuprofen and aspirin may inhibit melatonin production by affecting the enzymes involved in converting serotonin to melatonin. This effect appears to be most significant with regular, high-dose NSAID use rather than occasional use. While this interaction primarily affects endogenous melatonin production rather than directly antagonizing supplemental melatonin, it may reduce the overall melatonin levels and effectiveness when these compounds are used together. The clinical significance of this interaction for occasional NSAID users is likely minimal but could be relevant for chronic users. | 2 |
| Corticosteroids | Corticosteroids can suppress endogenous melatonin production and alter circadian rhythm regulation, potentially counteracting the effects of supplemental melatonin. These medications mimic the effects of cortisol, which naturally opposes melatonin in the body’s circadian system (cortisol peaks in the morning when melatonin is low, and vice versa). Chronic corticosteroid use is associated with sleep disturbances, including insomnia and reduced sleep quality. While supplemental melatonin may still provide some benefits for individuals on corticosteroids, the medications may reduce melatonin’s effectiveness for regulating sleep-wake cycles. | 3 |
Cost Efficiency
Relative Cost
Low
Cost Per Effective Dose
$0.03-$0.15 per day for basic tablets/capsules (0.5-5 mg); $0.15-$0.50 per day for extended-release formulations; $0.25-$1.00 per day for specialized delivery systems (sublingual, liquid, spray)
Value Analysis
Melatonin offers excellent value compared to many other sleep aids and supplements, providing evidence-based benefits at a remarkably low cost. Basic melatonin tablets or capsules typically cost $0.03-$0.10 per dose for standard formulations (1-3 mg), making it one of the most affordable evidence-based sleep supplements available. This translates to approximately $1-3 per month at standard dosing, significantly less expensive than most other sleep interventions. The value proposition is particularly strong considering that research suggests lower doses (0.3-1 mg) are often as effective as higher doses for sleep onset, meaning the most cost-effective approach may also be the most physiologically appropriate for many users.
When comparing melatonin to prescription sleep medications, the cost difference is dramatic. Prescription sleep aids typically cost $1-15 per dose without insurance coverage, making melatonin 10-500 times less expensive. While these medications work through different mechanisms and may be necessary for certain conditions, melatonin offers a significantly more affordable first-line option for occasional sleep difficulties. Compared to other natural sleep aids, melatonin also demonstrates excellent value.
Valerian root supplements typically cost $0.10-$0.30 per dose, while more specialized sleep formulas containing multiple ingredients often cost $0.50-$2.00 per dose. Melatonin not only costs less but also has a stronger evidence base for specific sleep parameters like reducing sleep onset latency. For specialized formulations, the value calculation becomes more nuanced. Extended-release formulations ($0.15-$0.50 per dose) cost more than immediate-release forms but may provide better sleep maintenance throughout the night for some individuals.
Similarly, faster-acting delivery systems like sublingual tablets and oral sprays ($0.25-$1.00 per dose) command premium prices but may offer advantages for those who need rapid sleep onset. When comparing melatonin products, significant quality variations exist in the market. Independent testing has repeatedly found substantial discrepancies between labeled and actual melatonin content in many supplements. Products verified by third-party testing organizations may cost slightly more but provide greater assurance of accurate dosing and purity, potentially offering better value despite the higher price.
For specific applications like jet lag, melatonin’s value is particularly notable. A typical course for jet lag management (3-5 days of use) costs approximately $0.15-$0.75 total, compared to prescription options or the productivity costs of unmanaged jet lag symptoms. For shift workers, the monthly cost of regular melatonin use ($1-5) is minimal compared to the potential benefits for sleep quality and overall health. The cost-effectiveness of melatonin extends beyond direct purchase price when considering potential healthcare savings.
Improved sleep quality may reduce healthcare utilization related to sleep deprivation, potentially including fewer doctor visits, reduced medication use for sleep-related symptoms, and lower risk of accidents or errors caused by fatigue.
Stability Information
Shelf Life
Melatonin stability varies based on the specific formulation, storage conditions, and protective measures implemented by manufacturers. Under optimal storage conditions, melatonin in solid dosage forms (tablets, capsules) typically maintains acceptable potency for 2-3 years from the date of manufacture. This is reflected in the expiration dates assigned by manufacturers, though these are often conservative estimates. The primary degradation pathway for melatonin is oxidation, which can be accelerated by exposure to light, heat, and moisture.
Melatonin is particularly sensitive to light degradation, with significant breakdown occurring upon exposure to both natural and artificial light. In liquid formulations, melatonin typically has shorter stability, with shelf lives ranging from 1-2 years when unopened and 1-3 months after opening, depending on the preservative system and packaging. Sublingual tablets may have intermediate stability between solid and liquid forms due to their partially hydrated nature and higher surface area. Extended-release formulations often incorporate protective matrices or coatings that can enhance stability by protecting melatonin from environmental factors.
Some manufacturers add antioxidants like vitamin E or butylated hydroxytoluene (BHT) to enhance stability by preventing oxidative degradation. Stability testing by manufacturers typically ensures that products maintain at least 90-95% of the labeled melatonin content throughout the stated shelf life when stored according to recommendations.
Storage Recommendations
Store in a cool, dry place away from direct light, preferably at temperatures between 15-25°C (59-77°F). Keep containers tightly closed to prevent moisture absorption, as moisture can accelerate degradation of melatonin. Avoid storing in bathrooms or other high-humidity areas where temperature and humidity fluctuate. Light protection is particularly important for melatonin stability.
Store in the original opaque container or packaging that blocks light exposure. If transferring to another container, ensure it is opaque and airtight. For liquid melatonin formulations, refrigeration after opening is often recommended to extend stability, though product-specific recommendations should be followed. Check for any specific storage instructions on the product label, as formulations vary in their sensitivity to environmental factors.
Some products include desiccants in the packaging to absorb moisture – these should be left in place but not consumed. Sublingual tablets are often more sensitive to moisture than regular tablets or capsules and should be kept especially well-protected from humidity. Extended-release formulations may have specific storage requirements to maintain their release characteristics – follow manufacturer recommendations. If melatonin supplements change color significantly (becoming yellow or brown), develop a strong odor, or show physical changes like excessive softening or hardening, they may have degraded and should be replaced.
When traveling with melatonin, maintain appropriate storage conditions as much as possible and keep in original packaging or a suitable light-protective container.
Degradation Factors
Light exposure (particularly UV and blue wavelengths, primary degradation factor), Oxidation (melatonin is highly susceptible to oxidative degradation), Heat (accelerates degradation reactions; significant degradation occurs above 40°C/104°F), Moisture (promotes hydrolysis and may enable microbial growth in some formulations), pH extremes (melatonin is most stable at slightly acidic to neutral pH), Oxygen exposure (contributes to oxidative degradation), Metal ions (particularly iron and copper, can catalyze oxidation reactions), Microbial contamination (primarily in liquid formulations), Interactions with other ingredients in combination formulations, Repeated freeze-thaw cycles (for liquid formulations)
Sourcing
Synthesis Methods
- Chemical synthesis (most common method for supplements)
- Enzymatic conversion from serotonin
- Extraction from animal pineal glands (historical method, rarely used today)
- Bacterial fermentation using genetically modified organisms
- Plant cell culture methods (emerging technology)
- Note: Most commercial melatonin is synthetically produced through chemical processes
- Note: Synthetic melatonin is bioidentical to endogenous melatonin in molecular structure
- Note: Production methods can affect purity and presence of contaminants
Natural Sources
- Endogenously produced in the pineal gland of humans and other animals
- Tart cherries (Montmorency variety contains significant amounts)
- Goji berries (modest amounts)
- Eggs (small amounts)
- Fish (certain species contain trace amounts)
- Nuts (particularly pistachios and almonds, in small amounts)
- Mushrooms (certain varieties contain trace amounts)
- Rice (small amounts)
- Cereals (small amounts)
- Herbs like St. John’s Wort, feverfew, and Chinese skullcap (contain compounds that may support endogenous melatonin production)
- Note: While these natural sources contain melatonin, the amounts are generally too small to produce significant physiological effects comparable to supplements
- Note: Dietary melatonin content can vary significantly based on growing conditions, harvest time, and food processing methods
Quality Considerations
When selecting a melatonin supplement, several quality factors should be considered. The purity and accurate dosing are critical concerns, as independent testing has repeatedly found significant discrepancies between labeled and actual melatonin content in many supplements. Studies have found products containing anywhere from 83% less to 478% more melatonin than claimed on the label. Additionally, some products have been found to contain serotonin, a controlled substance not permitted in supplements. Third-party testing and certification from organizations like USP, NSF, or ConsumerLab provide additional assurance of quality, purity, and accurate dosing. Look for products that have undergone such verification. The specific formulation significantly impacts melatonin’s effects. Immediate-release formulations are generally better for sleep onset issues, while extended-release formulations may be more beneficial for sleep maintenance problems. Some products combine both for comprehensive sleep support. The presence of additional active ingredients should be considered based on your specific needs. Some melatonin supplements include synergistic compounds like L-theanine, magnesium, or GABA, which may enhance certain effects but could also introduce additional variables. For those with specific dietary restrictions, verify that the melatonin supplement is compatible with your needs (vegetarian, vegan, gluten-free, etc.). Most synthetic melatonin is considered vegan, but some products may contain animal-derived ingredients in the capsules or other components. The delivery method affects both onset of action and duration of effects. Sublingual tablets and oral sprays may provide faster onset due to partial absorption through the oral mucosa, bypassing first-pass metabolism. Capsules and regular tablets typically take longer to take effect but may provide more sustained action. For children, liquid formulations with precise dosing capabilities are preferable to allow for the lower doses typically recommended for pediatric use. The stability of melatonin can be affected by exposure to light, heat, and moisture. Look for products in opaque, well-sealed containers with appropriate expiration dates. Some manufacturers add stabilizers to enhance shelf life. The country of manufacture and regulatory oversight can affect quality. Products manufactured in facilities that follow Good Manufacturing Practices (GMP) generally provide better quality assurance. Some countries have stricter regulatory standards for supplements than others.
Historical Usage
Unlike many traditional medicinal compounds derived from plants or minerals, melatonin has a relatively short history as a supplement, as it was only identified and characterized in the mid-20th century. However, the history of its discovery and development provides important context for understanding its current uses. The story of melatonin begins in 1917 when Carey P. McCord and Floyd P.
Allen discovered that feeding tadpoles with extracts from bovine pineal glands lightened their skin color. This observation suggested that the pineal gland produced a substance affecting pigmentation, but the specific compound remained unidentified for decades. The breakthrough came in 1958 when dermatologist Aaron B. Lerner and his colleagues at Yale University isolated and identified the hormone from bovine pineal glands.
They named it ‘melatonin’ from ‘mela’ (referring to melanin) and ‘tonin’ (suggesting its effect on skin pigmentation). Lerner was searching for compounds that might treat vitiligo, a skin pigmentation disorder, but melatonin did not prove effective for this purpose. In the 1960s and early 1970s, researchers began to uncover melatonin’s role in regulating circadian rhythms and seasonal reproduction in animals. The discovery that melatonin production followed a distinct daily pattern, rising at night and falling during daylight, established its role as a ‘darkness hormone’ and biological timekeeper.
The pioneering work of Julius Axelrod and his team at the National Institutes of Health in the 1960s elucidated the biosynthetic pathway of melatonin, showing how it was produced from serotonin in the pineal gland. This research earned Axelrod the Nobel Prize in Physiology or Medicine in 1970 (though for his broader work on neurotransmitters rather than specifically for melatonin). The connection between melatonin and sleep in humans began to emerge in the 1970s and 1980s. Richard Wurtman and his colleagues at MIT conducted influential research showing that melatonin could induce sleep in humans.
This work laid the foundation for melatonin’s eventual use as a sleep aid. In the late 1980s and early 1990s, research on melatonin expanded dramatically, with studies exploring its potential for treating jet lag, shift work sleep disorder, and various forms of insomnia. The first commercial melatonin supplements became available in the United States in the early 1990s after the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994, which allowed melatonin to be sold as a dietary supplement without requiring FDA approval as a drug. This regulatory classification led to rapid market growth and widespread availability.
The 1995 publication of the book ‘The Melatonin Miracle’ by Walter Pierpaoli and William Regelson popularized melatonin among the general public, making bold claims about its anti-aging and health-promoting properties. While many of these claims went beyond the scientific evidence available at the time, the book significantly increased public awareness and use of melatonin supplements. Throughout the 1990s and 2000s, scientific research on melatonin continued to expand, with studies investigating its effects on sleep disorders, jet lag, immune function, cancer, and various other conditions. The discovery of melatonin receptors in the brain and other tissues in the 1990s provided a mechanistic understanding of how melatonin exerts its effects on various physiological systems.
In the early 2000s, the European Medicines Agency approved a prescription melatonin product (Circadin, a 2 mg prolonged-release formulation) for short-term treatment of primary insomnia in patients aged 55 years and older. This represented one of the first regulatory approvals of melatonin as a medicinal product rather than a supplement. In recent decades, research has increasingly focused on melatonin’s broader physiological roles beyond sleep regulation, including its antioxidant properties, immune modulation, and potential neuroprotective effects. Studies have explored its applications in conditions ranging from cancer to neurodegenerative diseases to COVID-19.
Today, melatonin remains one of the most popular dietary supplements globally, used primarily for sleep and circadian rhythm disorders but increasingly investigated for its potential in various other health conditions. The scientific understanding of melatonin continues to evolve, with ongoing research exploring optimal dosing, timing, formulations, and potential new applications for this multifaceted hormone.
Scientific Evidence
Evidence Rating
Key Studies
Meta Analyses
Ongoing Trials
Melatonin for prevention of delirium in hospitalized older adults, Long-term effects of melatonin on cognitive function in mild cognitive impairment, Melatonin as an adjunctive treatment for depression, Comparison of different melatonin formulations for sleep maintenance, Melatonin for sleep disturbances in children with autism spectrum disorders, Effects of melatonin on gut microbiome composition and function, Melatonin for prevention of chemotherapy-induced neuropathy, Melatonin supplementation for metabolic syndrome, Optimal dosing of melatonin for circadian rhythm sleep disorders, Melatonin for COVID-19 related sleep disturbances and recovery
Disclaimer: The information provided is for educational purposes only and is not intended as medical advice. Always consult with a healthcare professional before starting any supplement regimen, especially if you have pre-existing health conditions or are taking medications.