Melatonin is a neurohormone secreted mostly by the pineal gland in the brain and is most well known for regulating sleep, as the absence of light causes less suppression of melatonin synthesis and its relatively high levels facilitate sleep. The primary use of melatonin is to normalize abnormal sleep patterns, and is sometime taken 30 minutes prior to bed in a dose of 500mcg to 5mg to induce sleep and keep the person 'on schedule'.
Melatonin works primarily through reducing sleep latency, which is the time that is required to fall asleep once you rest and want to fall asleep. A good sleep latency will result in falling asleep once your head hits the pillow, a prolonged sleep latency will result in the subject needing 30 minutes or so to fall asleep. Melatonin works only by this mechanism, but this may indirectly cause an improvement in sleep quality if it allows you to get more sleep.
Abnormal sleep patterns are associated with a wide variety of health problems and premature aging, and melatonin's usage to normalize sleep patterns is thus seen as preventative medicine. Practically, melatonin is seen as highly effective in normalizing sleep abnormalities seen with jet lag and shift work.
Beyond abnormal sleep patterns, there are some demographics that appear to have less rhythmic secretion of melatonin. Smokers tend to have a normalization of melatonin throughout the day (which may not be the best idea) yet are less reponsive to melatonin supplementation; older individuals routinely have lower melatonin peaks at night after the age of 40-50 (a range in which the drop occurs most significantly), and in some clinical settings such as depression melatonin may be lesser.
Usage of melatonin is not associated with negative feedback like other exogenous hormones (a situation where ingestion of the hormone from outside sources causes suppression of natural production), due to this melatonin is commonly said to be fine to take permanently.
Other benefits of melatonin include general neuroprotective effects, which are potent and only partly due to melatonin being a powerful anti-oxidant. Anti-cancer effects through multiple pathways are also seen with melatonin, and currently being investigated into breast cancer. Melatonin does not appear to significantly influence Lean Mass nor fat mass, but may be anti-obesity over a lifetime (not inducing loss of Fat Mass, but reducing the rate of gain) Despite the lack of effects on these two tissues, melatonin at low doses appears to increase Growth Hormone secretion for a short time.
Other benefits associated with Melatonin supplementation include eye health, possible reductions in the symptoms of tinnitus, and improved mood secondary to better sleep (ie. if sleep reduced your mood then melatonin may improve it). No significant toxicity is seen with melatonin monotherapy (Melatonin usage in isolation)
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N-Acetyl-5-Methoxytryptamine, Melatonine, Melovine, Melatol, Melatonex, Circadin
Any person taking any neurally active agent (pharmacotherapy such as anti-depressants or ADHD medication) should consult with their doctor prior to taking melatonin, as it is highly involved in many body systems and drug:drug interactions are very likely.Examine.com Medical Disclaimer
For regulating the sleep cycle (preventative health before bed, jet lag, shift work, etc) doses of Melatonin between 500mcg (0.5mg) and 5mg appear to be either insignificantly different or the lower doses may work better; start with 500mcg and work up to 3-5mg and, if it doesn't work significantly better (seen in some studies, but not consistent enough for a general recommendation), return to 500mcg and use that dose.
Growth Hormone appears to be spiked slightly better at 5mg than 500mcg, although both doses are fairly effective at doing this job.
Higher doses of 20mg may be used, but do not confer much more significant benefits and the benefits of melatonin are not necessarily dose-dependent.
Similar to how our Whey Protein page can also be a testament for having a protein rich diet (beyond the supplement itself) this page can also be a testament to having a proper circadian rhythm; many of melatonin's long-term benefits may be through normalizing sleep patterns, but this is not inherent to melatonin supplementation. It is inherent to proper sleep cycles.
The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Melatonin has in your body, and how strong these effects are.
|Grade||Level of Evidence|
|A||Robust research conducted with repeated double blind clinical trials|
|B||Multiple studies where at least two are double-blind and placebo controlled|
|C||Single double blind study or multiple cohort studies|
|D||Uncontrolled or observational studies only|
|Level of Evidence ||Effect||Change||Magnitude of Effect Size ||Scientific Consensus||Comments|
A notable protective effect against both aspirin and heliobacter pylori induced stomach ulceration is seen with melatonin either alone or with other agents (such... show
Plasma melatonin is increased at both night and daylight following supplementation of melatonin. Although the degree of increase is a tad unreliable, it seems to always... show
There appears to be an increase in serum gastrin levels following ingestion of melatonin in persons with stomach ulceration, this increase is thought to be related to the... show
Mixed influences on leptin, but melatonin may be able to increase leptin levels following acute administration
|B||Symptoms of Tinnitus|
Melatonin may reduce symptoms associated with tinnitus in persons who suffer from the state, as assessed by questionnaire
An increase in sleep quality can occur following treatment of conditions known to impair sleep quality (insomnia and tinnitus)
|B||Symptoms of Jet Lag|
Insomnia related to jet lag is reliable reduced with melatonin supplementation taken in accordance to the destination's time zone; secondary to better sleep, many other... show
An acute decrease in blood pressure occurs following melatonin ingestion, but this decrease in temporary and abolished upon standing; likely not practically relevant in... show
Melatonin is the reference drug for insomnia related purposes, and appears to be highly effective at 3mg (time release formulation) or lower concentrations when taken before sleep.
There do not appear to be any influence of melatonin ingestion on plasma adrenaline, either inherently or from influencing the spike in adrenaline from stress
A decrease in noradrenaline appears to reliably occur after melatonin ingestion, but only at rest; this reduction is abolished upon moving
There appears to be a significant protective effect on life in cancer patients with solid tumors, although the protective effect does not reach 'half risk' (RR of 0.50)... show
No significant influence on IGF-1 levels
No significant influence on circulating estrogen levels
An increase in Ghrelin appears to exist following acute supplementation of melatonin
An increase in insulin sensitivity has been noted to be secondary to reducing liver fat; an inherent influence on insulin sensitivity is uncertain
An increase in adiponectin has been noted following acute ingestion of melatonin
A decrease in liver enzymes has been noted in persons with fatty liver given melatonin supplementation, although not to a remarkable degree
No significant influence on resistin noted
No significant influence on fasting insulin levels noted with melatonin
Related to the antioxidative effects, a reduction in exercise-induced oxidation has been noted
A reduction in lipid peroxidation has been noted with melatonin
A reduction in inflammatory cytokines is noted with melatonin supplementation
A decrease in muscle damage biomarkers (creatine kinase) has been noted with melatonin supplementation
Oral supplementation of melatonin (500mcg) is able to reduce intraocular pressure in otherwise healthy persons
Appears to increase circulating levels of growth hormone
Mixed results, a possible increase when measuring whole-day cortisol levels (when taken in the AM) with no augmentation of stress-induced cortisol increases; may reduce... show
No significant influence on prolactin concentrations
A possible reduction in triglycerides to a minor degree is noted with melatonin supplementation, but this is not reliable
|C||Anti-Oxidant Enzyme Profile|
Mixed effects on antioxidant enzymes, but there appears to be potential for melatonin to increase their content
No significant influence on LDL cholesterol is noted with melatonin
No significant influences on HDL-C are noted with melatonin supplementation
No significant influence on total cholesterol levels
May decrease biomarkers of oxidation in serum
An increase in fibrinogen has been noted
No significant influence on blood glucose levels
No significant influence on C-reactive protein
No detectable influence of melatonin on migraines that exceeds placebo
|C||Symptoms of GERD|
Symptoms of GERD, most notably heart burn, are reduced significantly following daily melatonin ingestion at 3mg
A notable decrease in heartburn symptoms occurs after melatonin supplementation, thought to be related to a strengthening of the lower esophageal sphincter
|C||Lower Esophageal Pressure|
Has been noted to increase LES pressure, which is thought to underlie symptoms reduction in GERD
An increase in memory retention under periods of stress has been noted
A decrease in alertness has been noted with melatonin supplementation
Despite the reduction in alertness, no significant influence on sustained attention tests
No significant influence on state anxiety during stress testing
No significant influence of melatonin on heart rate during waking either at rest or ambulation
Has been noted to increase blood flow at rest
Serum dopamine has been noted to be slightly reduced (37%) during waking at rest, but this decrease was eliminated upon walking
|C||Cerebral Blood Flow|
No significant influence on cerebral blood flow rates
|D||Breast Cancer Risk|
Too preliminary to conclude any relation to breast cancer, but urinary melatonin metabolites are positively correlated with breast cancer risk (not applied yet to supplementation)
Melatonin (N-acetyl-5-methoxytryptamine) is a peptide hormone and neurotransmitter most well known for its regulation of sleep, where darkness causes increased synthesis and secretion of melatonin to induce sedation and initiate the sleep cycle. Due to its structure, it is also classified as an indoleamine.
Melatonin is also found in a variety of foods, and is universally found in plants although possibly in minute quantities and this melatonin is bioactive. Good sources of melatonin that are commonly consumed include:
While common supplements (or herbs not commonly used as food products) that contain melatonin are (64 total, not all listed):
Producted naturally in the body (endogenously) and is also a functional food component, similar to its amino acid precursor L-Tryptophan and some intermediate metabolites such as serotonin (found in some foods)
Melatonin is made de novo in the human body in multiple locations, with the pineal gland in the brain being the most well known, but other locations being bone marrow cells, the retina, and the gastrointestinal tract.
The biosynthetic pathway of melatonin starts from the dietary amino acid L-tryptophan, which is converted to 5-hydroxytryptophan, or 5-HTP, by Tryptophan-5-hydroxylase. 5-HTP is converted to the active hormone serotonin by the enzyme Aromatic L-amino acid decarboxylase, further converted to N-acetylserotonin by the enzyme Serotonin-N-Acetyltransferase (sometimes also known as arylalkylamine-N-acetyltransferase), and finally converted to N-acetyl-5-methoxytryptamine (Melatonin) by the enzyme Hydroxyindole-O-methyltransferase(HIOMT). Increases in melatonin from supplemental L-tryptophan have been noted in non-human species to varying degrees and sometimes failing to increase melatonin; this may be due to the first rate limiting enzyme Tryptophan-5-Hydroxylase (regulating conversion of dietary tryptophan to serotonin) and thus supplementing melatonin appears to circumvent this rate limit. The 'true' rate-limiting enzyme is arylalkylamine-N-acetyltransferase which mediates conversion from serotonin to N-acetylserotonin and is the control point for external regulation by light and darkness, being suppressed with light-induced signals from the retina.
Just the details about how melatonin is made (from serotonin, which is made from dietary L-tryptophan) and its regulation (sunlight in the retina, mostly)
Given how the suprachiasmatic nuclei (SCN) of the pituitary expresses melatonin receptors, it is thought that supplemental melatonin can suppress endogenous secretion via negative feedback.
In regards to supplementation, oral melatonin supplements at 500mcg over a period of a week in shift workers did not influence basal secretion, as cessation for one day prior to measurements did not show differences when compared to secretion status prior to supplementation. 24-hour melatonin levels in this study, when graphed, essentially overlapped suggesting next to no variance. These results indicating a lack of negative feedback have been replicated with 2mg and 5mg.
When supplemented in a dose of 50mg to a blind person in one case study (blind persons being an example of a population with no sunlight-mediated melatonin production), this dose 100-fold higher than the standard 500mcg did not significantly influence basal secretion status. In this population (blind) lower doses of 500mcg are also effective and without apparent negative feedback.
Results in blind persons suggest that an override of regulation from sunlight/darkness may not be the factor behind the lack of negative feedback, as some studies do control for persons with no conscious light perception.
Regulation of melatonin secretion from the pineal gland does not appear to be negatively influenced by melatonin supplementation over the long term (multiple days) and no negative feedback from melatonin supplementation (less natural secretion after a period of supplementation) has been observed
Beyond just fluctuating throughout every day (higher in evening, lower during waking hours), Melatonin may fluctuate throughout the seasons in humans, following a bimodal distribution with peaks in January and July.
Some alterations of circulating melatonin level depending on season, clinical relevance unknown
The circadian rhythm of melatonin appears to shift towards earlier clock hours later on in the aging process.
When investigating rats divided into three ages (correlating with youth, adult, and elderly), it appears that overall melatonin levels are highest in adults (only due to youth having smaller pineal glands; youth has the highest density of melatonin) and a drop in melatonin is apparent in elderly rats. Similar trends were seen in N-acetylserotonin, another pineal hormone. This higher density in rat pups is seen in human youth, where spikes in melatonin occur around age 2-4 and then decline until puberty where they remain constant for a while and then gradually decline over the rest of the lifespan. The most drastic drop in nightly melatonin levels appears to occur around the ages of 41-60, where the age bracket of 41-50 is significantly higher than the age bracket of 51-60.
Melatonin appears to fluctuate with age, decreasing steadily after puberty but taking a significant decrease in average nightly melatonin levels around the ages of 41-60
Melatonin levels appear to correlate with one's dietary lifestyle, and consumption of plant-based products may influence circulating melatonin levels due to plants containing melatonin in possibly physiologically relevant levels when a sufficient amount is consumed. At least in survey research, the highest quartile of vegetable intake (relative to the lowest quartile) is associated with a 16% higher urinary melatonin level.
In studies on fasting persons (or food restriction to less than 300 calories daily) note that circulating melatonin levels can decrease by up to 20% with no change of urinary secretion rates over a period of 2-7 days. This may be secondary to transient glucose deprivation, as supplementation with glucose at 0.5g/kg during these periods restores circulating levels of melatonin (and suggest that the pinealocytes that secrete melatonin may require glucose for optimal functioning). However, when investigating rats that conduct caloric restriction (40% of basal metabolic rate) for the purposes of longevity, melatonin levels in serum are increased.
Melatonin levels appear to interact with overall caloric and food intake, as well as some food selections. Melatonin may be relevant for explaining some of the health benefits of vegetable, and this could potentially extend to Alcohol containing products
In persons with major depressive disorder, serum melatonin disorders appeared to be lower than age-matched controls with no difference in this sample during depressive episodes and in remission.
In persons with bipolar disorder, serum melatonin disorders appeared to be lower than age-matched controls.
Some alterations in circulating melatonin levels depending on clinical state
When comparing active smokers of tobacco against non-smoking controls, smokers appear to have approximately twice the circulating levels of melatonin when measured during the daytime (11-12h) according to this study; 17.44+/-1.8 pg/ml in smokers relative to 9.77+/-1.4 pg/ml in non-smokers, while a study on 21 young female smokers taking measurements of serum melatonin at night (23-24h) found that, relative to non-smokers, smokers had reduced levels of melatonin (47.9+/-14.5pg/mL) and nonsmokers 47% higher (70.5+/-18.9pg/mL). A later study on smokers found endogenous levels of melatonin smokers just above 2nmol/L/h, which is not significantly different from the nonsmokers in the previous study. This latter study did note, however, that smokers were about twice less responsive to blood increases in melatonin from supplements, due to induction of the aromatase enzyme from Polyaromatic Hydrocarbons (PAHs) in cigarrete smoke.
Alterations in melatonin status and smoking are complex and understudied; there may be a normalization of the circadian rhythm, which needs to be confirmed with further studies. Smokers appear to have less response to melatonin supplementation than do nonsmokers
Epithalamin is a hormone secreted from the pineal gland (similar to melatonin) that has been implicated in prolonging lifespan in Drosophilia, C3H/Sn Mice, and Rats; no influence was found on SHR mice. For those that saw an improvement in lifespan, the values ranged from 10-35%, with rats experiencing a 57% reduction in mortality. In these tested animals, epithalamin administration increases melatonin secretion.
One study administering epithalamin (6 courses of treatment of 10mg every third day for 15 days, spanning 3 years) to persons aged 60-69 with aged cardiovascular systems and low serum melatonin noted that, 12 years after cessation of epithalamin treatment and during follow-up, appeared to attenuate or reverse some parameters assocaited with aging; having the epithalamin group outperform placebo on cycling power, improved lipid and glucose metabolism, and appeared to normalize the suppressed nightly spike of melatonin in the aged control.
Peptide hormone related to melatonin that seems to be able to prolong lifespan in research animals, and improve biomarkers in elderly humans
In a model of delayed sleep phase syndrome, 500mcg of Melatonin appears to be as effective as ten-fold the dose (5mg) and a comparative study between 300mcg and 3mg in age-related insomnia noted that 300mcg was more effective than 3mg.
A comparative study between 500mcg and forty-fold the dose (20mg) showed that 500mcg was more effective at regulating the circadian rhythm in this case study involving a blind person (with no external melatonin regulation from darkness). A lower dose of 10mg in blind persons appears to be more effective than 20mg as well, although insignificatly different from 500mcg.
Although differences between very low (300-500mcg) and higher (3-5mg) doses tend to go back and forth in regards to efficacy, they both seem to be more potent than superloaded doses (20mg)
Oral doses of 500mcg Melatonin (seen as the lowest active dose) in shift-workers resulted in a Cmax of 1,580+/-329 pg/ml after a Tmax of 1+/-0.14 hours, noting that this high dose was above physiological ranges for up to three hours, but after the fourth hour levels returned to the physiological range of 24-198pg/mL. Other studies that use 500mcg note serum levels of 3,054+/-3,022pmol/L (709.4+/-701.9pg/mL) with a half-life of 0.68 hours.
With 6mg of Melatonin, in one hour serum levels of 1,171.3+/-235.2pg/mL are seen.
One study assessing 100mg melatonin (200-fold higher dose than the lowest active dose) noted serum peaks approximately 100 minutes after administration, or 652,310+/-82,456pmol/L (151,517+/-19,153pg/mL). This dose is able to stay in circulation for longer than smaller doses, still affecting biology up to bedtime when taken at 8am, and in the study noting the higher serum peak they were measured at 95+/-15pmol/L (22.06+/-3.48pg/mL) the next morning at 8am, which was still above baseline for these participants.
Serum peaks are quite unreliable; although all small doses tend to increase circulating melatonin around 8-10 times greater than the highest physiologically relevant concentration. Higher doses increase melatonin levels even further, and delay the time to peak concentrations while also delaying the excretion rates
A large dose (80mg) Melatonin to healthy persons in the morning (7:30am) the various parameter recorded were a 24m half-life, with stable levels 60-150 minutes after ingestion and a gradual decline in serum melatonin levels until 9pm where they returned to physiologically relevant levels. The peak observed values were highly variable and significant in magnitude (350-10,000fold higher than previously observed peak levels, such variability has been seen elsewhere), and hourly dosing of 80mg Melatonin was able to attenuate but unable to inhibit the decline throughout the day.
The fast absorption appears to be similar between higher doses (80mg, 100mg) and lower doses (6mg) One study testing four low doses (100mcg, 500mcg, 1mg, 5mg) also noted that the absorption rates appeared to be nonsignificnatly different, all taking within 0.78-1.25 hours to reach Cmax.
Appears to be rapidly absorbed and very rapidly excreted, with the concentration in the blood between these times being significantly higher than normal melatonin levels
When administerted intranasally (snorted) to rabbits, had bioavailability of 94% when paired with sodium glycocholate but 55% without. This route of administration was accompanied by a 5 minute Tmax and a 13 minute halflife with 1.5mg Melatonin confering a Cmax of 493+/-290ng/mL at 5 minutes, and these parameters mimicked intravenous injections.
Administration by the nasal route may me markedly more effective than oral supplementation
At the stage of 6-hydroxylation of Melatonin into its main urinary metabolite (6-hydroxymelatonin), aromatase (CYP1A1/2) appears to be highly important with some metabolism by CYP1B1 and CYP2C19. Metabolism of melatonin by CYP1B1 appears to be of greater relevance to central (neural) melatonin, due to not being expressed much in the liver. Due to metabolism by aromatase, co-ingestion of aromatase inhibitors (in this case, Fluvoxamine) can increase melatonin AUC and overall exposure and habits that induce aromatase (such as tobacco smoking) appear to be correlated to reduced circulating melatonin.
Melatonin exerts many of its effects vicariously through Melatonin receptors, similar to how insulin affects the insulin receptor. The Melatonin receptor are named MT1 and MT2, and are G-protein coupled receptors (GPRCs) coupled to Gi proteins (a heterotrimer of α, β, and γ that dissociates into α and βγ when the receptor is activated). These two receptors are quite different from each other, as they structures pharmacological characteristics and chromosomal location yet both have high affinity for melatonin. A third 'receptor' exists known as MT3, but it is not a GPRC like MT1/2 and due to the cytoplasmic protein quinone reductase II having the same melatonin binding properties as 'MT3' and deletion of quinone reductase II causing 'MT3' to disappear, MT3 may just be quinone reductase II.
Two G-Protein Coupled receptors with different actions mediate the actions of melatonin, MT1 and MT2. There is a third player that is Quinone Reductase II that may bind to melatonin and was thought to be a third receptor (MT3), but is a cytoplasmic protein; may still be relevant
A fourth receptor, located on the nucleus rather than the cytoplasm, appears to be intimately involved with nuclear melatonin signalling via cytoplasmic receptor cross-talk
Expression of Melatonin receptors are in; the Suprachiasmatic Nuclei (SCN) of the Pineal gland, where MT1 and MT2 both exist and MT1 activation suppresses neuronal firing, the Hypothalamus where both receptors suppress gonadotropin releasing hormone release, the retina where MT2 reduces dopamine release and an MT3 receptor reduces ocular pressure, the pars tuberalis of the Pituitary gland, the Kidneys (MT1), the pancreas and beta-cells of the pancreas (both MT1 and MT2), the Adrenal Cortex where MT1 activation suppresses cortisol secretion, the testes where MT1 suppresses testosterone, the pituitary where MT1 suppresses FSH, LH, and Prolactin, Vasculature where each main receptor mediates either vasoconstriction (MT1) or vascodilation (MT2) and on some adipocytes where MT1 negatively regulates adipose tissue proliferation and increases leptin secretion (no MT2 on white adipose tissue, but expression of MT2 on brown adipose suppresses glucose uptake)
Most heavily localized to the brain and associated neuroorgans, and also possesses a heavy presence on sex organs. Seems to be fairly ubiquitous though, with expression on fat cells, immune cells, and cardiac cells as well as the blood stream cells
GPR50 is an orphan receptor (belonging to the same GPRC family as melatonin receptors) which appears to have roles in adaptive thermogenesis and is expressed in humans (specifically the dorsomedial nucleus of the hypothalamus and tanycytes that line the third ventricle), knockout of this receptor (abolishing its effects) appears to confer resistance to diet induced obesity yet paradoxically reduces the amount of weight lost in a fasted state and reduced nighttime thermogensis despite 25% higher locomotion during waking hours. GPR50 appears to interact with leptin signalling, as administration of leptin can improve GPR50 nuclear activity in obese mice (with seemingly suppressed levels of GPR50) but not in GPR50-/- mice, suggesting leptin acts vicariously through this receptor, but only on matters related to thermogenesis (as feeding patterns appear unaltered). In fact, after leptin administration to rats with the standard leptin receptor but no GPR50 receptor, the amount of genes activated by leptin in control mice (2,705) is reduced just over 50% (to 1,327). It should be noted that melatonin is not a direct ligand of this receptor.
GPR50 is an orphan receptor which seems to mediate the aspects of leptin related to thermogenesis, but not appetite (anorexia), and may mediate up to half of the effects of leptin as well
GPR50 appears to heterodimerize with the melatonin receptor MT1, which results in reduced efficacy of MT1 signalling (through preventing binding of agonists to MT1). GPR50 has the capacity to heterodimerize with MT2, but does not influence the functions of MT2 similar to how MT1 and MT2 heterodimerization does not influence binding of ligands. Melatonin normally has a Ki of 0.73±0.26nM yet the heterodimerization has a Ki of 0.37±0.28nM. Secondary to this, GPR50 appears to antagonize the effects of MT1. Co-expression of GPR50 alongside MT1 does not affect basal MT1 actions, but reduced the maximal response of MT1 by melatonin agonism by 50%, reducing the expresison of GPR50 reverses these observations.
Expression of GPR50 appears to reduce the actions of MT1, and may alter the signals sent through MT1 via melatonin
Melatonin supplementation exerts most of its benefits through decreased sleep latency, or a reduction of the time it takes to fall asleep.
Some studies do not note a significant decrease in sleep latency, although the majority tend to note a shortening of time to fall asleep in otherwise healthy subjects. Although some studies measuring REM sleep (indicative of sleep quality) note improvements, this is not inherent to melatonin. One study using 10mg Melatonin 1 hour prior to sleep for 28 days in persons aged 28+/-5 years (n=30) noted that this decreased sleep latency could occur without benefit to REM latency/density or sleep architecture. Improvement in sleep may also not necessarily be dependent on circulating melatonin levels, and the best predictor of response to melatonin could be age (55yrs or greater) or the status or insomnia.
A part of Melatonin's pro-sleep mechanisms may be related to a decrease in body temperature, as the two are highly associated.
Appears to be quite reliable in shortening sleep latency, and inducing faster sleep; this may be related to the hypothermic (temperature lowering) effects of Melatonin, and do not necessarily indicate better sleep quality
In older persons with primary insomnia, melatonin (2mg of a slow release formula) has shown efficacy in improving sleep quality and has shown efficacy in children with insomnia with affecting development. In this latter study, kids with an average age of 12 (8.6-15.7yrs) using melatonin in ranges of 0.3-10mg (average dose of 2.69mg) for an average of 3.1 years did not significantly differ from a non-supplemented control when assessed by Tanner Stages, three questions used to assess physical maturation of puberty. No differences in mental maturity were seen. Benefits to insomnia have also been noted to persons who suffer from insomnia and also experience migraines with auras, which may be correlated.
Due to melatonin shortening the time it takes to fall asleep (sleep latency) it shows most efficacy in insomnia and, despite being used in all age groups, is surprisingly free of withdrawal and other side-effects at the doses used
Melatonin has shown some efficacy in improving sleep quality for persons suffering from tinnitus.
At least one study has noted synergistic sedative effects of melatonin and MAO-A inhibitors, in this frog study clorgyline and moclobemide were used.
Jet Lag is a term used to refer to disregulation between external regulators of time (light and darkness) and the internal clock located, in part, in the Suprachiasmatic Nuclei (SCN) of the brain. Jet Lag is named after plane travel between time zones causing disregulation of hours up to half a day (depending on time zones trasversed) although this general phenomena of disregulation of the circadian rhythm also applies to shift-work (due to working at a time normally reserved for sleep), fluorescent lights in the late PM disrupting melatonin secretion, and also in blind persons due to no influence from light or darkness.
Melatonin is investigated for its usage in Jet Lag due to its ability to 'reentrain' the circadian rhythm and restore desyncronization via signalling the Suprachiasmatic nuclei (SCN) through MT2 receptors.
In conditions where external stimli (sunlight and darkness cycles) and internal stimuli (the internal clock) are not in accordance with each other and disregulated, supplemental melatonin is thought to help re-establish balance
A Cochrane database meta-analysis of 10 studies that transversed at least 5 timezones found that melatonin was significantly more effective than placebo, when taken at the destination's bed time, in normalizing the circadian rhythm and reducing the symptoms of jet lag. Of the studies reviewed, they suggest that there is no significant difference between 500mcg and 5mg in the effects of melatonin in reducing jet lag with some better sleep noted with 5mg, and that . It should be noted that some persons still experienced jet lag, as the meta-analysis noted that of the two studies that reported individual statistics about 18% of subjects still experienced jet lag after melatonin (with placebo at 67%). The one study which did not report benefits can be found here,
In studies comparing melatonin against other sedatives, it appears to be less effective than zolipedam (Ambien or Sublinox as brand names) but also associated with less side-effects.
Other interventions using Melatonin and jet lag (in regards to travel) indexed in Medline are found here, and this phenomena as it applies to shift work is noted here.
Melatonin, taken at some point in the evening (sometimes 30 minutes before sleep, at times up to 4-5 hours before sleep with a higher dose) appears to normalize abnormal circadian rhythms; for usage in jet lag, it should be timed with the clock of the time zone currently residing in
Interestingly, green light treatment in the morning combined with melatonin at 3mg the night prior additively (but not synergistically) benefits correction of abnormal circadian rhythms. Bright light in the morning also aids in normalizing the circadian rhythm or otherwise shifting it to another time. Bright light, when observed in the PM and combined with melatonin, partially abolishes the effects of melatonin. In this study, while light treatment during the hours of 2100 and 2400 delayed normalization of the cicadian rhythm by 0.68 hours and supplemental melatonin at 2040 corrected it by 0.4 hours, the combination failed to be significatly different than placebo; these results also suggest that melatonin can negate the negative effects of light at night when it applies to jet lag.
Melatonin at night works well with Bright Light Therapy in the morning, but is antagonistic to bright lights prior to sleep
The 'First Night' effect is a delay in sleep onset due to sleeping in new settings, common during travel. Similar to Panax ginseng, Melatonin is effective in reducing sleep latency (time to fall alseep) and as an aid against the First Night effect, which is sometimes seen in any study assessing patients in clinical settings during sleep.
In a study able to assess 6 months (n=112) and 12 months (n=96) of melatonin treatment at 2mg of a controlled release capsule taken 1-2 hours prior to sleep, persons aged 20-80 with primary insomnia failed to show any tolerance to the treatment; the authors noted a slight sensitization to the effects of melatonin at the 3-4 month period, which was attributed to better entrainment of the circadian rhythm. These results have been replicated in another study lasting 6 months with a sample of 791 persons failed to notice any tolerance with Melatonin usage and in one lasting 6 months 421 persons.
A handful of large scale, 6-12 month studies suggesting no tolerance to melatonin upon continued administration
Possibly since benzodiazepines are a leading sedative and known to have withdrawal effects, it is a common concern as to whether Melatonin supplementation confers withdrawal or dependence in otherwise healthy persons; this concern is somewhat backed by melatonin interacting with benzodiazepine receptors and melatonin is sometimes used for prolonged periods in youth with clinically meaningful sleep disturbance problems.
This study investigating children with sleep onset problems taking melatonin (1-5mg depending on individual efficacy) for 3 weeks, halving the dose for 1 week to then cease the supplement, the termination of effects were replicated where half-dosing for a week reduced the benefit to sleep latency nonsignificantly, but ceasing treatment removed the benefits of melatonin. This study also made note of an unpublished thesis where the benefits of 3-week melatonin usage were abolished upon cessation, but said thesis is not available online. One other study on persons with rapid-cycling bipolar disorder given 10mg noted negative effects, and in this sample of persons (n=5) it was noted that delayed sleep onset relative to baseline was observed.
In contrast to this, at least one large scale (n=791) double-blind study on insomniacs noted that there was no withdrawal symptoms associated with stopping melatonin usage after 6 months at 2mg of a sustained release formulation, as withdrawal as assessed by the Tyrer questionnaire was about 28% in both placebo and melatonin. As follow-up, data from 6-12 months of melatonin usage in insomniacs noted that during a 2-week monitoring period after cessation of melatonin there was a slight residual effect of better sleep, no tolerance during long-term melatonin treatment, and no noted withdrawal effects significantly different than placebo. An apparent absence of withdrawal or dependence is more common in older persons with insomniac symptoms, where Melatonin for usage of up to 6-12 months is not associated with dependence nor withdrawal symptosm (being exacerbation of insomnia upon cessation).
Currently no good evidence to suggest withdrawal nor dependence on Melatonin supplementation, and some evidence to affirm that there is no adverse effect on drug dependence or withdrawal. Doses higher than 2mg have not been sufficiently studied
It is possible that the termination of the benefits to sleep upon discontinuing Melatonin may be seen as 'reactive insomnia', as sleep quality returns to the quality that it was prior to melatonin intervention
Melatonin appears to act to inhibit dopamine release in the ventral hippocampus, medulla pons, preoptic area, and the hypothalamus (posterior and median) yet no inhibition occurs in the cerebral cortex, striatum, cerebellum, nor dorsal hippocampus. This inhibition appears to be mediated by inhibiting calcium influx into co-stimulated nerves. In accordance to this inhibition, active in physiologically relevant nM ranges (although maximal potency at pharmacological mM ranges), dopamine experienecs a diurnal rhythm of release vicariously through melatonin suppression, and this inhibition of dopamine release appears to apply to amphetamine-induced dopamine release (of concern to Ephedrine supplementation).
Mechanistically, Melatonin appears to be a negative regulator of dopamine release in neurons
In humans, 3mg of melatonin is able to attenuate a stress-induced rise in adrenaline and noradrenaline in young healthy men but is unable to abolish it. Without a stressor, oral melatonin at low doses (1-2mg) appears to reduce circulating adrenaline by about 60-90 minutes after ingestion.
May be able to reduce circulating adrenaline and noradrenaline concentrations
Melatonin, at 500mcg, is able to increase the secretion of oxytocin and vasopressin when taken by otherwise healthy males aged 19-23, with most significance 40-60 minutes after oral adminsitration and 5mg of melatonin having no significant effect; 5mg melatonin was able to suppress an exercise-induced increase in vasopressin. Another study using 50mcg as well as 500mcg and 5mg noted that, in roughly the same population, that 50mcg was not significantly different than placebo in regards to vasopressin and barely more significant in increasing oxytoxin where 500mcg significantly increased both neurohormones by 40 minutes, and appeared to normalize by 150 minutes; 5mg showed a suppressive effect once again and this suppression was noted in a third study using 5mg nightly for 4 days.
Melatonin has been investigated for its usage in treating Migraines due to Migraines having a circadian rhythm and insomnia being correlated with morning migraines. One study that tested this hypothesis in persons aged 18-65 with an attack frequency of 2-7 per month noted that melatonin failed to exert more benefits than placebo when taken at 2mg one hour before sleep for 8 weeks, although a (nonsignificant) improvement in sleep quality (assessed by the PSQI) was noted with melatonin it became significant when controlling for persons with insomnia (correlated highly with those who had auras with their migraines). This study was criticized for its methodology, mainly due to the combination of a crossover design and 8 weeks in duration limits the length observations could be observed and how the placebo response rate was much higher than expected, suggesting design flaws.
Has not yet been shown to reduce frequency or intensity of migraine attacks, but has not conclusively been shown to be ineffective. More robust evidence is required
Melatonin is mainly implicated in neuroprotection as an anti-oxidant compound and as a protector against the harmful effects of beta-amyloid pigmentation, both directly by reducing levels of said pigmentation and by protecting from downstream effects thereof. It also seems to have preventative affects on hyperphosphorylation of TAU, which is a risk factor for Alzheimer's disease.
Melatonin may also show neuroprotection via mediating the Akt/mTOR pathway, as it can induce the pathway in times of ischemia-reperfusion injury (where it should be supressed), methamphetamine induced suppression of mTOR, and suppresses overexpression of this and the MAPK pathways via H202 stimulation.
Melatonin shows synergism with Resveratrol in regards to protection against beta-amyloid pigmentation in regards to AMPK phosphorylation and its downstream effects; although its effects on the glycogen synthase enzyme expression (GSK-1) and glutathione depletion (both risk factors neuropathy) were not synergistic in vitro.
In a study in elderly persons (86+/-6yrs) with mild cognitive impairment given a combination supplement of melatonin (5mg), soy phospholipids (160mg), L-tryptophan (95mg), and Fish Oil (720mg DHA, 286mg EPA, Vitamin E at 16mg) noted that nightly ingestion for 12 weeks significantly reduced the rating score of the MMSE and MNA (indicative of cognitive enhancement) without influencing short or long term memory parameters; the improved score appeared to be through a minor trend to improve with supplement relative to a minor deterioration seen in control.
One study assessing memory at 3mg Melatonin in healthy young men noted that Melatonin supplementation was associated with improved memory encoding under stress. Taking melatonin one hour prior to a combined learning and stressful experience enhanced the amount remembered the next day relative to control, but tests conducted 15 minutes after the stressor (when cortisol was highest) were not different between groups.
There is a hypothesis known as the phase-shift hypothesis where seasonal depression in the winter months is associated with alterations in light-sleep cycles and melatonin, alongside bright light therapy (night and morning, respectively), are able to normalize disorders of the circadian rhythm including seasonal depression.
Adrenaline-mediated signalling (Adrenergic) is a regulator of cardiac function and, in some clinical populations, can be seen as undesirable due to its hypertensive and pro-contractile properties.
Melatonin appears to have anti-adrenergic actions in heart tissue, one in vitro study using excised cardiac tissue from rats noted that melatonin (50uM, with 25uM having no effect) appears to reduce cAMP production in the heart by up to 34% via the melatonin recepetors, although abolishing NO, PKC, or guanyl cyclase also abolished the effects of melatonin.
Acutely, 1-2mg melatonin is able to reduce blood pressure in men and women, possibly secondary to a reduction in adrenaline which is also observed. The difference between groups appears to be reduced when subjects are standing and mobile, and not all studies note a decrease in blood pressure acutely; suggesting these acute effects (measured in a passive supine position) may not hold much practical relevance.
One intervention using 5mg of melatonin supplementation for 2 months taken 2 hours before bed noted that melatonin, in persons with metabolic syndrome, was able to reduce blood pressure from 132.8+/-9.8 systolic to 126.3+/-11.5 (95.1% of baseline) and decrease diastolic from 81.7+/-8.7 to 76.9+/-9.2 (94.1% of baseline). These effects were independent of major changes in body weight, and may have been secondary to melatonin's antioxidative effects.
At least one study has investigated blood partitioning after ingestion of melatonin (3mg) in participants in a supine position, and noted that a greater blood flow to the forearms and less to the kidneys (without influencing cerebral blood flow) occurred 45 minutes after ingestion of melatonin; independent of changes in heart rate or blood pressure.
When taken at 5mg for 2 months, 2 hours before bed, in persons with metabolic syndrome there are no significant effects of melatonin on LDL cholesterol, HDL cholesterol, or total cholesterol.
Although administration of 5mg of melatonin nightly for 2 months in persons with metabolic syndrome does not appear to significantly influence triglyceride levels, triglycerides may be acutely affected as assessed by this study with melatonin (6mg) taken prior to exercise, where the expected decrease in triglycerides during exercise was exacerbated with melatonin.
Melatonin is being investigated for life extending properties for a few reasons. Firstly, in regards to the gland that produces melatonin in the brain (Pineal Gland) a study in rats that actually removed the pineal gland from young rat pups and put them into live elder male mice induced a 12% increase in lifespan and theorized to be secondary to melatonin. This hypothesis results are strengthed by the reverse study where old pineal glands into younger rats accelerates aging, and the pineal gland does appear to be involved in aging. Additionally, the only currently validated method of life extension (caloric restriction) is associated with up to twofold higher circulating levels of melatonin when compared to control rats fed ad libitum. It is unsure if this is a biomarker of longevity or causative thereof.
Additionally, a study comparing young healthy controls (n=20), clinically healthy old (n=24) and centaurians (n=24) found that those over 100 years of age had standard aging of thyroid parameters and Dehydroepiandrosterone (decreases in accordance with age) but that the difference between daily and nightly melatonin excretion (urine) was more similar to youthful control rather than the aged cohort, which experienced a normalization of sorts.
Melatonin and the Pineal gland are highly associated with longevity, and due to the levels of melatonin declining during aging supplementation is seen as 'restorative' to some
Melatonin is one of the few supplements with demonstrated interactions with the telomerase enzyme (such as Astragalus membranaceus) which is correlated with lifespan. In general, with older subjects less telomerase activity is seen relative to younger subjects that have higher telomerase activity. Telomerase is composed of two subunits, the catalytic TERT subunit and the RNA containing TR subunit.
In one study comparing young against old rats fed 10mg/kg IP injections of melatonin daily for 21 days, melatonin was found to increase telomerase activity in gastric mucosa; when only 55% of rat pups had detectable levels of telomerase activity in this study, melatonin increaed it to 100% while older rats went from no detectable telomerase to 45% of the rats having detectable levels (assessed by telomerase PCR ELISA kit).
In vitro activation of the membrane receptor (MT1) was able to increase the RNA levels of the catalytic subunit of telomerase, TERT (observed in research as it correlates well with telomerase), in an MCF-7 cell line by about 50% at 1nM concentration with no dose-dependence. However, binding of an agonist to RZR/RORα (a nuclear receptor melatonin can bind with) can reduce expression of TERT in a dose-dependent manner by 30-40% depending on concentration (1pM-1nM; the latter being the level of circulating melatonin). Neither receptor appears to influence the TR subunit.
Melatonin appears to be able to positively and negatively regulate the catalytic subunit of telomerase, which appear to be of equal potency at physiologically relevant concentrations of 1nM, and at least one rat study noted that pharmacologically high levels via supplementation increased telomerase expression
Estrogens appear to be able to induce telomerase activity, due to an imperfect estrogen response element on the telomerase (TERT) promotor and estradiol can upregulate telomerase via the ERα. Melatonin has the ability to regulate aromatase, and suppress excessive telomerase activity induced by estrogens and estrogenic compounds such as cadmium, which is useful for estrogen-responsive cancers that express higher levels of telomerase for cell viability. This inhibition of TERT expression in cancerous estrogen responsive cell lines has been observed in vivo with 0.1mg/mL melatonin in rat drinking water.
Appears to be able to suppress excessive expression of telomerase by environmental and endogenous estrogens, through regulation of TERT transcription. This is more of an anti-cancer mechanism, however, with its implications towards longevity currently unexplored
Combination therapy of melatonin (1mg/kg) and growth hormone (2mg/kg) has been found to reverse some increases in inflammatory cytokines (TNF-α and IL-1) and increase others (IL-10) in cardiac tissue of rats and abolished age-related changes in nF-kB distribution (cytosol and nuclear membrane). The reduction in mitochondrial potential seen with aging in cardiac cells (SAMP8 mice) appears to also be normalized and is seen in rats in a rehabilitative manner as well (30 days of supplementation to older rats).
A cardioprotective effect against aging appears to be apparent with melatonin administration, and this is not abolished by growth hormone therapy (study unable to assess synergism or additive effects)
In SAMP8 mice and Wistar rats, oral melatonin (1mg/kg) appears to reduce some effects of aging on the skin.
A reduction in age-related changes associated with oral intake of melatonin at 1mg/kg in rats and mice (0.08-0.16mg/kg bodyweight humans, or 5.45mg for a 150lb person) appear to extend to all measured organs
Administration of melatonin via the drinking water to BALB/c female mice between the hours of 1800h to 0830h at a concentration of 10ug/mL increased lifespan from an average of 715 days in control to 843 days in melatonin-treated; an 18% increase; a life extension effect was also seen when male mice started melatonin at 19 months of age (elderly status). Another part of the study using NZB mice given melatonin either nightly or throughout the day noted that nightly administration increased lifespan from 19 months to 23 months with statistical significance, but administration throughout the day only increased lifespan by one month and was not statistically significant.
In the testes' Leydig cells (Hamsters used as research models), melatonin appears to suppress androgen signalling via the MT1 receptor. Melatonin agonism of the MT1 receptor leads to downregulation of the StAR enzyme as well as other steroidogenic enzymes such as 3β-HSD and 17β-HSD; seemingly opposite effects of D-Aspartic Acid and in parallel to the actions of Corticotropin-releasing hormone. Melatonin appears to increase intracellular corticotropin-releasing hormone levels which paired with the passive diffusion of CRH from leydig cells led to researchers pairing melatonin with an antagnist of the CRH receptor, which completley abolished the inhibitory effects of melatonin on testosterone synthesis. Melatonin appears to work via MT1 to decrease phosphorylation of p38, which increases synthesis of CRH, and then CRH suppresses androgen synthesis.
Indirect negative regulator of testosterone in the testes
When supplemented to otherwise healthy men, melatonin at 6mg does not appear to significantly influence testosterone levels; it may trend to attenuate the exercise-induced decrease in testosterone. This same dose taken nightly for a month does not alter testosterone levels (nor LH or FSH) in otherwise healthy men.
Despite the mechanisms of negative regulation, does not appear to actually influence testosterone levels in healthy men
When investigating postmenopausal breast cancer survivors, there do not appear to be any influences on circulating estrogens (17b-estradiol measured) after 4 months of daily 3mg Melatonin usage prior to sleep.
When looking at the aromatase enzyme (CYP1A1/2, conversion of testosterone to estrogen) Melatonin appears to interact with aromatase. In MCF-7 (breast cancer) cells conditioned to proliferate after testosterone administration (via estrogen), Melatonin was found to slightly suppress proliferation and inhibit aromatase more at physiological concentrations (approx. 58% of control levels at 1nM) than pharmaceutical (75% at 10uM), and was able to suppress cAMP or cortisol-induced aromatase upregulation. These actions appear to be through activation of the MT1 receptor secondary to downregualting aromatase-inducing genes. These effects have also been noted in fibroblast cells, a source of estrogen production in post-menopausal estrogen-responsive breast cancer.
Appears to regulate aromatase, but the concentrations at which it does this may be more of a 'prevent a deficiency' issue (pertinent to aging) rather than a pharmacological intervention that would be used with testosterone supplements
Melatonin supplementation appears to stimulate growth hormone secretion secondary to resensitizing the pituitary gland to GHRH, as evidenced by augmenting the effects of single injected doses of GHRH and normalizing the magnitude of the second pulse (repeated doses of GHRH have an attenuated spike due to desensitization). It is thought that the mechanism is similar to that of pyridostigmine.
Both 500mcg and 5mg of Melatonin appear to be similarly effective in increasing Growth Hormone levels 1 hour after ingestion during waking, showing trends to normalize by 150 minutes after ingestion, with the AUC until this point being increased by 16+/-4.5 to 17.3+/-3.7mUh/L; 50mcg not significantly different than placebo. 5mg has been tested elsewhere and measured over 24 hours, but the overall increase was lesser (increasing basal levels from 3.4+/-1.3mU/l to 5.3+/-2.4mU/l) and not statistically significant.
Elsewhere, melatonin (500mg) may inhibit the release of growth hormone that is induced by serotonin, which appears to be exercise-related and insulin-induced hypoglycemia (low blood sugar).
At rest in otherwise healthy young males, melatonin supplementation in the range of 500-5,000mcg is able to acutely increase growth hormone levels which is thought to be due to sensitizing the pituitary to the effects of GHRH, rather than a direct stimulatory effect
Interactions between melatonin and exercise in regards to Growth Hormone are somewhat mixed, as one study using 500mcg and 5mg of melatonin against placebo in young and otherwise healthy persons with experience resistance training noted that, for 120 minutes after exercise, 5mg melatonin significantly increased growth hormone response relative to placebo in men while 500mcg trended towards significance; this study has a research grant from Iovate Health Sciences. Other studies on the subject matter note that 5mg melatonin taken before anaerobic bicycle exercise can significantly increase the peak and overall exposure to growth hormone after a single oral dose 60 minutes prior to exercise by approximately 72%, and one other study in resistance trained adult men undergoing full-body resistance training with 6mg melatonin an hour before exercise noted that melatonin actually decreased the exercise-induced spikes in growth hormone relative to placebo.
One human study using melatonin supplementation and measuring serum leptin noted that, in a population of 11 persons with idiopathic stomach ulcers, that leptin increased from 6.2-7.0ng/mL to 12.2-16.2ng/mL after 7 days, maintaining up to 21 days, after 5mg of Melatonin taken twice a day (morning and evening). This same dose (10mg) in persons with Non-Alcoholic Fatty Liver disease over 28 days with elevated leptin, a further elevation of 33% was observed.
These effects have also been seen in rats at 25mcg/mL in drinking water (about 500mcg daily) for 9 weeks with either a high fat (35% fat, 35% carbs) or a low fat (4% fat, 60% carbs) diet where leptin AUC was increased, but interestingly only when measured from early morning to early evening (with no significant difference at any time point in the evening). Another study in rats using a lower dose 10mcg/mL (ended up being 35mcg daily) of water also found influences on circulating leptin where they were increased to approximately 150% of control (data derived from graph) after 1 month, this study also found an increase in circulating Zinc and similar results have been seen in cases of excessive melatonin administration (3mg/kg in mice via I.V) where over 6 months leptin was increased to 127% that of control.
Due to interactions with the circadian rhythm, concrete numbers pertaining to the leptin increase may not be reliable. That being said, it appears to be reliable in that melatonin supplementation over a period of longer than a week increases circulating leptin without changes in body fat or food intake. This increase does not appear to be dose-dependent
When looking at isolated fat cells (where most leptin is produced), the amount of leptin secreted is not significantly enhanced when incubated with 1nM melatonin. However, this may be due to incubation with melatonin alone as other studies pairing melatonin with insulin note that melatonin may augment the insulin-induced secretion of leptin as neither alone induced leptin secretion in vitro while the combination increased secretion by 120% and mRNA content by 50%, and adding dexamethasone to the mixture increased this to 250% and 100%, respectively. Melatonin was able to suppress a cAMP-induced suppression of leptin release and be synergistic in inducing IRb and Akt phosphorylation by insulin in adipocytes, and its effects were abolished when the MT1 receptor was prevented from acting. These effects were later replicated by the same research group with the same potency when adipocytes were incubated on a 12 hour on/12 hour off protocol to mimick the circadian rhythm.
Appears to potentiate insulin-induced leptin secretion
Please refer to the section on Mechanisms and the subheader 'Non-Melatonin Receptors' for discussion on GPR50, a leptin receptor that negatively influences melatonin signalling through MT1. The increase in leptin may be a mechanism of negative feedback on melatonin signalling.
Supplemental melatonin in young healthy men at the doses of 50mcg, 500mcg, and 5mg does not appear to influence circulating cortisol levels when taken at 2:30 and measured for 150 minutes afterwards. When taken at 5mg at 5pm nightly for four nights in a similar demographic and then measured during sleep, the 24-hour AUC of cortisol was slightly increased.
In a clinic study on non-obese post-menopausal women aged 54-62, a large dose of 100mg melatonin (able to keep melatonin elevated for up to 12 hours) taken at 8am was able to increase cortisol 24-hour AUC slightly (from 219+/-17 to 229+/-14nmol/L, a 4.5% increase) but caused a significant increase during the hours of 2000-0100, which was suppressed by exogenous estrogen.
Melatonin at 50mcg, 500mcg, and 5mg does not appear to significantly influence prolactin levels over 150 minutes post-ingestion, a time frame where melatonin influences other hormones. 5mg of melatonin taken for four days appears to positively influence 24-hour prolactin levels, however.
Melatonin has been investigated for its interactions with obesity due to rats lacking pineal glands that secrete melatonin (pinealectomized rats) experiencing increased lipogenesis and reduced lipolysis. The pairing of a lack of melatonin secretion and synthesis with weight gain suggests that melatonin may either be anti-obesogenic (reducing fat gain) or may induce fat loss.
Melatonin appears to be somewhat of a negative regulator of adipocyte physiology, being able to influence mesenchymal stem cell (MSC) differentiation away from adipocytes and promote osteogenic cell growth secondary to PPARy inhibition and suppress proliferation of mature 3T3-L1 adipocytes secondary to suppression of C/EBPbeta transcriptional activity.
When treated in 3T3-L1 preadipocytes, melatonin is able to induce proliferation; this appears to be through MT1 receptor activation.
At the level of the Mesenchymal cell (a cell that can develop into either adipose cells or bone cells), Melatonin appears to influence this cell line towards bone rather than fat; a process similar to that seen with Resveratrol
In a model of PAZ6 adipocytes (human brown preadipocyte cell line) it was found that the mRNA for both melatonin receptors existed, and via MT2 receptors suppressed GLUT4 translocation and glucose uptake by approxiately 25% over 14 days incubation but failed to significantly reduce activity after 1 day. In this study, brown and white adipocytes were both tested and although white had less MT1 than brown adipose, white expressed no MT2. A study using luzincole (agonist of mostly MT2 but some affinity to MT1) demonstrated it was less effective than melatonin at these effects, supporting the lack or either relative absence of active MT2 on white adipocytes.
Activation of melatonin receptors appears to be associated with less activation (suppression) of adenyl cyclase and decrease in cAMP levels, and this decrease in cAMP levels (associated with the Gi protein coupled to melatonin receptors) can suppress lipolysis induced from beta(2)adrenergic stimulation.
White adipose expresses MT1 and either no or little MT2; although glucose metabolism is heavily influenced in brown adipocytes, humans do not have many (relative to rats) and these may not be practically relevant. Signalling via MT1 in white adipose may be the most practically relevant mechanistic pathway of melatonin to humans
When investigating oxidation, incubation of preadipocytes with melatonin is associated with increased levels of both Cu/Zn and Mn Superoxide Dismutases (SODs), and an increaes in Catalase after 24 hour incubation; these trends reversed at 48 hours of incubation.
When rats are fed 500mcg melatonin daily via the drinking water and concurrently given a high fat (35%) diet, the rate of weight gain is attenuated independent of changes in calories. This has been replicated with 0.4mcg/mL, where a 7% decrease in body weight and 16% lower intraabdominal adipose mass was recorded.
When 5mg of melatonin is administered 2 hours before bedtime in a sample of persons with metabolic syndrome, a small but statistically significant reduction of BMI is seen (from 29 to 28.8) over two months, which correlates with improvments in blood pressure and antioxidant profile.
Unlikely to be a potent weight loss or anti-weight gain agent, although it does seem to beneficially influence these parameters
When melatonin at 6mg is taken by youth (18-20) immediately (30m) prior to exercise, it was able to reduce the amount of lipid peroxidation induced by exercise (serum MDA) and appeared to significantly preserve (perhaps slightly elevate) levels of endogenous antioxidant enzymes. In this study, plasma triglycerides from exercise were also significantly reduced with melatonin relative to control.
After rats are subject to crush injury, melatonin injections at 10mg/kg bodyweight were associated with better muscle function (tetanic and twitch force) at 4, 7, and 14 days after injury relative to control, about 1.2 to 1.3-fold better recovery. This appears to be secondary to an increase in satellite cells (2-fold) and decrease in apoptotic cells measured after the first dose up to the 4 day marker (50% decrease) with no further influence; this increase in sattelite cells was not observed in uninjured tissue. A reduction in apoptosis and mitochondrial dysfunction has also been observed with Ischemia/Reperfusion injury to skeletal muscle. The mechanism of mitochondrial protection seems to be related to preserving membrane permeability, possibly secondary to melatonin's anti-oxidative capacity.
At least one study pertaining to athletes investigated whether nightly melatonin usage (5mg) hampered daytime physical activity failed to note any harm to physical performance from sedation.
In a study where 5mg melatonin was taken 3 hours prior to exercise, it was found that melatonin increased sedation and reduced reaction time whereas it did not significantly affect physical performance as assessed by 4km cycling test; the authors suggested that the hindering effect of melatonin on physical performance during the day was more neural than physical.
Melatonin is a multi-modal anti-oxidant, being implicated in increasing the concentration of certain anti-oxidant enzymes such as catalase and the superoxide dismutases as well as inherently having a structure that confers anti-oxidative properties per se. It has shown benefit in inhibiting oxidation secondary to oxygen-based free radicals, hydroxyl radicals, and reactive nitrogen species such as peroxynitrate and nitric oxide.
Via anti-oxidant means, melatonin can inhibit mineral-induced damage to DNA (in this study, CrIII was used) in a dose-dependent manner, with 24+/-1% inhibition at 1uM and 80+/-3% at 100uM. Melatonin was the most protective tested on a concentration dependent basis (outperforming Green Tea Catechins, Resveratrol, and Alpha-Lipoic Acid) and had an IC50 value of 3.6+/-0.1uM.
Melatonin has been cited in one meta-analysis to reduce the risk of death after 1 year in persons with solid tumor cancers with a relative risk (RR) of 0.66 and 95% CI of 0.59-0.73, suggesting approximately a quarter risk.
May exert a general protective effect in cancer patients which results in less death
It has been hypothesized that melatonin levels, through markers such as circadian rhythm disturbances and urinary metabolite levels, is inversely correlated with breast cancer (and that a reduced melatonin status increases breast cancer risk).
A few mechanisms have been investigated for melatonin's role in breast cancer such as; its role as a modulator of aromatase enzyme protein content, modulation of the cell cycle via suppressing Cyclin D1, and influencing transcriptional activity of nuclear receptors.
Melatonin at high doses (18mg) has been investigated in a trial on advanced gastrointestinal cancer, with or without high dose Fish Oil (4.9g EPA, 3.2g DHA). This study had either treatment for the first 4 weeks, and combination therapy for the next 4 weeks; no changes in circulating biomarkers or cytokines were seen although both the fish oil and melatonin had limited efficacy in stabilizing weight or inducing weight gain (38% of patients on fish oil, 27% on melatonin) while the combination had additive effects (68%), suggesting promise for cancer-related cachexia and anorexia.
Melatonin works through the MT1 receptor on the Suprachiasmatic Nuclei (SCN) to inhibit CREB phosphorylation secondary to pituitary adenyl cyclase activating polypeptide (PACAP) and through the MT2 receptors of the SCN to facilitate changing of the circadian rhythm, a phenomena known as phase shifting; this appears to be mediated via PKC. It is through mostly MT2, but to a lesser extent MT1, that melatonin acts to regulate sleep-wake cycles. MT2 works to regulate the phase shifts while MT1 exerts general supperssive actions on cell activation.
In at least one blinded intervention, melatonin at 3mg nightly (the manner of which to improve sleep) also improved subjective ratings of Gastro-Esophageal Reflux Disease (GERD) and reduced heartburn. It was less effective than omeprazole, but they were additive when used in combination.
In patients with stomach ulcers that test positive for Heliobactor Pylori, twice daily dosing of 5mg Melatonin over 21 days (paired with omeprazole in all groups) complete healing of ulcers was seen in the Melatonin group (n=7) and the L-tryptophan group, but only 3/7 had complete healing in control given only omeprazole. These healing effects on ulcers have also been seen with H.Pylori negative stomach ulcers in combination with omeprazole, and in a study on aspirin-induced stomach ulcers, melatonin in isolation showed protective effects.
One study investigating Melatonin and Tinnitus found that 3mg of Melatonin taken nightly for 30 days (double-blind crossover with 1 month washout) was associated with improvements on at least 2 of 3 rating scales for tinnitus (Tinnitus Matching, Tinnitus Severity Index, Self-Rated Tinnitus), with 57% of the melatonin group experiencing benefits and only 25% of the placebo reporting benefit; it appeared to benefit men slightly more than women. This study was a similarily structed replication of a previous study which reported 46.5% of the melatonin group experincing benefit, and 20% of the placebo reporting such. Only one other study has been conducted on melatonin and tinnitus thus far, and in this prospective open-label study 3mg of Melatonin taken for 4 weeks was also associated with decreased symptoms of tinnitus that appeared to be, overall, unrelated to the benefits of melatonin on sleep.
In another trial pairing melatonin at 3mg with the blood-flow enhancing drug Sulodexide at 250-500mg (with the other two groups being melatonin in isolation and contrl) both combination therapy and melatonin were found to be more effective than placebo while additive benefits against tinnitus were seen with combination therapy. Improvements were seen in 79.4% of combination therapy and 58.8% of persons in melatonin only when assessed by both THI and acufenometry. This study is duplicated in Pubmed.
Not a cure, but appears to be more effective than placebo at suppressing tinnitus-related symptoms and improving sleep secondary to less subjective sensation of tinnitus
Melatonin is able to influence eye health, as it expresses melatonin receptors (MT1 and MT2) on the eye itself, where activation of retinal MT1 receptors decreases ocular pressure, and this is seen after supplemental Melatonin in healthy men and when pre-loaded before cataract surgery. 500mcg of Melatonin administered orally at 6pm to otherwise healthy men was able to significantly reduce intra-ocular blood pressure at 9-10pm, and retained statistically insignficant suppression at 8pm as well as 11-12pm (latest measurement).
One study investigating mechanisms noted that incubation of retina with melatonin agonists was associated with modulation of adrenaline receptors, downregulation of the beta(2)adrenergic receptor and upregulation of the alpha(2)adrenergic receptor which is suppressive of adrenaline's actions. Protein content of carbonic anhydrases is also reduced with melatonin agonists, which may also confer reductions in ocular blood pressure.
Melatonin appears to regulate ocular blood pressure, by reducing intra-ocular blood pressure through melatonin receptors. This may be through suppressing the actions of adrenaline-mediated blood pressure increases. 500mcg orally can reduce ocular blood pressure 2-3 hours after administration
The concentration of melatonin in the eye (aqueous humor) appears to be roughly similar between glaucoma patients and normal persons when measured in the morning and early afternoon (800 and 1600h), a time where they are lower than in the evening; it is not known if persons with glaucoma have lower sleeping melatonin levels in the aqueous humor.
In an open-label pilot study using 3mg Melatonin nightly for 6 months on 55 persons (110 tested eyes), Melatonin was associated with either a slight bettering or stability of disease pathology in the majority of patients.
At least one study in human skin cells noted that glycolic acid, a small α-hydroxy acid commonly found in skin care products, reduced lipid peroxidation (as assessed by TBARS) by up to 14% at 1mM concentration, yet putting in melatonin at a 1:200 ratio (much less than glycolic acid) exerted 80% anti-oxidative synergism as assessed by TBARS. More potent anti-oxidative synergism was shown between glycolic acid and Vitamin E, however.
The pathophysiology of hair loss involves oxidative stress which seems to extend to androgenic hair loss, as the hair follicles have increased sensitivity to oxidative stress. Due to the potency of melatonin as a direct antioxidant and the fact that hair follicle cells express and produce melatonin, it has been investigated for its role in preventing hair loss. Topical application of melatonin to the scalp does not significantly increase serum concentrations of melatonin (a clinically irrelevant increase in peak values with no change in 20 hour mean values).
In vitro, 1-5mM of melatonin has been found to accelerate the growth of hair (inhibitory at 30mM) which is thought to be secondary to the melatonin receptor as the effect is abolished by receptor antagonists (study cannot be located online, mentioned vicariously through this paper). These growth enhancing effects were confirmed in a pilot study using 1mL of a solution of 0.1% melatonin in women with androgenic alpoceria over 6 months where anagen phase was promoted and a later study noted that there was a response rate of 54.8% of participants in regards to increase hair density and hair cell count over 3 months with topical melatonin (0.03%), with the increase being measured at 27.2% (3 months) and 42.7% (6 months) more than control.
Although the study cannot be found online (again mentioned vicariously through a review), there appears to be a large open-label study of 1891 persons with androgenic hair loss which reported that the rate of no hair loss rose from 12.5% to 61.5%, but stimulated hair growth in 22.5% of the sample.
Melatonin receptors are expressed in hair cells, and it appears to have a role in promoting hair growth. While it does appear to be both effective and potent at inducing hair growth and stalling hair loss, even in androgenic hair loss (receding hair line), it appears to be somewhat unreliable and does not affect 100% of subjects
Hypothermic effects appear to be mediated through MT1 and MT2 receptors, as the pharmaceutical melatonin agonist ramelteon also shows efficacy in reducing body temperature. Additionally, cross-talk with serotonergic receptors appears to be involved as activation of the serotonin 1A receptor subset (5-HT1A) appears to be associated with hypothermia and melatonin potentiates activation of this receptor. Interestingly, activation of the other serotonin receptor (5-HT2A) abolishes this hypothermic effect.
At least from rat studies, it is possible that the hypothermic effect of Melatonin supplementation may not occur in periods of heat (31°C) despite occurring under the same conditions when the temperature is near room-temperature (22°C) or cold (8°C).
Supplementation of Melatonin, at 5mg and measured 5.25 hours after ingestion, is able to reduce intra-aural (within the ear) temperature by 0.49 ± 0.79°C relative to placebo (both groups underwent exercise); intraaural temperature appears to be a reliable way to measure body temperature changes during exercise. A bedrest study comparing 100mcg, 500mcg, 1mg, and 5mg and measured for 4 hours after ingestion noted that the two higher doses were able to significantly reduce body temperature and 5mg maintained this suppression for up to 4 hours while 1mg appeared to trend to normalize at 2.5 hours; maximum drops in core temperature with the four doses were 0.08, 0.15, 0.20, and 0.25°C, respectively.
At least in a resting position, melatonin appears to be able to reduce body temperature (which may be related to the decrease in sleep latency)
Melatonin has been shown (in rats) to alleviate the hyperoxidative state induced upon the mitochondria that occurs with aging. This can be seen as a protective effect, but not exerting a protective effect above what is observed in youth.
Caffeine is an adenosine receptor antagonist with affinity towards A2(A), and is seen as anti-sleep due to its effects. For a short while it is also stimulatory, but these effects wane with time.
Both Caffeine and Melatonin are metabolized by the same enzyme class and specifically, the aromatase enzyme (CYP1A1/2). Coingestion of the two appears to exert competition in metabolism, as the AUC of melatonin is increased by 120% when ingested with caffeine without significantly affecting the half-life of melatonin.
When investigating mitochondrial function in mice and in vitro, caffeine appears to exert similar effects as melatonin in preventing against Alzheimer's related cognitive deficit but was less potent and actively inhibited melatonin's benefit when coingested. This does not appear to be through the adenosine receptors per se, but through PDE4 inhibition and increasing cAMP levels which oppose melatonin's decrease of cAMP.
Alcohol is a component of some beverages that, surprisingly, contain a Melatonin content (beer and wine). However, when investigating how alcohol consumption in general affects circulating melatonin levels at a level of social drinking (10-100g ethanol) it seems that some studies suggest a reduction of circulating or salivary melatonin levels with inhibition measured at night being up to 41%. Some studies suggest an increase melatonin, as according to one study using beer (7.2%) where women had 330mL and men had 660mL seeing an increase in melatonin levels 45 minutes after ingestion.
When measuring urinary melatonin levels, however, there do not appear to be any significant influences from alcohol consumption and one study suggests a decrease in urinary melatonin secretion between 9-17% (2-4 drinks, no effect seen from 1).
Interactions of alcohol on melatonin levels are not completely clear
An in vitro study assessing melatonin (1uM) and Vitamin C at 0.5uM demonstrated synergism in protecting DNA from oxidative damage induced by Chromium III. The slightly pro-oxidative effects seen with Vitamin C in this assay were reversed when melatonin was coincubated.
An in vitro study assessing melatonin (1uM) and Alpha-Lipoic Acid (5uM) found that, in protecting DNA from chromium III induced oxidative damage, that the two were synergistic in their protective effects.
Tryptophan is the amino acid which is metabolized into 5-HTP, which can then be produced into serotonin and then melatonin.
Melatonin appears to inhibit the tryptophan 2,3-dioxygenase (TDO) enzyme, which acts to direct tryptophan away from production into 5-HTP by enhancing its catabolism; inhibition of TDO via melatonin can enhance the amount of bioavailable tryptophan independent of supplementation.
EGCG is the main polyphenol referred to as Green Tea Catechins, and in an in vitro test on DNA-induced oxidation it was found that co-incubation of melatonin and EGCG both at 1uM slightly suppressed each other's actions; demonstrating antagonism. It should be noted that the overall protection exerted with both was still greater than either in isolation, but that there was a less than additive benefit.
When tested in vitro Resveratrol, the wine polyphenol, did not show synergism nor antagonism with melatonin in protecting DNA from oxidative damage. However, the slightly pro-oxidative effects of resveratrol on the DNA were abolished when melatonin was added to the medium.
Resveratrol does display synergism with Melatonin in regards to neuroprotection, where melatonin and resveratrol both showed dose-dependent protection from toxicity in hippocampal cells from beta-amyloid pigmentation (associated with Alzheimer's) since the combination required less of a dose to exert the same effects as either in isolation. This appeared to be mediated via anti-oxidative means, and superloading either in isolation overrode synergism.
Although not a nutrient, melatonin has shown synergistic effects with physical exercise in regards to accelerating neuronal repair after nerve injury, and in general neuroprotective effects. The former study noted more motor neurons in the ventral horn and improved functional capacity were seen in rats given 10mg/kg melatonin daily in conjunction with exercise relative to exercise alone, and this was hypothesized to be via a suppression of iNOS in neurons (which was observed, and iNOS tends to be increased during neuronal injury). The latter study notes that in mice highly prone to Alzheimer's Disease that this same dose of melatonin paired with free access to a running wheel is able to preserve reflexes and memory function while synergsitically decreasing neural oxidation and Alzheimer's pathology in the brain. Melatonin plus exercise appeared to significantly increase CoQ9 in brain mitochondria, the precursor to CoQ10.
Galantamine is a cholinergic drug that can inhibit the acetylcholinesterase enzyme, and elevate levels of acetylcholine in the brain (a mechanism similar to Huperzine-A). When subeffective levels of melatonin (0.3-10uM) and galantamine (10-300nM) was able to confer synergistic protection against rotenone-induced oxidative stress, 300nM galantamine and 10uM melatonin protected neurons by 56% and 50%, respectively, while 0.3uM melatonin and 10nM galantamine combined confered the same level of protection despite being in concentrations 30 to 33-fold lower. This synergism may not be restricted to the molecules, but may be mediated through the nicotinic and melatonin receptors.
In older persons with insomnia, 6 months of melatonin at 2mg (long-release formula) is not assocaited with any overt harm and appears to be safe and effective at 5mg (according to caretaker interview) in children with the average age of 6 (at onset of treatment) with sleep disorders as symptoms of other medical problems (autism, cerebral palsy, epilepsy), when the caretakers were interviewed 3.8 years after starting treatment (some caretakers upped the dose to 10mg or 15mg).
(Common misspellings for Melatonin include meltonin, melatoni, melontonin, melontonine)
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