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  1. #21
    Senior Member shamus's Avatar
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    <div class='quotetop'>QUOTE (ATB @ Mar 14 2010, 08:18 AM) <{POST_SNAPBACK}></div><div class='quotemain'>yes, melatonin stimulates immune inflammation, as indicated in arthritis.

    The dose you actually need is more like 300mcg, not mg range. The doses in the animals were huge. Inflammation is not good for testosterone. In order for melatonin to work, it has to be broken down apparently in the mitochondria. If you take too much, the rhythm is disturbed. People get confused with the action of melatonin and the chemical properties of mega doses of melatonin, which would be fine, if it wasn't a signal in the biorythm.</div>


    I think it was at imminst where I read that 3mg doses eventually inhibit your natural production. In the same piece it was advised 300mcg is the optimal dose, I don't remember if there were studies to support it though.

  2. #22
    Senior Member ((Vibe))'s Avatar
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    <div class='quotetop'>QUOTE (Josh @ Mar 13 2010, 01:59 PM) <{POST_SNAPBACK}></div><div class='quotemain'>Has anyone trialled various amounts of melatonin with unrestricted wakeup times, and seen the relationship between melatonin dose and length of sleep? Formally/Quantitatively or Informally/qualitatively is fine?

    J</div>

    A summation of my experience with melatonin:

    ~300 mcg's, as ATB suggested, seemed to be the best dose and didn't impart a groggy feeling upon wakening.

    I also noticed that as my (unperceived) sleep debt shrank, the effects of melatonin became greatly reduced, to the point where even very high doses were not sleep promoting.

    ie

    2mg's taken in the middle of the day w/even a small amount of unperceived sleep debt => out like a light
    5mg's taken in the middle of the day after having slept in for several days => nothing

    That may or may not seem obvious,...and I'm not really satisfied with how I worded all of that (kind of hard to describe),...but I found it interesting at the time.
    “When mental energy is allowed to follow the line of least resistance and to fall into easy channels, it is called weakness” -James Allen

    "That by which a man is overcome, by this he is enslaved." 2 Peter 2:19

  3. #23
    Senior Member Benson's Avatar
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    <div class='quotetop'>QUOTE (shamus @ Mar 14 2010, 08:04 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I think it was at imminst where I read that 3mg doses eventually inhibit your natural production.</div>

    I've yet to see anything showing shut-down in humans as a result of exogenous supplementation.
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  4. #24
    Senior Member nightop's Avatar
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    I've been taking 3mg every night for many years without any problems that I can notice and experience numerous benefits from it.

    About a year ago, I went on vacation and forgot to bring melatonin and thus had to sleep a night or two without it before I would be able to pick some up at a drug store. The first night I had been drinking and went to sleep just fine, the second night took longer for me to go to sleep and the quality/duration was bad, but I felt fine the next day. By the third day I decided to just go without melatonin instead of buying it, and I finished the vacation without it just fine. Things felt like they had normalized after about 5-6 days, although I still missed the immediate "knock-out" effect of the melatonin, and resumed use upon returning home.

    Long story short, I don't think 1-3mg is a big deal.
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  5. #25
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    Asthma Patients Cautioned About Melatonin
    ScienceDaily (Sep. 8, 2003) — People with asthma should consider limiting the use of melatonin as a sleep aid, according to researchers at National Jewish Medical and Research Center. Pulmonologist Rand Sutherland, M.D., M.P.H., and his colleagues report in the September 2003 issue of the Journal of Allergy and Clinical Immunology that higher levels of melatonin were associated with an overnight loss of lung function in asthma patients. Previous studies by the same group have shown that melatonin induces the release of chemicals that promote inflammation, a hallmark symptom of asthma.

    "For patients whose asthma worsens at night, we found that higher levels of naturally occurring melatonin are associated with impaired lung function," said Dr. Sutherland. "Those findings, on top of previous ones linking melatonin to inflammation, suggest that all patients with asthma should avoid using melatonin supplements until more is known about their safety."

    Melatonin, a hormone secreted by the pineal gland in the brain, is an important regulator of circadian rhythms in the body, especially sleep. It is released at night, generally beginning in the evening hours before bedtime, peaking in the middle of the night, and ending about the time people awaken. Because of its association with sleep, over-the-counter melatonin has become a popular dietary supplement sold as a treatment for jet lag and insomnia.

    However, melatonin has also been shown to enhance inflammation in cell and animal studies of asthma. Airway inflammation is one reason people with asthma have difficulty breathing. A significant portion of asthma patients experience increased symptoms at night. Dr. Sutherland and his colleagues hypothesized that melatonin may play a role in this nighttime worsening of asthma.

    The researchers had seven people with nocturnal asthma, 13 with non-nocturnal asthma, and 11 healthy controls establish a regular sleep schedule for seven days. On the eighth night, small blood samples were taken from the sleeping patients every two hours. These samples were evaluated for their melatonin levels. The study subjects also performed lung function tests before going to bed and after waking up.

    The patients with nocturnal asthma had the highest levels of melatonin and the greatest drop in lung function overnight. Peak levels of melatonin averaged 67.5 picograms/milliliter in nocturnal asthmatics, 61.1 pg/mL in non-nocturnal asthmatics, and 53.5 in healthy controls. Lung function, as measured by the amount of air patients can exhale in one second (FEV1), dropped an average of 18.8 percent in nocturnal asthmatics, 5.1 percent in non-nocturnal asthmatics, and increased 1.5 percent in healthy controls. The correlation between overnight change in FEV1 and melatonin levels showed a strong 0.79 correlation in patients with nocturnal asthma. There was a slight, but not statistically significant, correlation among patients with non-nocturnal asthma.

    "These findings suggest that melatonin naturally produced by people with nocturnal asthma increases inflammation in their airways, leading to worse lung function," said Dr. Sutherland. "Given that previous work has shown that melatonin promotes inflammation in the cells of both nocturnal and non-nocturnal asthmatics, any person with asthma should be cautious about taking supplements that would further raise their melatonin blood levels."

    http://www.sciencedaily.com/releases/2003/...30908070842.htm

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  6. #26
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    Melatonin has complex interactions. The two types of sleep, that controlled by the body clock, or rebound sleep, involve inflammatory signalling. Melatonin at the wrong time is going to interfere with this complex system. It acts in concert with certain inflammatory signalling. Once the body clock is programmed, the inflammatory signalling will alter, as will the actions of melatonin. If you are to benefit most, you want sleep efficiency, which is connected to rhythms. This is connected to a number of aspects of immune health. Inflammation can come from over or under active immune systems (ie due to infection). The key event is the slow response to infection, which in gut dissorders is linked to increasing inflammation (as hypothesised). The sleep rhythm plays a huge role in immune competency and avoidance of infection. Melatonin taken at innapropiate times will not help this. Melatonin rhythms that are abnormally flat, whether high or low, are not associated with health. High day time melatonin also associated with RA, which is associated with infection and immune overactivity.

    Large doses are powerfully antioxidant and dysruption of normal rhythms should occur. A large dose may provide antioxidant protection. If you want an antioxidant, there are many alternatives, like astaxanthin.

    So in short, no data compares melatonin mega therapy side by side with antioxidants and appropriate mcg doses of melatonin taken at the right time to induce sleep efficiency.

    In normal sleep, TNF alpha and IL-1 signal as part of the biorhythm, though a natural mechanism exists, possibly connected to melatonin, in NF-Kappa B availability. This second factor limits inflammatory signalling and seems to balance the system, nevertheless, a rhythm in these various factors is supposed to exist, and to establish that not much melatonin is needed.



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  7. #27
    Senior Member Benson's Avatar
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    <div class='quotetop'>QUOTE (ATB @ Mar 14 2010, 04:04 PM) <{POST_SNAPBACK}></div><div class='quotemain'>"These findings suggest that melatonin naturally produced by people with nocturnal asthma increases inflammation in their airways, leading to worse lung function,"</div>

    As it says in my .sig, no matter how good the theory sounds, you should occasionally check the results...

    Am J Respir Crit Care Med. 2004 Nov 1;170(9):947-51. Epub 2004 Aug 11.
    Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study.
    Campos FL, da Silva-Júnior FP, de Bruin VM, de Bruin PF.
    Department of Pharmacy, Universidade Federal do Ceará, Fortaleza, CE, Brazil.

    Disturbed sleep is common in asthma. Melatonin has sleep-inducing activity and reportedly affects smooth muscle tone and inflammation. The aim of this study was to evaluate the effect of melatonin on sleep in patients with mild and moderate asthma. This was a randomized, double-blind, placebo-controlled study. Twenty-two consecutive women with asthma were randomized to receive melatonin 3 mg (n = 12) or placebo (n = 10) for 4 weeks. Sleep quality and daytime somnolence were assessed by the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale, respectively. Pulmonary function was assessed by spirometry. Use of relief medication, asthma symptoms, and morning and evening peak expiratory flow rate were recorded daily. Melatonin treatment significantly improved subjective sleep quality, as compared with placebo (p = 0.04). No significant difference in asthma symptoms, use of relief medication and daily peak expiratory flow rate was found between groups. We conclude that melatonin can improve sleep in patients with asthma. Further studies looking into long-term effects of melatonin on airway inflammation and bronchial hyperresponsiveness are needed before melatonin can be recommended in patients with asthma.

    PMID: 15306531
    Remember, believe none of what you hear and half of what you see...





  8. #28
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    That melatonin was taken at night, and we have every reason to assume that the benefits experienced were due to the sleep-enhancing effect, which we have always advocated. In fact, the problem is that the chronic inflammation state actually inteferes with the body clock, so the benefits are apparently that this helped entrain sleep, and block the action of inflammation. If the action was more due to an antioxidant effect, the same effect can be seen from gamma toc.

    So, we still haven't established anything. The need is only for about 300mcg which has been shown to be best for purposes of sleep. That study prospectively established that 300mcg plus an extrenuous 3700mcg was helpful in re-establishing sleeping rhythm, and may have been inferior to the action of 300mcg alone. However, it is possible that the inflammatory breathing condition benefitted from higher doses.

    Several unknowns exist - inflammation associated with day time melatonin may not show up in 4 weeks - RA does not show in 4 weeks.

    It may be that over time excessive melatonin has a deminishing effect.

    It may be that the anti-inflammatory actions of the melatonin are better provided by lower doses of melatonin and a classic antioxidant or diet.

    It may be that the action is effected by additional, unknown factors, such as age. Is the blunting of melatonin rhythms and high day time melatonin caused by higher melatonin, and therefore by mega therapy, or is it instead a symptom of the disease ie failure to clear the melatonin, or production in tissues during the day.

    One confounder is also, types of inflammation. Airway inflammation, especially nasal, increases in the evening. Large doses of melatonin may reduce this inflammation but so does antioxidant therapy. But what happens to the immune system during the day? Does the mega dose remain in the blood in the day, and if it does, we would associate this with immune dysfunctions and depressed mood.

    The immune dysfunction may not show up as instant increases in aggressiveness, but instead, in diminished function, and infection, then subsequently as inflammation - which would create secondary problems plausibly involving symptoms like RA, which is associated with day time melatonin.

    There are numerous problems with the studies done, such as when the melatonin is taken, and whether the subjects may differ in their need and ability to metabolise that melatonin.

    If everyone can be shown to clear large doses of melatonin in time for waking then I would be much more inclined to consider larger doses to enhance an antiinflammatory effect. In my experience, there is a definite harmful effect of increasing or reducing inflammation by diet or supplements before sleep.
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  9. #29
    Senior Member Benson's Avatar
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    <div class='quotetop'>QUOTE (ATB @ Mar 15 2010, 03:46 PM) <{POST_SNAPBACK}></div><div class='quotemain'>That melatonin was taken at night, and we have every reason to assume that the benefits experienced were due to the sleep-enhancing effect, which we have always advocated.</div>

    Or, asthma is better controlled with melatonin use so asthmatics sleep better when using melatonin.

    <div class='quotetop'>QUOTE </div><div class='quotemain'>So, we still haven't established anything.</div>

    Except that, contrary to what one might suppose from the in vitro inflammation studies, asthmatics don't experience more attacks when using melatonin, even doses far larger than they produce endogenously. IBS sufferers also experience fewer symptoms when taking melatonin which calls into question the idea that melatonin is pro-inflammatory in vivo.

    <div class='quotetop'>QUOTE </div><div class='quotemain'>If everyone can be shown to clear large doses of melatonin in time for waking then I would be much more inclined to consider larger doses to enhance an antiinflammatory effect.</div>

    These subjects experienced significantly less daytime sleepiness while using the melatonin indicating that there was no 'hangover' effect from their melatonin use the evening before.
    Remember, believe none of what you hear and half of what you see...





  10. #30
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    <div class='quotetop'>QUOTE </div><div class='quotemain'>Alteration of the amount of daylight from season-to-season affects melatonin secretion, and thereby can affect seasonal fertility in many mammals. In deer, the decreased light during the Fall season leads to increased fertility and breeding. For hamsters, increased melatonin during Fall and Winter leads to testicular regression in males and estrus inhibition in females. Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland. Humans may be similar to hamsters because pituitary-gonadal function and conception rates are lower for people living in the Arctic during Winter months [THE NEW ENGLAND JOURNAL OF MEDICINE; Brzezinski,A; 336(3):186-195 (1997)]. Melatonin can inhibit ovulation in women and has even been suggested for use in conjunction with other contraceptives [ THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Voordouw,BCG; 74(1):108-117 (1992)]. A small study of men, however, showed no suppression of reproductive hormones with melatonin [HUMAN REPRODUCTION; Luboshitzky,R; 15(1):60-65 (2000)].

    Melatonin interacts with the hypothalamic-pituitary-adrenal hormonal system to reduce the harmful effects of excessive glucocorticoids -- notably damage to the hippocampus [NEUROENDOCRINOLOGY; Konakchieva,R; 67:171-180 (1998)]. Melatonin is necessary for normal sexual maturation. Melatonin supplementation improves thyroid function and can delay the onset of menopause [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES; Lopez,BP; 1057:337-364 (2005) and Bellipanni,F; 1057:393-402 (2005)].</div>

    <div class='quotetop'>QUOTE </div><div class='quotemain'>The most worrisome experiments involving melatonin are those that show increasing incidence of cancer in certain species of mice (usually female mice) that are given melatonin. Ironically, a study of this kind showed an overall 5.4% increase in mean lifespan and a 17% increase in maximum lifespan despite the increased incidence of tumors [JOURNALS OF GERONTOLOGY; Anisimov,VN; 56A:B311-B323 (2001)]. By contrast, melatonin in other strains of female mice has been shown to suppress tumors [JOURNAL OF PINEAL RESEARCH; Subramanian,A; 10(3):136-140 (1991) and BREAST CANCER RESEARCH AND TREATMENT; Rao,GN; 64(3):287-296 (2000)]. The anti-cancer effects of melatonin are also seen in rats [BREAST CANCER RESEARCH; Lenoir,V; 7(4):R470-R476 (2005)].</div>

    http://www.benbest.com/nutrceut/melatonin.html

    Melatonin is an interesting supplement, that is for sure.

    http://www.immunityageing.com/content/2/1/17

    That review covers the broad immune-stimulatory role which it shows occurs after 1 to 2 weeks in some systems.

    Back to benbest article:

    For melatonin, more is not better. Blood concentrations which are ten times normal youthful levels can cleave heme molecules to liberate iron and induce oxidative stress [NEUROCHEMISTRY; Clapp-Lilly,KL; 12(6):1277-1280 (2001)]. Even higher levels of melatonin concentrations deplete reduced glutathione levels [LIFE SCIENCES; Osseni,RA; 502:127-131 (2001)].

    Melatonin can counteract the effectiveness of steroid drugs, can worsen allergic responses and can worsen auto-immune disease. Melatonin readily crosses the placenta, but the effects of above-normal quantities on a developing fetus or a pregnant woman have not been thoroughly studied

    Although supplement doses a hundred times the typical 3 mg per day have proven to be safe, higher doses may be unnecessary or even harmful. Doses in the 1 mg to 5 mg range should be safe and sufficient insofare as these doses produce blood levels 10 to 100 times higher than the usual nighttime peaks [THE NEW ENGLAND JOURNAL OF MEDICINE; Brzezinski,A; 336(3):186-195 (1997)].

    .....Night-time blood levels of melatonin peak at about 120 picograms per milliliter just before the age of puberty. By age 30 blood levels have fallen by half and by age 60 the levels of melatonin in the blood are usually about 5 picograms per milliliter or less. Melatonin supplementation is of much more value for older adults, because their natural production of melatonin is so low [EXPERIMENTAL GERONTOLOGY; Pandi-Perumal,SR; 40(12):911-925 (2005)].

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Melatonin Reduces Nighttime High Blood Pressure
    By Jeremy Appleton, ND, CNS
    Healthnotes Newswire (November 30, 2006)—A hormone known as a treatment for insomnia and sleep disorders may have a new use: lowering high blood pressure. Melatonin, which regulates sleep cycles, has been shown in a new study to lower blood pressure in people with nighttime high blood pressure (nocturnal hypertension).

    “People with high blood pressure may have disturbances of their biological clocks,” said Ehud Grossman, MD, of the Department of Internal Medicine D and Hypertension Unit at the Chaim Sheba Medical Center in Tel Hashomer, Israel. “Their nighttime blood pressure may not fall to normally lower levels. These people appear to be at particularly high risk of cardiovascular events, such as heart attack and stroke.”

    Blood pressure, like many other body functions, has a daily rhythm. It normally goes down at night while you sleep. In the morning when you rise, your blood pressure rises as well, peaking in the mid-afternoon. In the late afternoon and evening, blood pressure once again starts to go down.

    Nocturnal hypertension is associated with a high risk of disease and death. It is a better predictor of cardiovascular risk than daytime blood pressure. The body’s melatonin processing appears to be impaired in people with nocturnal hypertension, leading to a possible deficiency of the hormone. However, in previous studies taking melatonin appeared to interfere with the blood pressure–lowering activity of some hypertension medications.

    Grossman and colleagues tested 38 people who were managing their hypertension with drugs, so the researchers were able observe if there was any interaction between the drugs and melatonin supplements. The participants were randomly assigned to receive 2 mg of controlled-release melatonin or a placebo two hours before bedtime, nightly for four weeks. Special 24-hour blood pressure–monitoring equipment was used to assess changes in blood pressure.

    At the end of four weeks, those taking melatonin supplements had significantly reduced nighttime blood pressure, whereas the placebo had no effect.

    “Our results suggest that melatonin supplements improve nighttime blood pressure control in treated patients with nocturnal hypertension,” concluded Grossman. “Though its exact mechanism is unknown, melatonin appears to influence how the nervous system regulates blood vessel dilation and pressure. Larger, long-term studies using varying amounts of melatonin are now needed to confirm these preliminary findings.”

    (Am J Med 2006;119;898–902)</div>

    http://www.healthmonthly.co.uk/health/news...06_11_30_2.html

    Taken together, it appears we were right, but the safe dose range is probably extended upwards to several milligrams, however that is also contricted in the article, because ten times youthful levels had a prooxidanant effect - significance unknown. On the whole, probably the body can cope with it. But I would be simply most concerned with whatever dose had the optimum sleep enhancing effect, and recent research suggested that was just 300mcg, which is why it was adopted.

    As for whether day levels are elevated by 10x that dose, I cannot find any data on that yet, but that would be an issue for me if it did.
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  11. #31
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    Now I've come across suggestions of a study that puprted to test melatonin on 'high and low excretors' of melatonin metabolite. In the high excretors, the high dose increased effectiveness a bit.

    It would be well worth examining what causes low levels of melatonin in the elderly, and assess if low melatonin in elderly might be related to inlammation, perhaps not only because of impact on production, but also by altering metabolism. Melatonin in the body originates from many sources, not just brain, so we also need to know what they are and also understand what regulates melatonin in the periphery.

    On metabolism, the following could be profoundly influenced by inflaammation:

    http://www.ncbi.nlm.nih.gov/pubmed/15616152

    Drug Metab Dispos. 2005 Apr;33(4):489-94. Epub 2004 Dec 22.

    Metabolism of melatonin by human cytochromes p450.
    Ma X, Idle JR, Krausz KW, Gonzalez FJ.

    Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

    In humans, the pineal hormone melatonin (MEL) is principally metabolized to 6-hydroxymelatonin (6-HMEL), which is further conjugated with sulfate and excreted in urine. MEL O-demethylation represents a minor reaction. The exact role of individual human cytochromes P450 (P450s) in these pathways has not been established. We used a panel of 11 recombinant human P450 isozymes to investigate for the first time the 6-hydroxylation and O-demethylation of MEL. CYP1A1, CYP1A2, and CYP1B1 all 6-hydroxylated MEL, with CYP2C19 playing a minor role. These reactions were NADPH-dependent. CYP2C19 and, to some extent CYP1A2, O-demethylated MEL. The K(m) (microM) and V(max) (k(cat), pmol min(-1) pmol(-1) P450) for 6-hydroxylation were estimated as 19.2 +/- 2.01 and 6.46 +/- 0.22 (CYP1A1), 25.9 +/- 2.47 and 10.6 +/- 0.32 (CYP1A2), and 30.9 +/- 3.76 and 5.31 +/- 0.21 (CYP1B1). These findings confirm the suggestion of others that CYP1A2 is probably the foremost hepatic P450 in the 6-hydroxylation of MEL and a single report that CYP1A1 is also able to mediate this reaction. However, this is the first time that CYP1B1 has been shown to 6-hydroxylate MEL. The IC50 for the CYP1B1-selective inhibitor (E)-2,4,3',5'-tetramethoxystilbene was estimated to be 30 nM for MEL 6-hydroxylation by recombinant human CYP1B1. Comparison of brain homogenates from wild-type and cyp1b1-null mice revealed that MEL 6-hydroxylation was clearly mediated to a significant degree by CYP1B1. CYP1B1 is not expressed in the liver but has a ubiquitous extrahepatic distribution, and is found at high levels in tissues that also accumulate either MEL or 6-HMEL, such as intestine and cerebral cortex, where it may assist in regulating levels of MEL and 6-HMEL.

    PMID: 15616152 [PubMed - indexed for MEDLINE]
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  12. #32
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    <div class='quotetop'>QUOTE </div><div class='quotemain'>Melatonin levels peak during the night but also increase after eating,26 which partly explains why one may feel sleepy after a meal and why patients with advanced cancer who suffer diminished appetite or tissue wasting have been shown to have reduced levels of melatonin.32-34 Once produced, melatonin remains in the bloodstream only a short time, on average between 20 and 90 minutes.23,35 This is because melatonin is highly fat soluble (lipophilic) and somewhat water soluble (hydrophilic), enabling it to easily penetrate every cellular compartment (membrane, cytoplasm, and nucleus) and, as far as is known, every cell in the body.36 Melatonin’s amphiphilicity, or ability to both absorb and repel water—in conjunction with its ability to act as a weak preventive antioxidant,37 a weak metal ion chelator,38 and in certain circumstances, a direct free radical scavenger39—enables it to counteract oxidative stress within the chaotic tumor microenvironment.40</div>

    http://www.alternativehealth.co.nz/e...atoninmain.htm

    Another thing, is the role of melatonin as an antiviral agent - this appears to be via a stimulation of IL-1. Antibodies to IL-1 completely blocked the life protecting effect of melatonin in virally inffected animals. The action of TNF alpha was found to be much less, although melatonin stimulates this too. IL-1, like melatonin TNF-Alpha and histamine, is part of the evening hormonal signalling in sleep.

    The basic hypothesis was that melatonin was a proinflammatiory agent that stimulated the antiviral wing of the immune system.

    But that was before we reckoned with NF-Kappa B receptor rhythms. It appears different parts of the body deal with these inflammatory signals differently. In the brain TNF-Alpha is likely more involved in rebound sleep, the type also controlled by the immune system in sickness.

    The reason seems to be that in the brain, the night is a time of nutrient uptake and anabolism, and low oxygen uptake. NF-Kappa B would block nutrient uptake and growth in order to check viral reproduction, and boost immune function. It seems that melatonin and the need for rebound sleep/fever induces the inflammatory cascade but something checks this in the brain, and probably elsewhere and differently in different parts of the immune system, by reducing expression of the NF-Kappa B and other receptors. This reduced binding checks the effective signal and allows anabolism in the brain and maybe in some immune cells (dendritic, t-regs? mast cells?). This checking process most probably is programmed in as part of the diurnal rhythm and is thererfore influenced by regularity and strength of melatonin rhythm, but their might be direct actions of melatonin.

    No idea what the effective half life is, nor how much supplemental melatonin in mg range effects this.

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  13. #33
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    <div class='quotetop'>QUOTE (ATB @ Mar 15 2010, 02:02 PM) <{POST_SNAPBACK}></div><div class='quotemain'>Now I've come across suggestions of a study that puprted to test melatonin on 'high and low excretors' of melatonin metabolite. In the high excretors, the high dose increased effectiveness a bit.

    It would be well worth examining what causes low levels of melatonin in the elderly, and assess if low melatonin in elderly might be related to inlammation, perhaps not only because of impact on production, but also by altering metabolism. Melatonin in the body originates from many sources, not just brain, so we also need to know what they are and also understand what regulates melatonin in the periphery.</div>

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Radiation, which frequently causes inflammation of the mucosa (mucositis), may substantially reduce melatonin levels in the body13 by damaging the mucosa of the gastrointestinal tract where melatonin is known to be localized.26</div>

    http://www.alternativehealth.co.nz/e...atoninmain.htm

    Its a start
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  14. #34
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    Any thoughts on this?

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Clin Endocrinol (Oxf). 1993 Aug;39(2):193-9.
    Melatonin stimulates growth hormone secretion through pathways other than the growth hormone-releasing hormone.

    Valcavi R, Zini M, Maestroni GJ, Conti A, Portioli I.

    2a Divisione di Medicina Interna, Arcispedale S. Maria Nuova, Reggio Emilia, Italy.
    Abstract

    OBJECTIVE: There is evidence that melatonin plays a role in the regulation of GH secretion. The aim of this study was to investigate the neuroendocrine mechanisms by which melatonin modulates GH secretion. Thus we assessed the effect of oral melatonin on the GH responses to GHRH administration and compared the effects of melatonin with those of pyridostigmine, a cholinergic agonist drug which is likely to suppress hypothalamic somatostatin release. DESIGN: The study consisted of four protocols carried out during the afternoon hours. Study 1: oral melatonin (10 mg) or placebo were administered 60 minutes prior to GHRH (100 micrograms i.v. bolus). Study 2: GHRH (100 micrograms i.v. bolus) or placebo were administered at 0 minutes; oral melatonin or placebo were given at 60 minutes and were followed by a second GHRH stimulus (100 micrograms i.v. bolus) at 120 minutes. Study 3: placebo; oral melatonin (10 mg); oral pyridostigmine (120 mg); melatonin (10 mg) plus pyridostigmine (120 mg) were administered on separate occasions. Study 4: placebo; oral melatonin (10 mg); oral pyridostigmine (120 mg); melatonin (10 mg) plus pyridostigmine (120 mg) were administered on separate occasions 60 minutes prior to a submaximal dose (3 micrograms i.v. bolus) of GHRH. SUBJECTS: Four groups of eight normal male subjects, ages 22-35 years, were randomly assigned to each protocol. MEASUREMENTS: Growth hormone was measured by RIA at 15-minute intervals. RESULTS: Oral melatonin administration had a weak stimulatory effect on GH basal levels. Prior melatonin administration approximately doubled the GH release induced by supramaximal (100 micrograms) or submaximal (3 micrograms) doses of GHRH. Melatonin administration restored the GH response to a second GHRH challenge, given 120 minutes after a first GHRH i.v. bolus. The GH releasing effects of pyridostigmine, either alone or followed by GHRH, were greater than those of melatonin. However, the simultaneous administration of melatonin and pyridostigmine was not followed by any further enhancement of GH release, either in the absence or in the presence of exogenous GHRH. CONCLUSIONS: Our data indicate that oral administration of melatonin to normal human males increases basal GH release and GH responsiveness to GHRH through the same pathways as pyridostigmine. Therefore it is likely that melatonin plays this facilitatory role at the hypothalamic level by inhibiting endogenous somatostatin release, although with a lower potency than pyridostigmine. The physiological role of melatonin in GH neuroregulation remains to be established.

    PMID: 8370132 [PubMed - indexed for MEDLINE]</div>

    Also,

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin.
    del Río B, García Pedrero JM, Martínez-Campa C, Zuazua P, Lazo PS, Ramos S.

    Departamento de Bioquímica y Biología Molecular and Instituto Universitario de Oncología Del Principado de Asturias, Universidad de Oviedo, 33071 Oviedo, Spain.

    Melatonin is an indole hormone produced mainly by the pineal gland. We have previously demonstrated that melatonin interferes with estrogen (E(2)) signaling in MCF7 cells by impairing estrogen receptor (ER) pathways. Here we present the characterization of its mechanism of action showing that melatonin is a specific inhibitor of E(2)-induced ERalpha-mediated transcription in both estrogen response element- and AP1-containing promoters, whereas ERbeta-mediated transactivation is not inhibited or even activated at certain promoters. We show that the sensitivity of MCF-7 cells to melatonin depends on the ERalpha/ERbeta ratio, and ectopic expression of ERbeta results in MCF-7 cells becoming insensitive to this hormone. Melatonin acts as a calmodulin antagonist inducing conformational changes in the ERalpha-calmodulin (CaM) complex, thus impairing the binding of E(2).ERalpha.CaM complex to DNA and, therefore, preventing ERalpha-dependent transcription. Moreover the mutant ERalpha (K302G,K303G), unable to bind calmodulin, becomes insensitive to melatonin. The effect of melatonin is specific since other related indoles neither interact with CaM nor inhibit ERalpha-mediated transactivation. Interestingly, melatonin does not affect the binding of coactivators to ERalpha, indicating that melatonin action is different from that of current therapeutic anti-estrogens used in breast cancer therapy. Thus, they target ERalpha at different levels, representing two independent ways to control ERalpha activity. It is, therefore, conceivably a synergistic pharmacological effect of melatonin and current anti-estrogen drugs.

    PMID: 15229223 [PubMed - indexed for MEDLINE] -- Full Text</div>

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    <div class='quotetop'>QUOTE (slugs @ Apr 12 2010, 07:02 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Any thoughts on this?</div>

    The first study is one of the reasons I am taking it nightly (don't have any trouble sleeping). Never seen the second one but that is helpful to know.
    Remember, believe none of what you hear and half of what you see...





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    <div class='quotetop'>QUOTE (Benson @ Apr 12 2010, 07:22 AM) <{POST_SNAPBACK}></div><div class='quotemain'>The first study is one of the reasons I am taking it nightly (don't have any trouble sleeping). Never seen the second one but that is helpful to know.</div>

    Interesting, never seen that study.

    How much do you take a night, Ben?
    “When mental energy is allowed to follow the line of least resistance and to fall into easy channels, it is called weakness” -James Allen

    "That by which a man is overcome, by this he is enslaved." 2 Peter 2:19

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    <div class='quotetop'>QUOTE (((Vibe)) @ Apr 12 2010, 08:30 AM) <{POST_SNAPBACK}></div><div class='quotemain'>How much do you take a night, Ben?</div>

    3mg of a time-release formula
    Remember, believe none of what you hear and half of what you see...





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    There are a lot of positive studies related to melatonin! That's why I'm weary of this one..

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Cancer Lett. 2009 Aug 18;281(1):1-7. Epub 2008 Dec 12.

    Circulating melatonin and the risk of breast and endometrial cancer in women.
    Viswanathan AN, Schernhammer ES.

    Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. aviswanathan@lroc.harvard.edu

    Abstract
    Several decades of observational data have accumulated to implicate a potential role for melatonin in cancer prevention. Experimental studies suggest that the antineoplastic action of melatonin arises through many different mechanisms, including melatonin's antioxidant, antimitotic, and antiangiogenic activity, as well as its ability to modulate the immune system and alter fat metabolism. Melatonin interacts with membrane and nuclear receptors, and may be linked to the regulation of tumor growth. Of particular relevance to breast cancer risk, melatonin may also block the estrogen receptor ERalpha and impact the enzyme aromatase, which produces estradiol. A growing number of epidemiologic studies have evaluated the relationship between night shift work as well as how varying duration of sleep affects peak melatonin secretion at night. While the studies demonstrate lower nightly melatonin levels in night workers, the evidence for an association between sleep duration and melatonin production is less clear. Similarly, both case-control and prospective cohort studies have consistently linked night shift work with breast cancer risk and, more recently, endometrial cancer - another tumor highly sensitive to estrogens. While, to date, the evidence for an association between sleep duration and breast cancer risk is less convincing, overall, there is increasing support for a potentially important link between melatonin and breast cancer risk and perhaps the risk of other tumors. As evidence increases, modifiable factors that have been shown to affect melatonin production, such as night shift work, are likely to gain increasing recognition as potential public health hazards. Additional studies are needed to delineate further the potential of melatonin in cancer prevention.

    PMID: 19070424 [PubMed - indexed for MEDLINE]PMCID: PMC2735793 [Available on 2010/8/18]</div>

    and of more relevance to this original thread

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Human Reproduction, Vol. 15, No. 1, 60-65, January 2000
    © 2000 European Society of Human Reproduction and Embryology
    Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men
    Rafael Luboshitzky1,5, Michal Levi2, Zila Shen-Orr3, Zeev Blumenfeld4, Paula Herer2 and Peretz Lavie2

    1 Endocrine Institute, Haemek Medical Center, Afula 18101, 2 Sleep Research Center, 3 Endocrine Laboratory, Rambam Medical Center, Haifa and 4 The B.Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel

    The role of melatonin in the regulation of reproduction in humans is still controversial. In the present study the effects of melatonin were examined, 6 mg given orally every day at 1700 h for 1 month in a double-blind, placebo controlled fashion, on the nocturnal secretory profiles of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and inhibin ß in six healthy adult men. Serum concentrations of LH, FSH, testosterone and inhibin ß were determined before and after treatment every 15 min from 1900 to 0700 h over 3 nights in a controlled dark-light environment with simultaneous polysomnographic sleep recordings. The following sleep parameters were determined: total recording time, sleep latency, actual sleep time, sleep efficiency, rapid eye movement (REM) sleep latency and percentages of sleep stages 2, 3/4 and REM. There were no statistically significant differences in all sleep parameters between baseline and placebo or between baseline and melatonin except for longer REM latency and lower percentage REM at baseline than under melatonin treatment. These are explained as reflecting first-night effect at baseline. The mean nocturnal LH, FSH, testosterone and inhibin ß integrated nocturnal secretion values did not change during the treatment period. Likewise, their pulsatile characteristics during melatonin treatment were not different from baseline values. Taken together, these data suggest that long-term melatonin administration does not alter the secretory patterns of reproductive hormones in normal men.

    Key words: follicle-stimulating hormone/ß inhibin/luteinizing hormone/melatonin/testosterone

    5 To whom correspondence should be addressed</div>
    (full text of above)

    one more with respect to cortisol:

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Rev Med Chil. 2008 Nov;136(11):1390-7.

    [Melatonin reduces cortisol response to ACTH in humans]
    [Article in Spanish]

    Campino C, Valenzuela F, Arteaga E, Torres-Farfán C, Trucco C, Velasco A, Guzmán S, Serón-Ferré M.

    Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Lira 85, S degrees piso, Santiago, Chile. ccampino@med.puc.cl

    Abstract
    BACKGROUND: Melatonin receptors are widely distributed in human tissues but they have not been reported in human adrenal gland. AIM: To assess if the human adrenal gland expresses melatonin receptors and if melatonin affects cortisol response to ACTH in dexamethasone suppressed volunteers. MATERIAL AND METHODS: Adrenal glands were obtained from 4 patients undergoing unilateral nephrectomy-adrenalectomy for renal cancer. Expression of mRNA MT1 and MT2 melatonin receptors was measured by Reverse TranscriPtase Polymerase Chain Reaction (RT-PCR). The effect of melatonin on the response to intravenous (i.v.) ACTH was tested (randomized cross-over, double-blind, placebo-controlled trial) in eight young healthy males pretreated with dexamethasone (1 mg) at 23:00 h. On the next day, at 08:00 h, an i.v. line was inserted, at 08:30 h, and after a blood sample, subjects ingested 6 mg melatonin or placebo. At 09:00 h, 1-24 ACTH (Cortrosyn, 1 microg/1.73 m2 body surface area) was injected, drawing samples at 0, 15, 30, 45 and 60 minutes after. Melatonin, cortisol, cortisone, progesterone, aldosterone, DHEA-S, testosterone and prolactin were measured by immunoassay. RESULTS: The four adrenal glands expressed only MT1 receptor mRNA. Melatonin ingestion reduced the cortisol response to ACTH from 14.6 +/- 1.45 microg/dl at 60 min in the placebo group to 10.8 +/- 1.2 microg/dl in the melatonin group (p < 0.01 mixed model test). It did not affect other steroid hormone levels and abolished the morning physiological decline of prolactin. CONCLUSIONS: The expression of MT1 melatonin receptor in the human adrenal, and the melatonin reduction of ACTH-stimulated cortisol production suggest a direct melatonin action on the adrenal gland.

    PMID: 19301769 [PubMed - indexed for MEDLINE]</div>

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