MELATONIN - "The darkness hormone"/ natural sleep aid

What is MELATONIN?

MELATONIN is a hormone and a neurotransmitter produced / secreted by the pineal gland (pea-sized gland located in the center of the brain) during darkness under control of the body’s master “Biological Clock” (Body’s central circadian pacemaker in the hypothalamus – called the Suprachiasmatic nucleus (SCN).  MELATONIN is an indoleamine compound, derived from the amino acid tryptophan, in such as turkey, chicken, milk, eggs, cheese, nuts, legumes and avocados.  

    Tryptophan ➔ 5-HTP ➔  SEROTONIN ➔  MELATONIN 

MELATONIN is well-known for promoting sleep, but has many additional benefits:

MELATONIN is both lipid and water soluble.   Facilitates passage both in the blood and across cell membranes.After release into circulation, it gains access to various fluids, tissues and cellular compartments (E.g. saliva, urine, cerebrospinal fluid, pre-ovulatory follicle, semen, amniotic fluid, milk). MELATONIN is rapidly metabolized (chiefly in the liver) and is excreted in the urine. 

MELATONIN has 3 cell-signaling actions: 

  • Endocrine – secreted by pineal gland into bloodstream . Also GI enterochromaffin cells release MELATONIN, some of which fnds its way to the bloodstream,
  • Autocrine – MELATONIN binds to receptors of same cell which secreted it
  • Paracrine – secreted by tissues / cells to act on local target cells

MELATONIN was discovered when it was found to lighten amphibian skin.

Study-supported benefits of MELATONIN supplementation

For older people ( > 60 yrs) – daily MELATONIN supplementation can be useful, since their pineal gland is not producing enough.

MELATONIN Induces / Improves Sleep

The need for darkness in order to produce MELATONIN is  why sleeping in total darkness is so important

Having a light on at night squelches the production of MELATONIN.    Dampening your mood, and possibly resulting in increased appetite and unwanted weight gain. When sleep deprived, your body decreases production of LEPTIN, the hormone that tells your brain there is no need for more food, whilst simultaneously increasing levels of GHRELIN, a hormone that triggers hunger.

Synchronizes circadian rhythms – sustained desynchonisation of the “Biological Clock” has a profound impact on health and wellbeing, including suppressed immunity and increased risk of cancer. Also, frequently accompanying these disturbances are neuropsychiatric disorders, such as depression, schizophrenia and Alzheimer’s. Desynchronisation occurs while the body’s clocks struggle to adapt to an abruptly shifted external light/dark cycle.

  • Frequent trans-meridian travel (Jet Lag).   E.g. Transcontinental flight personnel and frequent overseas fliers. Supplement MELATONIN on the day of the flight and continue for five days thereafter.
  • Shift-workers.    MELATONIN supplements may simulate the MELATONIN production at different times that does not occur during regular sleeping hours for people who work night shifts.   Straif K et al, 2007

An increase in serum MELATONIN levels, occurring ~ 9pm daily, signals the initiation of normal sleep onset

  • At night, the MELATONIN ▲  increase indirectly reduces production of DHEAâ–¼ (the consciousness hormone).   Achieved by MELATONIN’s ▲  inhibitory action on PROLACTIN ▼ (PRL) production (PRL▲ is shown to stimulate DHEA ▲  production).
  • Slow wave sleep (SWS) occurs when MELATONIN is in greatest concentration.   Thus during stage 4 (the deepest SWS), MELATONIN ▲  ▲  ▲  should be in greatest concentration and DHEA ▼ â–¼ ▼ least. MELATONIN and DHEA cycle through the night with overall MELATONIN declining and DHEA increasing.

Different Stages of Sleep

MELATONIN improves the efficiency of sleep.    Allows a person to spend a shorter time in bed to get a given amount of sleep; it does not improve total sleep time;

Insomnia

MELATONIN  exerts its biological effects to aid sleep primarily by two methods:

  • Via activation of MELATONIN receptors
  • In its role as a powerful antioxidant;

Cardiovascular disease

Prevent ischemic damage – in rats, reduces tissue damage due to ischemia in brain and heart; (ischemia is a restriction in blood supply causing a shortage of oxygen delivery to target organs / tissues)

Low nightime MELATONIN has been reported in patients with coronary heart disease and heart failure. Similarly, the link between high CORTISOL and hypertension is well established. Supplementation with MELATONIN has been shown to increase cardiac vagal tone, decrease circulating NOREPINEPHRINE, and reduce blood pressure. Pandi-Perumal SR et al, 2006

 

Learning, memory and Alzheimer's

First published evidence that MELATONIN may be useful in Alzheimer’s disease demonstrated that this neurotransmitter/hormone prevents neuronal death caused by exposure to the amyloid beta protein, a neurotoxic substance that accumulates in the brains of patients with the disorder.  Wang XC et al, 2005

MELATONIN also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates which seem to underlie the neurotoxicity of this protein, causing death of neurons and formation of neurofibrillary tangles, the other neuropathological landmark of Alzheimer’s disease.

Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK. MELATONIN prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neurosci. 1997 Mar 1;17(5):1683-90. PubMed

ADHD

  • Research shows that after MELATONIN is administered to ADHD patients on methylphenidate, the time needed to fall asleep is significantly reduced. Furthermore, the effects of the MELATONIN after three months showed no change from its effects after one week of use. Tjon Pian Gi, et al, 2003

Migraines / Headaches

Depression

  • Research shows that depressed patients have lower levels of MELATONIN than non-depressed patients.  However, although MELATONIN supplementation helps corrects sleep disorders in depression, it does not improve clinical symptoms of depression.   Pandi-Perumal SR et al, 2006

    Many studies suggest MELATONIN levels control mood-related symptoms, such as those associated with depression – especially Seasonal affective disorder (SAD) (winter depression, when days are shorter and light exposure is minimal).  In addition to treating SAD, MELATONIN is being considered for bipolar and other disorders in which circadian disturbances are involved. Is Internal Timing Key to Mental Health?

    • In a study published in May 2006 – researchers at the Oregon Health and Science University (OHSU) found that MELATONIN relieved SAD. The study found insomniacs are “out of phase”with circadian rhythms and natural sleeping times. Exposure to bright lights or by taking a MELATONIN supplement at a certain time of day can resynchronize your biological clock.  The treatment depends on exactly HOW the person is out of phase. Archives of General Psychiatry, 1998;
    • A 2010 study – found a correlation between circadian misalignment and severity of depression symptoms.
    • Studies have linked low MELATONIN levels to depression in several populations – including multiple sclerosis patients and post-menopausal women.  Parry BL et al, 2008
    • Bipolar and other disorders where circadian disturbances are involved – Supersensitivity to light has been an observed trait-marker for bipolar disorder, which causes a greater decrease in MELATONIN secretion in response to nighttime light exposure. This is contrasted with drug-free recovered bipolar people not showing light hypersensitivity.   Supersensitivity to light: possible trait marker for manic-depressive illness.    MELATONIN response to bright light in recovered, drug-free, bipolar patients. 

    High bedtime levels of CORTISOL are also associated with depression.  Brown ES et al, 2004

Cancer

  • A systematic review of unblended clinical trials involving a total of 643 cancer patients using MELATONIN found a reduced incidence of death. MELATONIN in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis.

    Reduced MELATONIN production has been proposed as a likely factor in the significantly higher cancer rates in night workers and breast cancer in women.

    Supplemental MELATONIN has been shown to slow tumor progression in a variety of cancers – and provide subjective improvement in quality of life.  Pandi-Perumal SR et al, 2006

Gallbladder stones

  • Natural PROGESTERONE inhibits Estrogenic action – PROGESTERONE decreases the target organs response to estrogen by decreasing the number of receptors the organ has for the hormone estrogen. Receptors are molecules on cells that recognize specific hormones and allow them to carry their message to the cell.
  • Hypothyroidism can occur because of estrogen dominance (deficiency of PROGESTERONE relative to estrogen) – estrogen dominance decreases thyroid hormone (TH) (and therefore thyroid function) by increasing production of a protein called thyroid binding globulin, which binds TH causing it to be inactive. Whereas, TH increases body’s metabolism rate and causes fat calories to be turned into usable energy, estrogen causes food calories to be stored as fat (in a premenopausal woman, the body stores fat to have enough energy for a fetus if a pregnancy develops).
  • Hypothyroidism, which results in weight gain and a host of other symptoms, can be corrected by the presence of natural PROGESTERONE in the body.

Obesity

Studies in experimental animals show that long-term MELATONIN supplementation in drinking water reduces body weight and abdominal fat, without changes to diet or being more active (especially in middle-aged rats) Daily MELATONIN administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. A proposed mechanism is that MELATONIN promotes the recruitment and activity of brown adipose tissue as well as enhances its activity. , which would raise the basal metabolic rate by stimulating thermogenesis. Significance and application of MELATONIN in the regulation of brown adipose tissue metabolism: relation to human obesity

Protection from radiation

 Animal and human (2nd Ref) studies have shown MELATONIN to provide more efficient protection from ionizing radiation than the commonly used drug amifostine. Its mechanism is thought due to the scavenging of harmful oxidants (E.g. free radicals), considered to be responsible for ~70% of ionizing damage to body tissues, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. MELATONIN has the advantage of being broadly protective, readily available for oral supplementation, and without significant side effects.

Tinnitus

Medical studies with adult patients show beneficial results in the treatment of tinnitus with MELATONIN

MELATONIN is associated with a statistically significant decrease in tinnitus intensity and improved sleep quality in patients with chronic tinnitus – MELATONIN is most effective in:  Hurtuk A et al, 2011

  • Men
  • Those without a history of depression
  • Those who have not undergone prior tinnitus treatments
  • Those with more severe and bilateral tinnitus
  • Those with a history of noise exposure.

The impact of MELATONIN on sleep was greatest among patients with the worst sleep quality, but its impact on tinnitus was not associated with the severity of the tinnitus.  Megwalu UC et al, 2006

MELATONIN has been shown to be useful in the treatment of subjective tinnitus – Patients with high THI scores and/or difficulty sleeping are most likely to benefit from treatment with MELATONIN.  Rosenberg SI et al, 1998

One publication explores the possible mechanisms of how MELATONIN works against tinnitus:   Exploring the reasons why MELATONIN can improve tinnitus, August 2010.

  • Its modulatory effect on central nervous system – resulting in a protective mechanism against an exaggerated sympathetic drive (sympathetic nervous system is responsible for regulating homeostatic conditions in the body);
  • Its capacity to induce a more steady hemodynamic condition – through a multifactorial and multi-organ activity, resulting in more regular blood flow in the inner ear;
  • A possible action on the skeletal muscle tending to a reduction of the muscular tone – which could relieve tinnitus of muscular origin deriving from contraction of tensor tympani muscles (located in the upper auditory canal) responsible for dampening sounds;
  • Its possible reported anti-depressive effect – which could indirectly act on tinnitus;
  • A direct regulation of inner ear immunity – as proposed in literature when melatonin was reported to be present in the inner ear.

Studies site a typical dose for positive effect on tinnitus as 3 mg MELATONIN / day – usually taken in the evening

GERD / GI tract ulcers

MELATONIN helps relieve gastric esophageal reflux disease (GERD) and stomach or duodenal ulcers via its protective roles in the GI tract.

Functions of MELATONIN

MELATONIN synchronizes body tissues to the daily cycle of light and dark

The primary physiological function of MELATONIN, whose secretion adjusts to night length (daily duration of high-level secretion is shorter during the summer, when the nights are short, and longer during the winter, when the nights are long), is to convey information concerning the daily cycle of light and darkness to body physiology

  1.  
  • The circadian rhythms affected by MELATONIN –  are the sleep cycle, the light/dark cycle, the thermoregulatory cycle, the reproductive cycle, gonadal development, and immune cell functioning.
  • Your master biological clock controls your “built-in” (i.e. endogenous) circadian (daily) rhythms – E.g. this inner timekeeper (a group of cells, called the SCN, residing in your brain’s hypothalamus) tells you when it’s time to wake up or go to sleep. Although self-sustained, the endogenousrhythms can be adjusted (entrained) by environmental factors, primarily by light and dark. (also forced activity and rest, feeding cues, knowledge of clock time, MELATONIN and others);

Light reaches your master biological clock (SCN) via your eye’s optic nerve, where it initiates events such as waking you up, and processes associated with being awake.

The Biological Clock

MELATONIN is produced/secreted under control of the master biological clock (in response to darkness), such that MELATONIN levels have a 24-hr cycle of marked circadian rhythmicity, which regulates core body temperatures, adrenal CORTISOL (stress hormone) and more

  • The circadian rhythm of MELATONIN inversely correlates with the temperature rhythm in humans – MELATONIN levels in blood increase as core body temperature decreases.
    • Low circulating levels of MELATONIN in the daytime
    • Rising to maximal levels of MELATONIN during the night

MELATONIN feeds back to the “Biological clock” to regulate its activity –most of the brain receptors for MELATONIN are located in the SCN (in mammals)

  • Circadian desynchrony(with its attendant sleep problems) is directly related to the degree of light perception –many blind people with no conscious or unconscious light perception living in a normal social environment show “free running”or abnormally synchronized MELATONIN and other circadian rhythms.
  • MELATONIN supplementation can produce shifts in circadian rhythms in a number of species – including rats, sheep, lizards, birds, and humans. Effects are most clearly evident when MELATONIN is given in the absence of light input. Thus, for example, giving MELATONIN to blind people can help set their biological clocks.

MELATONIN appears to have an inhibitory affect on the reproductive rhythm

  • In humans, MELATONIN secretion is inversely correlated with gonadal development – peak MELATONIN levels fall just prior to the onset of puberty; also, higher levels of plasma MELATONIN have been noted in women with amenorrhea (no menstruation).
  • In  mammals other than humans, MELATONIN possibly acts as a breeding and mating cue – since it is produced in greater amounts in response to the longer nights of winter and less so during summer. Dr. George Brainard found that the gonads of male hamsters increased and decreased in size depending on the breeding season or season. He could change their gonad size and MELATONIN production by altering their exposure to light/dark cycles. Animals who time their mating or breeding to coincide with favorable seasons (such as spring) may depend on MELATONIN production and the biological clock to regulate their reproductive cycles on the basis of the length of the solar day.

MELATONIN stimulates immune system / immunomodulator

Evidence suggests an immuno-enhancing function for MELATONIN – stimulation of natural killer cell activity, cytokine expression and inhibition of immune cell apoptosis have been reported.

  • A constant light condition and drug-induced inhibition of MELATONIN synthesis in mice is associated with suppressed humoral an cellular immunological responses.   Guerrero JM, Reiter RJ., 2002
  • MELATONIN can interact with cells in lymphoid organs
  • There is bidirectional interaction between pineal gland and I.S.    Since interleukins and cytokines (interferon gamma) affect MELATONIN synthesis/release.  Withyachumnarnkul B et al, 1990
  • MELATONIN provides a link between the neuroendocrine and immune systems.   May be explored in diseases that present daily rhythmic symptoms, such as rheumatoid arthritis and nocturnal asthma.
  • Animal research has shown that inhibition of MELATONIN synthesis weakens cell-mediated immunity (acquired immunity where T lymphocytes have predominant role) and humoral immunity (immune response, mainly against bacterial invasion, mediated by B cells).   Pandi-Perumal SR et al, 2006

MELATONIN increases production of interleukin 2 and 6 (IL-2 and IL-6). MELATONIN receptors are found in lymphatic tissue, which supports the premise that MELATONIN has a direct regulating effect on the immune system. A study evaluating IL-6 during nocturnal sleep,sleep deprivation and different sleep stages concluded that:

Loss of sleep may serve to decrease nocturnal IL-6 levels, with effects on the integrity of immune system functioning. Alternatively, given the association between sleep stages and IL-6 levels, depressed or aged populations who show increased amounts of REM sleep and a relative loss of slow wave sleep may have elevated nocturnal concentrations of IL-6 with implications for inflammatory disease risk.”

Laura Redwine, Richard L. Hauger, J. Christian Gillin and Michael Irwin. Effects of Sleep and Sleep Deprivation on Interleukin-6, Growth Hormone, Cortisol, and MELATONIN Levels in Humans. Home Archive Oct 2000 85 (10): 3597 JCEM

MELATONIN is a powerful antioxidant

MELATONIN helps protect the body from cell damage caused by free radicals:

  • Direct scavenger of OH• (hydroxyl radical), O2•-(superoxide radical), and NO• (Nitric oxide radical), ONOO(Peroxynitrite anion), 1O2 (singlet oxygen), and possibly LOO• (peroxyl radical);
  • Neuroprotective – Can easily cross cell membranes and the blood-brain barrier.   Kilic E et al, 1999;    Baydas, G et al, 2002
  • “Suicidal antioxidant“- unlike other antioxidants (such as vitamin C), MELATONIN can not be renewed (i.e. it does not undergo redox cycling, the ability of a molecule to repeatedly undergo reduction and oxidation to regain antioxidant property).
  • Demonstrated to prevent some carcinogenic damage to DNA.   Stops mechanism by which damaged DNA causes cancer.
  • Increases body’s “in-house” antioxidant glutathione.  Is equally effective as this important antioxidant
  • Debated as equal to vitamin E as a chain-breaking antioxidant against peroxyl radical.   Produced by lipid peroxidation, which e.g. damages cell membranes altering cellular function. The resulting cell membrane rigidity associated with aging;
  • Scavenges initiating radicals and breakdown products from lipid peroxidation.    Assured by the fact that it scavenges 1O2, ONOOand OH•, all of which are sufficiently reactive to initiate the peroxidative process. Prevents otherwise harmful changes to membrane fluidity and function.
  • Greatly reduced inflammatory response.    Both ONOO and NO• radicals are believed to be the mediators of the inflammation in animals treated with carrageenan.  Beckman J.S., Koppenol W.H et al, 1996
  • Protected against brain injury caused by ROS release in newborn rats
  • May reduce damage caused by some types of Parkinson’s disease
  • May play a role in preventing cardiac arrhythmia
  • May increase longevity.    Shown to increase average life span of mice by 20% in some studies.
  • Protects against sunburn.    Scientists at University of Zurich found that MELATONIN protects against UV radiation if topically applied before skin exposure;
  • Role in repairing burned skin.    In a study in Brain Research Bulletin, MELATONIN levels rose six hours after burn injury, then fell to normal.
  • May prevent cataract formation
  • In small amounts, causes skin cells to proliferate.    In large amounts it stops proliferation. People with psoriasis and atopic eczema have peak MELATONIN in the day (instead of at night), and low levels at night; not too surprising in that some scientists consider the skin to be another gland.

MELATONIN enhances bone mass

Bone health.    Bone resorption is a process by which osteoclasts break down bone and release the minerals. MELATONIN has been shown to inhibit bone resorption and increase bone mass through its ability to down-regulate activation of osteoclasts.

Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. MELATONIN: Nature’s most versatile biological signal? FEBS J. 2006 Jul;273(13):2813-38. PubMed

An adequate amount of ESTRADIOL is also needed for MELATONIN to benefit bone (a salivary ESTRADIOL test may be useful in cases where MELATONIN is low and bone loss is a concern).High CORTISOL levels also contribute to bone loss.

Raff H, Raff JL, Duthie EH, Wilson CR, Sasse EA, Rudman I, Mattson D. Elevated salivary cortisol in the evening in healthy elderly men and women: correlation with bone mineral density. J Gerontol A Biol Sci Med Sci. 1999 Sep;54(9):M479-83. PubMed

MELATONIN is an anti-cancer agent

At present, the validity of MELATONIN as an oncostatic agent seems well established.    The antitumor mechanisms of MELATONIN have been identified, including:

  • Anti-proliferative actions
  • Immuno-stimulatory effects on host anti-cancer defenses
  • Antioxidant activity.

Circulating levels of MELATONIN are depressed in a wide variety of cancers.    Including breast, endometrial, prostate, lung, gastric and colon.  Bartsch C & Bartsch H, 1999

There are, however, isolated reports of tumor growth stimulation, especially if MELATONIN is administered in the morning.    Indicating a circadian-stage dependency of antitumor action.  Bartsch H, Bartsch C, 1981

A recent controlled trial shows the possibility to improve chemotherapy – in terms of both survival and quality of life of patients with advanced disease by a concomitant administration of MELATONIN and cisplatinium etoposide in metastatic non small cell lung cancer. Lissoni P et al, 2003

Breast Cancer

  • Breast cancer risk was increased among subjects who frequently did not sleep during the period of the night when MELATONIN levels are typically at their highest.    There was also an indication of increased risk among subjects with the brightest bedrooms. Graveyard shiftwork was associated with increased breast cancer risk. Night shift work, Light at night, and Risk of breast cancer
  • Breast Cancer research clearly shows solid links between low late-night MELATONINand increased breastcancer cell growth.   A study demonstrated that MELATONIN-rich blood suppressed the growth of human breast cancer xenografts and rat hepatomas. No growth suppression occurred in tumors perfused with MELATONIN-deficient blood collected from the same women after short-term ocular exposure to bright light at night.  Blask DE et al.2005
  • cortisol levels are also tied to breast cancer risk.   Breast cancer patients with high average cortisol throughout the day and elevated cortisol at bedtime have earlier mortality, lower natural killer (NK) cell counts and decreased activity of NK cells The strength of the relationship between cortisol and MELATONIN levels.  Sandra E Sephton et al, 2001

Reduced MELATONIN production has been proposed as a likely factor in the significantly higher cancer rates in night workers.   In 2007, The World Health Organization cited late night shift work as a probable cancer-causing agent. When someone works in artificial light, they generally have lower MELATONIN, and without this antioxidant and suppressant of tumor development, they may be more likely to develop cancer.  Straif K et al, 2007

Lower nocturnal MELATONIN levels are associated withlarger tumors in patients with primary prostate cancer

Vijayalaxmi, Charles R. Thomas, Jr, Russel J. Reiter, Terence S. Herman. MELATONIN: From Basic Research to Cancer Treatment Clinics.Journal of Clinical Oncology, Vol 20, Issue 10 (May), 2002: 2575-2601JOCO

Endogenous MELATONIN stimulates anti-cancer defenses and exhibits anti-proliferative and antioxidant activity

Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of MELATONIN.Sleep Med Rev. 2005 Feb;9(1):11-24. PubMed

 

MELATONIN protects the GI tract and pancreas

  • Although MELATONIN produced in the GI tract has a direct effect on GI tissues, its major influence on GI organs seems to occur indirectly via the brain-gut axis.   This is because the GI tract source of MELATONIN also contributes to circulatory levels. Mechanisms affecting GI organs include peripheral receptors, sensory afferent (vagal or sympathetic) pathways and the central nervous system (CNS) acting on these organs via autonomic means.

    MELATONIN is produced by enterochromaffin cells of the GI mucosa and discharged into the gut lumen.   Where, produced in amounts many times greater than the pineal gland, MELATONIN has several surprising roles protecting the GI tract and pancreas from damage and preventing forms of gastritis and pancreatitis, via:

    • MELATONIN protects gastrointestinal esophageal mucosa against various types of injury. Konturek SJ et al, 2007
    • MELATONIN seems to control the lower esophageal sphincter (LES).  MELATONIN has been used successfully as an alternative to Proton pump inhibitors (PPIs), whose main action is a significant and long-lasting reduction of gastric acid production. Transient lower esophageal sphincter relaxation (TLESR) is a major mechanism of reflux in patients with GERD. Nitric oxide has an important role in TLESR. MELATONIN inhibits nitric oxide biosynthesis, providing an explanation of the regression of GERD symptoms when using MELATONIN and other nutrients
    • MELATONIN controls gastrointestinal motility, having an inhibitory action on gastric acid secretion.  Jaworek J et al, 2005;   Thor PJ et al, 2007
    • MELATONIN protects duodenal (1st part of small intestine) epithelium against gastric H+    By stimulating alkalizing bicarbonate (HCO3–) secretion from enterocytes.  Konturek PC et al, 2004
    • Low levels of MELATONIN can lead to ulcers, gastroesophageal reflux disease (GERD) and sleep disorders.    Commonly, patients with GERD also have a sleep disorder.  de Souza Pereira R, 2006    Pereira Rde S, 2006
    • Stress / anxiety disorders.    May cause tryptophan depletion, and as a consequence, low MELATONIN levels, since MELATONIN is a metabolite of this amino acid found in certain protein foods.   Zimmermann RC et al, 1993
    • MELATONIN appears to be implicated in stimulation of pancreatic enzyme secretion after eating.    Mediated by MELATONIN-induced release of cholecystokinin, acting through entero-gastro-pancreatic reflexes. Jaworek J et al, 2005

MELATONIN is involved in the regulation of seasonal and circadian fluctuations of other hormones/neurotransmitters:

MELATONIN synchronizes body tissues to the daily cycle of light dark by promoting or inhibiting synthesis / secretion of other hormones / neurotransmitters

PromotesPROLACTIN – Positive relationship between the nocturnal concentrations of MELATONIN and PROLACTIN, and a stimulation of PROLACTIN after MELATONIN administration in young men. PubMed
InhibitsLEPTIN – downregulated by MELATONIN PubMed, except in the presence of INSULIN, which increases LEPTIN PubMed; LEPTIN is secreted by adipocytes and is called the appetite suppressant hormone, informing the brain about the body’s overall adipose tissue, which role determines energy homeostasis in the body.With INSULIN, MELATONIN increases LEPTIN  â–², suppressing appetite â–¼ during sleep, so you stay asleep instead of being hungry all night. In a feedback loop: LEPTIN  tells your brain you are not hungry, such that you stay asleep and make more MELATONIN.
Estrogen;
DOPAMINE
;
GABA
;
GnRH
 (Gonadotropin-releasing hormone) – Down-regulates its mRNA production in hypothalamic GnRH-secreting neurons – a link to sexual development and puberty.
CommentsReciprocal with cortisol – which rises in the morning to its highest levels (ready for you to face the day), as MELATONIN declines (so you can wake up)
Other hormones involvedGonadal steroids, pituitary gonadotrophins, THYROXINE, and the adrenal hormones.   Spiegel K et al, 2003

MELATONIN production

Where is MELATONIN produced / secreted?

Pineal Gland.   MELATONIN is produced and secreted by the pineal gland under control of the hypothalamus mainly when it is dark.  Light /  dark status is provided by the hypothalamic “Master Clock” –  The Biological Clock

  • A pea-sized, pinecone-shaped organ located in the exact center of the brain – this gland is the first to form during human fetal development, being clearly distinguishable a mere three weeks after conception.
  • Composed of pinealocytes (pineal cells).   With a rich supply of adrenergic nerve fibers that influence its secretions.
  • MELATONIN is the only hormone secreted by the pineal gland.   Secreted by pineal parenchymal cells into the general circulation and into the cerebrospinal fluid, when stimulated by NOREPINEPHRINE. MELATONIN is an indoleamine compound, derived from the amino acid tryptophan, with SEROTONIN being its immediate precursor. MELATONIN was discovered when it was found to lighten amphibian skin.
  • MELATONIN secretion is regulated by sympathetic nervous System (SNS), increased in response to darkness.   Tightly controlled by the hypothalamic circadian pacemaker (“Master biological clock”), MELATONIN thus provides a hormonal signal of night-time darkness; MELATONIN secretion is also increased in response to hypoglycemia.
  • MELATONIN is not stored in the pineal gland.   We cannot rely on yesterday’s MELATONIN for today; it leaves the gland through simple diffusion with a short half-life during the initial few minutes, followed by a second longer phase. We need a liberal supply of MELATONIN each evening

Retina, Lens, GI tract, skin + –MELATONIN can also be produced directly by the retina, lens, GI tract, skin and other tissues/cells (E.g. bone marrow cells, lymphocytes and epithelial cells). These are NOT regulated by light/dark.    These cells do not directly release MELATONIN into the blood, but act on local target cells (i.e. by paracrine action) and some can reach peripheral circulation (has endocrine function )

  • MELATONIN produced by enterochromaffin cells of the GI mucosa represents the most important extra-pineal source of MELATONIN.   The GI tract contains ~400 times the amount of the pineal gland. This MELATONIN enters circulation, where it has an indirect, but profound, protective effect on the GI tract and organs via the brain-gut axis.
  • MELATONIN affects GI motility, is protective of duodenal epithelium and pancreas, prevents GERD and ulcers, and much more

What affects MELATONIN production / secretion?

Pineal / retinal MELATONIN production Inhibited by light and permitted by darkness

Light / dark MELATONIN production

MELATONIN production decreases with age

  • Fetal / Baby MELATONIN Levels
    • Early in pregnancy.    MELATONIN-binding sites are created in the suprachiasmatic nucleus (SCN) in the hypothalamus of the developing brain. Maternal MELATONIN crosses the placenta and can synchronize the fetal biological clock. Daily MELATONIN rhythm in milk could take over for newborn.
    • Shortly after birth.   Very little MELATONIN is detectable in body fluids, and although the circadian rhythm of MELATONIN does not exist at birth, it appears at 9-12 weeks of age and is fully established by 5-6 months of age.
  • Young child.    Nighttime levels reach a peak in children between on average 3 to 5 (another source says 1-3) years of age (may explain their tendency to sleep longer than adults) and decrease steadily throughout puberty. The abundant MELATONIN levels in children are believed to inhibit sexual development.
  • Puberty.    By the end of puberty, peak MELATONIN levels have decreased significantly.
  • Adult.  Levels continue to fall steadily throughout adult life.
  • Old age.  Lower levels are seen in old age.

Circadian profiles of serum MELATONIN concentrations at various ages

Gray area = Darkness.

MELATONIN production lowered by blue light.   Dr. George Brainard experimented on 600 healthy volunteers:

  • Blue light significantly lowered MELATONIN production.    Studies at 2:00 am (when MELATONIN levels at peak) exposed dilated pupils to different wavelengths of monochromatic light (only one color) over 90 minutes, found that the short wavelength in the blue portion of the visible spectrum was most potent at lowering MELATONIN production.
  • Special retinal photoreceptor regulates MELATONIN production.    It was revealed that it is not the visual rod and cone photoreceptor mechanism of the eye that is regulating pineal MELATONIN production, but that a novel photoreceptor in the retina was responsible. Only 0.5-1.7 foot-candles of blue-green light (509nm) and 10 foot-candles of broad-band white light can lower MELATONIN production under tightly controlled exposure conditions.

MELATONIN production lowered by fluoride

  • The pineal gland calcifies over time as a consequence of incorporating fluoride.    During the late 1990’s, scientist Jennifer Luke of the University of Surrey, England, was the first to study of the effects of sodium fluoride on the pineal gland. She determined that the pineal gland was a target for fluoride, absorbing more fluoride than any other physical matter in the body, even bones. The pineal gland is unique in that it can be classified as a soft or as a mineralizing tissue.
  • The result of 50 years of prophylactic fluorides in dentistry is that the aged pineal contains more fluoride than any other normal soft tissue.   Significantly higher than in muscle. In terms of mineralized tissue, the mean fluoride concentration in the pineal calcification was equivalent to that in severely fluorosed bone and more than 4x higher than in corresponding bone ash,
  • Given the pineal gland’s importance to the endocrine system, its calcification would block endocrine activity.   Providing an explanation of the physiological damage caused by sodium fluoride. Fortunately, a fluoride calcified pineal gland can be stimulated by frequent exposure to outdoor sunshine, 20 minutes or so at a time.

Anti-anxiety drugs suppress MELATONIN

  • Valium and Xanax (benzodiazepine drugs) shown to suppress MELATONIN and disrupt sleep patterns in humans and rodents.   Both cause decreased production of MELATONIN at night. In a study from the Niigata College of Pharmacy in Japan, Valium also inhibited N-acetylserotonin (NAS) and N-acetyltransferase (NAT), enzymes necessary for MELATONIN synthesis in the pineal gland. (See below)

Other factors promoting production:

  • Vitamins B6, B12, folate (synthesis cofactors of SAMe), Vitamin B3
  • Acetyl carnitine – acetylated form of L-carnitine;
  • Hypoglycemia;
  • Tryptophan – MELATONIN’s protein amino acid precursor;
  • SSRIs (anti-depressants);
  • Exercise (except late evening exercise)

Other factors inhibiting production

  • Fluoride – MELATONIN production lowered by fluoride
  • Alcohol; Caffeine;
  • Late evening exercise – during MELATONIN rising phase;  [Wiley]
  • Estrogen – Direct exposure to ESTRADIOL reduced α1 / β-adrenoceptor-induced stimulation of MELATONIN synthesis and release. [PubMed]
  • NSAIDS (Non-steroidal anti-inflammatoru drugs) – E.g. aspirin, Ibuprofen;
  • Beta blockers – keep MELATONIN levels from rising naturally at night; See:  β-blockers – Like leaving the light on all night
  • Calcium-channel blockers;
  • Diuretics;

MELATONIN synthesis pathway in the body

Pineal and retinal SEROTONIN (5-HT) synthesis is up-regulated at night controlled by ß-adrenergic signaling.   Sympathetic nerves from the superior cervical ganglion (SCG) innervate the pineal gland via NOREPINEPHRINE (NE)-stimulation of adenergic receptors (ARs). Increased SEROTONIN synthesis is due to increased protein expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme of SEROTONIN synthesis.

Circadian 5-HT pineal production regulated by adrenergic signaling.  Pineal 5-HT production displays a tri-phasic diurnal pattern, continuing in constant darkness and influenced by light intrusion at night. SEROTONIN content in the pineal gland is higher than in any other part of the body.

  1. During the day – Pineal 5-HT levels constant and high
  2. Early in the night (just after the lights are off) – Sharp rise in pineal 5-HT synthesis and release (controlled by α-adrenergic signaling by NE) precede nocturnal rise in MELATONIN synthesis.
  3. Late in the night – 5-HT levels are low, as 5-HT is used to make MELATONIN . However, in the absence of MELATONIN release, pineal 5-HTcan reach twice daily levels.

Diurnal variation in MELATONIN synthesis is brought about by NOREPINEPHRINE (NE).   Secreted by the postganglionic sympathetic nerves (the superior cervical ganglion / SCG) that innervate the pineal gland. NE interacts with ß1-adrenoreceptors on the surface of the pineal cells (pinealocytes) to increase pineal cAMP, which in turn activates the N-acetyltransferase (NAT) required for MELATONIN synthesis in the biosynthesis pathway, converting tryptophan to MELATONIN.

MELATONIN is synthesized from dietary tryptophan via 4 enzymes
 EnzymeConverts to:
1TPH (tryptophan hydroxylase) (vitamin B3-dependent enzyme**)Tryptophan → 5-HTP
2AADC (aromatic amino acid decarboxylase)(Aka 5-HTP decarboxylase) (vitamin B6-dependent enzyme)5-HTP → SEROTONIN (5-HT / 5-hydroxytryptamine)
3NAT (Serotonin N-acetyl transferase) (activated by NE interacting with ß1-adrenoreceptors on pineal cells)SEROTONIN → NAS (N-acetylSEROTONIN)
4HIOMT (hydroxyindole-O methyltransferase)
+ SAMe (Donates methyl group CH3 to HIOMT) (dependent on methionine, vitamins B6, B12, folate)

SAMe -And Other Methyl Donor Molecules

NAS → MELATONIN

** The body often uses Tryptophan to make vitamin B3, at a very high cost of 60mg L-Tryptophan to make just 1 mg B3.

SAMe (a methyl donor molecule made from the amino acid methionine and ATP) is essential for MELATONIN  production

  • SAMe is the daytime equivalent of MELATONIN – and like MELATONIN, it is produced under control of the master biological clock;
  • Natural synthesis of MELATONIN from acetylated form of SEROTONIN (NAS) depends on adequate SAMe synthesis during the day – SAMe donates a methyl group molecule (CH3) to the enzyme HIOMT that converts NAS to MELATONIN;
  • Vitamins B6, B12 and folate (folic acid) are essential cofactors of SAMe production
  • At night MELATONIN ▲  ▲  ▲  /  SAMe ▼  ▼  ▼  and in the day SAMe ▲  ▲  ▲  /  MELATONIN ▼  ▼  ▼  – SEROTONIN is also produced at night.

In addition to MELATONIN, the methylation function of SAMe is needed for synthesis of other neurotransmitters – such as SEROTONIN,   NOREPINEPHRINE (adrenaline),  EPINEPHRINE. DOPAMINE, and HISTAMINE;  SAMe is also an important cofactor in the conversion of  NOREPINEPHRINE (adrenaline) ➔  EPINEPHRINE. 

SAMe -And Other Methyl Donor Molecules

β-Blockers - Like leaving the light on all night

ß-blockers  (E.g. Inderal, Tenormin, Lopressor (Toprol)) are a common class of drugs  used to treat hypertension by blocking ß-receptors in the heart to diminish the effects of EPINEPHRINE (ADRENALINE) and other stress hormones.   The problem is that they also block brain receptors and blocking pineal ß-adrenergic receptors interferes with the synthesis of MELATONIN. 

People who take beta blockers (at least in the evening) are setting the stage for insomnia, depression and other mental disturbances –

  • MELATONIN synthesis depends on the stimulation of pineal ß-adrenergic receptors by NOREPINEPHRINE (NE).   This normally occurs as the sun goes down. NE-stimulation of ß-adrenergic receptors causes the release of Serotonin-N-Acetyltransferase (NAT), a crucial enzyme for MELATONIN synthesis. 
  • In addition to MELATONIN,  the methylation function of SAMe is needed for synthesis / inactivation of other neurotransmitter monoamines, such as SEROTONIN,  NOREPINEPHRINE (adrenaline),  EPINEPHRINE. DOPAMINE, and HISTAMINE;  SAMe is also an important cofactor in the conversion of  NOREPINEPHRINE (adrenaline) ➔  EPINEPHRINE.

Two studies that demonstrate the disruption to circadian rhythms (and hormones / neurotransmitters dependent on these rhythms) by taking ß-blockers

  • An animal study showed the disruption to circadian rhythms (and hormones dependent on these rhythms) by taking a ß-blocker before bedtime.   Effects are akin to leaving the lights on all night and closely resemble sleep deprivation:
    • SEROTONIN remains unnaturally high – which normally drops at night;
    • SAMe doesn’t decrease – which it should
    • MELATONIN doesn’t increase
  • In a human study, MELATONIN levels fell significantly in hypertensive patients taking ß-blocker compared to controls, and wakefulness increased.   Researchers gave hypertensive patients one of three beta-blockers: propranolol (Inderal), atenolol (Tenormin), or metoprolol (Lopressor or Toprol XL).   MELATONIN levels were measured against those of a control group. Metoprolol decreased MELATONIN more than atenolol or propranolol. The three patients with the lowest levels of MELATONIN reported nightmares. With chronic use of beta-blockers MELATONIN continues to be suppressed.  Brismar K et al, 1988

ß-blockers suppress SEROTONIN as well as MELATONIN.   Thus, it is not surprising that the Physicians Desk Reference lists mental depression, fatigue, short-term memory loss, insomnia and emotional problems as some of the side effects of Inderal and other ß- blockers. Apparently unaware of the role ß- receptors play in getting a good night’s sleep, the manufacturer of Inderal, Wyeth-Ayerst, recommends that these drugs be taken at bedtime!

How to boost MELATONIN levels

Ensure sufficinecy of B6, B12 and folic acid and protein foods rich in amino acids trytophan and methione

Synthesis of SEROTONIN and its conversion to MELATONIN depends on SAMe. (S-Adenosyl Methionine) and vitamin B vital for neurotransmitter metabolism.  SAMe donates methyl groups in the SEROTONIN to MELATONIN synthesis pathway. The body makes and recycles SAMe from the amino acid methionine in protein-rich foods, a process which requires enough vitamin B6, B12 and folate (folic acid) to maximize production.

  • B12 – Take 125mcg – 1 mg of methylcobalamin / day if you suspect deficiency (can be a problem for vegetarians);
  • B6 – Take no more than 10 mg/day as a supplement
  • Folic Acid  (Vitamin B9)

SAMe – And other methyl donors

Methionine-rich foods:

  •  Turkey, beef, fish, pork, tofu, milk,eggs,  cheese, nuts, beans, and whole grains like quinoa.

Tryptophan-rich foods :

  • Protein – turkey, chicken, fish, pheasant, partridge, cottage cheese, eggs, nuts, milk, cheese
  • Non-Protein – bananas, wheat germ, avocados, and the legumes (beans, peas, pulses, soy)

Eat foods rich in  MELATONIN

Bear in mind that circulation levels of MELATONIN vary from several ng in the day to a peak of about 50ng at night. 

FoodVarietyFormMELATONIN  ng /g
Pistachiossp.dry wt>200,000 ng /g
Almonds dry wt39 ng /g
WalnutJuglans regia L. 3.5 ng /g
walnut half= ~7ng
Basmati rice Dry wt38 ng /g
OatsAvena sativa L.fresh wt2 – 90 ng /g
BarleyHordeum vulgare L.fresh wt1 – 82 ng /g
WheatTriticum aestivum L.fresh wt125 ng / g
CranberryVaccinium oxycoccos L. 40 ng /g
    

Dietary Sources and Bioactivities of Melatonin – PMC (nih.gov)

Exercise boosts MELATONIN

Study demonstrates that exercise boosts MELATONIN – a study involving 7 healthy women demonstrated that 1 hour of exercise on a stationary bicycle could double or triple MELATONIN levels. Other studies have also demonstrated that physical exercise can boost MELATONIN levels. However, do not exercise right before bed, which has a stimulating effect;

Daytime sunlight  / Avoid light at night

Go out in the sun – several studies confirm that natural sunlight exposure increases MELATONIN levels. This is not surprising, since bright light is known to increase SEROTONIN production, preventing depression.

Sunlight – Let there be Light!

Reduce light exposure in the evening – artificial light sources and excessive light exposure after darkness onset in modern societies can lower MELAONIN production by desynchronizing your biological clock, making your body think it’s still daytime;

  • Use subdued lighting in the evening
  • Install F.lux sofware (free) on your computer to cut down on blue light emissions – don’t forget your children’s computers
  • Reduce computer screen brightness
  • Wear orange safety glasses at night to filter out blue light – Blue-filtering lights can also be installed in bathrooms (for the night-time excursions) or in the nursery / hall for nursing mothers who necessarily must attend to their baby at night, but don’t want to stop MELATONIN production.
  • Use candlelight (read how J.D. Moyer gave this a try for 30-days).

Supplements

5-hydroxytryptophan (5-HTP)  is a better supplement choice than MELATONIN.    5-HTP is higher up the metabolic pathway for MELATONIN, and allows the body the option of converting to MELATONIN on an as needed basis. Also supplies mood beneficial SEROTONIN along the way.

5-HTP ➔  SEROTONIN ➔  MELATONIN.

  • Dose: Take 100mg 5-HTP before bedtime – also ensure sufficiency of vitamins B6, B12, folic acid and magnesium, which are cofactors in conversion pathways

5-HTP

How to supplement MELATONIN

Supplementing with MELATONIN is appropriate in certain situations, however, be aware that chronic use of supplemental MELATONIN in younger people can result in the pineal gland becoming lazy

FIRST – Prefer 5-HTP supplementation to MELATONIN 5-HTP is higher up the metabolic pathway for MELATONIN, and allows the body the option of converting to MELATONIN on an as-needed basis. Also supplies mood beneficial SEROTONIN along the way.

  • Ensure sufficiency of the B vitamins: B6, B12, folic acid (B9)  which support enzymes in the conversion pathway from 5-HTP ➔ MELATONIN

5-HTP

MELATONIN supplements are readily available over the counter

Supplemental dosage of MELATONIN – Usually in the 1 – 3 mg range and always take at night before bedtime. Taking MELATONIN during the day can reset your body clock, giving you the equivalent of jet lag, which could make you drowsyand increase your risk of accidents.

  • Start low and build up –Start with 1 – 1.5 mg MELATONIN daily, taken 2 hours or less before bedtime. If this is not effective, gradually increase the dosage until an effective level is reached (up to 6 mg daily used for GERD – more is not usually necessary).
  • Chronic pain – 1.5 mg is useful
  • For sleep disorders/jet lag – 1.5 – 3 mgs seems to be adequate dosage;
  • For the elderly and those with grave sleep disorders /diagnosed disease states – 3-6 mg is normally adequate.

Other tid-bits

  • MELATONIN supplementation will ONLY produce a sedative effect when MELATONIN levels are low
  • MELATONIN is most effective for treating insomnia in the elderly – as MELATONIN production tends to decline with age.
  • Unlike sedatives, MELATONIN induces and maintains sleep without suppressing REM (dream) sleep – as suggested by several studies.
  • MELATONIN is used by travelers to “reset their clocks” and combat jet-lag – restoring restful sleep patterns after flying across one or more time zones.
  • MELATONIN safety studies – studies of MELATONIN’s safety are limited; isolated reports have indicated exacerbating depression, fatigue and coronary artery restriction;
  • High-dose MELATONIN supplementation can disrupt the normal circadian rhythm – In one study, a daily dosage of 8 mg / day for 4 days resulted in significant alterations in hormone secretions;

Certain people should not take MELATONIN:

  • Women who are pregnant, trying to conceive or nursing – Large doses of MELATONIN may prevent ovulation. The hormone has not been tested for effects on the fetus. MELATONIN can be found in breast milk and the effect of large doses on nursing babies is unknown.
  • People with immune system disorders – such as severe allergies, autoimmune diseases (like rheumatoid arthritis) or immune-system cancers (like lymphoma). High doses of MELATONIN may stimulate the immune system and may worsen such conditions.
  • Children and those under 40 – since children naturally produce high levels of MELATONIN, and production declines most rapidly only after age 40.
  • People with severe mental illness – high daytime doses have worsened the symptoms of some patients.
  • Those taking medication should consult with a physician – to check interactions
  • Steroid medications – MELATONIN may counteract the effects of the drugs
  • People taking monoamine oxidase (MAO) inhibitors – current MELATONIN supplements may be contaminated by vasoactive amines.
  • Those who are concerned about lowering their natural production of estrogen, TESTOSTERONE and thyroid hormones – which high doses of MELATONIN will do.

MELATONIN Toxicology

  • MELATONIN is water soluble and excess is excreted in the urine
  • MELATONIN has a very low toxicity in rats – Rat maternal toxicity: the no observable adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) were 100 and 200mg/kg/day, respectively, and the developmental toxicity NOAEL was >= 200mg/kg/day.

References

Archives of General Psychiatry 1998;55:863-864,875-882,883-889,890-896.

Bartsch H, Bartsch C. Effect of MELATONIN on experimental tumors under different photoperiods and times of administration. J Neural Transm 1981;52:269-79.

Bartsch C, Bartsch H. MELATONIN in cancer patients and in tumor-bearing animals. Adv Exp Med Biol. 1999;467:247-64. PubMed

Baydas, G., H. Canatan and A. Turkoglu, 2002. Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin induced diabetes mellitus. J. Pineal Res., 32: 225-230. PubMed

Beckman J.S., Koppenol W.H. Nitric oxide, superoxide, and peroxynitrite: The good, the bad and ugly// Am. J. Physiol.-1996 PubMed

Blask DE et al. MELATONIN-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res. 2005 Dec 1;65(23):11174-84. Pub Med

Brismar K, Hylander B, Elilasson K, Rossner S and Wetterberg L. 1988. Melatonin secretion related to side-effects of beta-blockers from the central nervous system. Acta Med Scand 223: 525-30.

Brown ES, Varghese FP, McEwen BS.Association of depression with medical illness: does cortisol play a role? Biol Psychiatry. 2004 Jan 1;55(1):1-9. PubMed

de Souza Pereira R. Regression of an esophageal ulcer using a dietary supplement containing MELATONIN. J Pineal Res. 2006;40:355-356. PubMed

Guerrero JM, Reiter RJ. MELATONIN-immune system relationships. Curr Top Med Chem 2002;2:167-79.

Hurtuk A, Dome C, Holloman CH, Wolfe K, Welling DB, Dodson EE, Jacob A (July 2011). “MELATONIN: can it stop the ringing?”. Ann. Otol. Rhinol. Laryngol. 120(7): 433-40. Pubmed

Jaworek J, Brzozowski T, Konturek SJ.MELATONIN as an organoprotector in the stomach and the pancreas JJ Pineal Res. 2005 Mar;38(2):73-83. PubMed

Kilic E, Özdemir YG, Bolay H, Kelestimur H, Dalkara I. Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia. J Cerebr Blood Flow Metab 19:511-516, 1999.Medline

Konturek PC, Konturek SJ, Hahn EG. Duodenal alkaline secretion: its mechanisms and role in mucosal protection against gastric acid. Dig Liver Dis. 2004;36:505-512. PubMed

Konturek SJ, Zayachkivska O, Havryluk XO, Brzozowski T, Sliwowski Z, Pawlik M, Konturek PC, Cze?nikiewicz-Guzik M, Gzhegotsky MR, Pawlik WW.Protective influence of MELATONIN against acute esophageal lesions involves prostaglandins, nitric oxide and sensory nerves. J Physiol Pharmacol. 2007 Jun;58(2):361-77. PubMed

Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res. 2003 Aug;35(1):12-5.  PubMed

Megwalu UC, Finnell JE, Piccirillo JF (February 2006). “The effects of MELATONIN on tinnitus and sleep”. Otolaryngol Head Neck Surg 134(2): 210-3.Pubmed

Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. MELATONIN: Nature’s most versatile biological signal? FEBS J. 2006 Jul;273(13):2813-38. PPubMed

Parry BL, Meliska CJ, Sorenson DL, Lopez AM, Martinez LF, Nowakowski S, Hauger RL, Elliott JA, Increased Melatonin and Delayed Offset in Menopausal Depression: Role of Years Past Menopause, Follicle-Stimulating Hormone, Sleep End Time, and Body Mass Index. J. Clin Endo & Metab, Vol 93 Iss. 1, 1 Jan 2008 Pgs 54-60 JCEM

Pereira Rde S. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with MELATONIN, vitamins and aminoacids: comparison with omeprazole. J Pineal Res. 2006;41:195-200. PubMed

RosenbergSI, Silverstein H, Rowan PT, Olds MJ (March 1998). “Effect of MELATONIN on tinnitus”. Laryngoscope 108(3): 305-10. Pubmed

Sandra E. Sephton,Robert M. Sapolsky,Helena C. Kraemer,David Spiegel (2001 Jun 21) Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. Oxford Journals Medicine JNCI Volume92, Issue12 Pp. 994-1000 PubMed

Spiegel K, Leproult R, Van Cauter E. [Impact of sleep debt on physiological rhythms]  [Article in French]. Rev Neurol (Paris). 2003 Nov;159(11 Suppl):6S11-20.  

Straif, Kurt; Baan, Robert; Grosse, Yann; Secretan, BéAtrice; Ghissassi, Fatiha El; Bouvard, VéRonique; Altieri, Andrea; Benbrahim-Tallaa, Lamia et al (2007). “Carcinogenicity of shift-work, painting, and fire-fighting”. The Lancet Oncology 8 (12): 1065-6.  PubMed.

Thor PJ, Krolczyk G, Gil K, Zurowski D, Nowak L. MELATONIN and serotonin effects on gastrointestinal motility. J Physiol Pharmacol. 2007;58 Suppl 6:97-103.PubMed

Tjon Pian Gi, Cecil V.; Broeren, Joris P. A.; Starreveld, J. Sander; A. Versteegh, Florens G (2003). “MELATONIN for treatment of sleeping disorders in children with attentiondeficit/hyperactivity disorder: a preliminary open label study”. European Journal of Pediatrics 162(7-8): 554-5.

Wang XC, Zhang J, Yu X, Han L, Zhou ZT, Zhang Y, Wang JZ. Prevention of isoproterenol-induced tau hyperphosphorylation by MELATONIN in the rat.Sheng Li Xue Bao. 2005 Feb 25;57(1):7-12 PubMed.

Withyachumnarnkul B, Nonaka KO, Santana C, et al. Interferon-gamma modulates MELATONIN production in rat pineal glands in organ culture. J Interferon Res 1990;10:403-11.

Zimmermann RC, McDougle CJ, Schumacher M, Olcese J, Mason JW, Heninger GR, Price LH. Effects of acute tryptophan depletion on nocturnal MELATONIN secretion in humans. J Clin Endocrinol Metab. 1993;76:1160-1164. PubMed

Chronic low-level inflammation

Electrotherapy
- The Medical kit of the future

Benefits:

  • Detoxifies
  • Boosts immune system / cellular energy
  • Anti-inflammatory / Pain-relief
  • Aids sleep / Reduces stress
  • Accelerates healing of tissue, bone, muscles, scars
  • Improves circulation +++

Successful electrotherapies:

Pulsed Electromagnetic Field (PEMF) therapy

Near Infrared (NIR) class 4 laser therapy

Rife therapy

Ozone therapy

Hormones-related: