MELATONIN production

Where is MELATONIN produced?

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

MELATONIN Health Benefits

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.

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 pinealocytes (pineal cells) to increase pineal cAMP, which in turn activate the N-acetyltransferase (NAT) required for MELATONIN synthesis in the biosynthesis pathway, converting tryptophan to 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 and SEROTONIN 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 (and SEROTONIN) depends on adequate SAMe synthesis during the day - SAMe donates a methyl group molecule (CH₃) to the enzyme HIOMT that converts the acetylated form of SEROTONIN (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.

SAMe -And Other Methyl Donor Molecules