Melatonin is a billion years old molecule of of nature has recently caught interest in, and going to change our approach to medicine for the next millenium.
With the birth of first living form 5 billion years ago, maintaining internal milieu was the first task.
Homeostasis first described by Claude Bernard a century ago is a mean state around which life function oscillate.
Circadian rhythms provide a mechanism by which organisms can maintain synchrony with their environment Circadian rhythms influence not only activity, but also physiological processes and metabolic rates .
Body clock was recognized by Chinese 5000years ago. There is a flow of energy at different organ at different time of the day.
Chronobiology is relatively new subject. All body function has rhythmic changes.
Homeopathy also has remedies selected on the basis of symptoms at different time of the day.
The hamster tests, as we've termed them, involved transplanting the SCN from one hamster into another hamster to observe what effect the transplant had on each animal ( 3 ). In a hamster that has had its SCN removed, the regular daily pattern that has been set by that hamster's SCN is destroyed. When that hamster's SCN is re-implanted, the hamster once again picks up its original daily rhythm. If a genetically speedy SCN is placed into a normal hamster, the normal hamster speeds up, picking up the donor rhythm. If that hamster is then re-implanted with its original SCN, it will once again pick up its original daily rhythm.
Each night the SCN send impulses, via a series of neurons in the hypothalamus and spinal cord, up to the pineal gland to stimulate melatonin secretion. Melatonin, in turn, induces sleep. The timing mechanism in the SCN itself is controlled by sunlight that enters the retina and reaches the SCN via the retinohypothalamic pathway. Thus, it is the solar cycle that drives circadian cycles -- a process called &quot;entrainment&quot; - - and regulates the rhythms of rest and activity, and also the rhythms of a large number of physiologic and endocrine functions. Cutting the retinohypothalamic tract abolishes entrainment, but not vision or the reflex response to light. Cutting the optic tracts abolishes vision and light reflex, but not circadian entrainment. In the absence of light, people still show a circadian rhythmicity, but the cycle of rest and activity is not exactly 24 hours. The solar cycle is necessary to entrain the cycle to an exact 24 hours. People who are completely blind have no way to control their circadian pacemaker; they can use social cues to modify their sleep-wake behavior, but the period of the pacemaker is not 24 hours. Circadian rhythm is endogenous, melatonin modulates it. Light dark cycle of the day provide the timing cues important for the entrainment of the rhythm (the setting of the actual hours of the rhythm ). They have no special adaptation to specific locations or regional environmental conditions. Circadian rhythms are genetically controlled. Melatonin is modulator of circadian rhythm. Some strains of mice have no melatonin secretion. Pinealectomy doesn't disturb circadian rhythm unless challenged there is a compensatory mechanism present after pinealectomy.When pineal present with abnormal rhythm produces problem
Melatonin secretes at night and signals absence of light.
Melatonin secretion decreases with night.
Red line is hypothetical normal pacemaker. With darkness at night ther is melatonin secretion phases with sleep and circadian cycle.
In winter nights there is increases duration of melatonin secretion.
Summer nights melatonin secretion reduces with longer days.
There is relationship of melatonin secretion over whole life and duration of sleep. Melatonin secretion starts at 3 months of age and reaches peak by puberty. Thereafter there is progressive fall over whole life. Sleep duration is also at it’s peak during infancy from 20 hours to 12hours by childhood. Adult sleep for 8 hours and there is gradual decline till old age to few hous.
Melatonin is produced in pineal gland through tryptophan.
Physiologist know melatinin as the hormone that keeps us in sync with the rhythms of the day and the season. Through its actions on other hormones, it helps determine when people sleep and horses breed, when birds migrate, dogs shed their coats and certain frogs change color. But cellular biologists have recently discovered that melatonin has an even more basic function, which is to protect oxygen-based life from the toxic effects of...oxygen.
&quot;Seasonal Affective Disorder (SAD) a depression occurring in the Winter months and associated with hypersomnia,weight gain and craving for carbohydrate has been found to improve with bright light treatment (Rosenthal et al., 1984) The benefit appeared to be related to light rather than Melatonin inhibition as these workers found that pharmacological suppression of Melatonin did not improve their depression.&quot;
Jet-lag is the result of long distance travel east/west crossing time zones at a rapid rate. Symptoms such as sleep disturbance, loss of appetite, reduced psychomotor efficiency and general malaise may occur. The problem for aircrews on longhaul schedules has been coped with by alterations in sleep patterns. Short naps may alternate with intermediate and long periods of sleep.Synchronisers &quot;zeitgebers&quot; (time givers) are environmental factors that help to keep the organism in phase. Travel at rapid rates across time zones disturbs the normal rhythm. One adapts more easily after a flight Westward because there is a longer day and we have an endogenous clock of about 25 hours. Circadian rhythms need about one day to adapt for each time zone crossed. In other words 5 hours' time difference will require approximately 5 days adaptation. (2)
A study was done in shift workers. 5mgs melatonin was given at bedtime and increased alertness in waking hours was observed. Authors caution that effects on performance need careful evaluation. (5) Nocturnal melatonin secretion may be involved in physiologic sleep onset and exogenous melatonin may be useful in treating insomnia. 0.3mgs or 1mg were given at 6 and 8 pm close to times of endogenous melatonin release and habitual sleep onset. No &quot;hangover &quot; effects were noted as assessed by mood and performance tests administered the morning after treatment. (6) Melatonin has been found to be efficacious in delayed sleep phase syndrome. 5mgs/day was administered for one month. Mean sleep onset time was advanced 115 mins and mean final awakening hour by 106mins. (7)
Research also suggests that melatonin is nontoxic but can cause headaches, diarrhea, and abdominal cramps when taken in large doses (3,000-6,000mg). It can cause drowsiness, so it shouldn't be used during the day or while driving. Melatonin is not recommended for children, teenagers, or pregnant or lactating women. It is recommended to take one capsule (1.0 mg) daily, 30 minutes before bed.
The research suggests that melatonin is not addictive, but rather seems to replenish depleted stores in the body. However, one should recognize that by taking melatonin, one is consuming a synthesized hormone and not stimulating the pineal gland to produce the body's own supply. It is possible that over long periods of time, taking melatonin could reduce the body's ability to manufacture its own supply. You may not wish to use this product on a continual basis.
1) Follow the body's natural cycles. Not so long ago, people went to bed when it was dark, and rose with the sun. Try going to bed by 10 p.m. and sleeping in a pitch dark room. The next morning, expose yourself to bright light as soon as possible (open your shades or go outside). This alone will increase melatonin levels. Remember to expose yourself to bright light during the day, too -- sit by a sunny window or walk outside. 2) Get your melatonin from foods. Go for the real stuff: oats, sweet corn, rice, barley, tomatoes and bananas are all rich in melatonin. Eating any of these about an hour before bed can help get your prepped for sleep. Carbs also release tryptophan, which in turn helps the body manufacture melatonin (that's why you may feel sleepy after eating pasta, for example.) Just remember that to get these benefits, starchy foods should be eaten on a fairly empty stomach, without any protein. 3) Certain supplements can increase melatonin production. Vitamins B3 and B6 convert tryptophan to seratonin, which is the precursor of melatonin. It's best to get these vitamins from foods like dried apricots, barley, whole wheat, tuna and turkey, rice, bananas, lentils, shrimp and carrots. If you opt for supplements, take B6 during the day because it may promote alertness. B3 can be taken at night, with 1,000 mgs. of calcium and 500 mgs. of magnesium.
4) Meditate regularly. Studies show that people who do so have higher levels of melatonin. 5) Avoid too much caffeine and alcohol, and stop smoking. All these substances drain your melatonin reserves. 6) Keep your pineal gland -- which manufactures melatonin --healthy by taking anti-oxidant supplements
Melatonin seems to be the hormone that directs aging. Children have higher levels of melatonin until they reach puberty. Levels of melatonin continue to decrease with age, To test melatonin's effect on aging, Pierpaoli transplanted the pineal glands of young mice into old mice. Then he took the pineal glands of the old mice and gave them to the young mice. The young mice started to age, lose hair, get cataracts in their eyes, and hobble around. The muscles of the old mice became stronger and their hair grew thicker. A daily supplement of melatonin could help humans stayyounger and healthier as they age A review of several studies done on the pineal gland suggest that this production of melatonin at night decreases with age, which results in an increasingly higher ratio of serotonin to melatonin. It is thought that this change in balance has numerous effects on the body's cells. Because serotonin is a vasoconstrictor, it can promote atherosclerosis and, by increasing blood pressure, may be a factor in stroke. And without melatonin's regulatory influence, serotonin may have an inflammatory effect on cells that can promote the spread of cancer
Melatonin is a highly important antioxidant. Free radicals are chemical constituents that have an unpaired electron. If an electron is added to O2 then the superoxide anion radical O2- is formed. O2- is reduced by superoxide dismutase to H2O2 which is toxic at high concentrations and can be reduced to.OH. The hydroxyl radical (.OH) damages cells. Melatonin is an efficient neutraliser of.OH. (9) Age related brain deterioration is extremely costly in terms of quality of life. One of the potential major causes of age-related destruction of neuronal tissue is toxic free radicals that are a natural result of aerobic metabolism. The brain is particularly susceptible to free radical attack. (10( Vitamin antioxidants.vitamin E (alpha- tocopherol in particular) and vitamin C (ascorbate) aid in protecting the brain from oxidative stress by directly scavenging toxic radicals. The pineal hormone melatonin is rapidly taken up by the brain. In vitro melatonin is more effective than glutathione in scavenging the highly toxic (.OH) radical and also more efficient than vitamin E in neutralising the peroxyl radical. It also stimulates the main antioxidant enzyme of the brain, glutathione peroxidase. In vivo melatonin is a potent antioxidant. (10)
We found only one citation in the current literature which dealt with melatonin and its use in cataracts. An experiment was done in newborn rats that were purposefully induced into developing cataracts. In one set of rats (15 of them) they injected melatonin while the other set got placebo (18). They found that all 18 rats in the placebo group developed cataracts versus only 1of 15 in the melatonin group. Still the mechanism in which melatonin may have inhibited cataract development was unclear to the researchers. They believe it might be due to melatonin's ability to modulate certain chemicals which inhibit &quot;oxidative stress&quot; or that it may directly be an anti-oxidant itself. Clearly more studies are needed (preferably in humans) to confirm that melatonin actually does work in preventing cataracts because the current research is a long way from making melatonin a standard of eye care.
Evidence that it has an ability to fight cancerous tumours underlines the crucial role of melatonin. Studies show that some types of cancer are stimulated when the pineal gland has been surgically removed, especially ovarian and breast cancers. In rats and mice, melatonin appears to slow the growth of prostate and breast cancer and leukemia. Studies focusing on melatonin's role in fighting breast cancer provide some of the best evidence for its protective role: it imitates tamoxifen, a potent anti-estrogen used as standard breast cancer therapy. Several studies conclude that the anti-tumour effects of melatonin may be due to its ability to curtail hormones that help activate cancers, including prolactin and growth hormone. And here is where the anti-aging effect comes into play: while these substances are crucial to the reproductive phase of most organisms (that is, the youthful phase), the melatonin produced at night offsets their potential to cause damage. But with the decrease in melatonin over time, the damage-control it usually exerts is minimized and, as we grow older, allows these substances the free rein that helps cancer cells to grow: a growth that might otherwise be inhibited if enough melatonin were available. Researchers have found that the pineal hormone melatonin, which synchronizes our body clocks to the cycle of day and night, has intriguing anti-cancer properties. In vitro , it can halt the growth of some breast cancer cell lines, and add to the efficacy of tamoxifen in performing the same task. In vivo , melatonin has been shown to reduce secretion of the hormones estrogen and prolactin, as well as other hormones linked to breast cancer such as cortisol, and by reducing estrogen, to also cut production of growth factors on which the tumour thrives. Lastly, melatonin has the potential to reverse some of the malignant characteristics of cancer cells, and to stimulate the expression on the surface membrane of cancer cells of certain proteins known as estrogen receptors, the presence of which improves the prognosis of breast cancer patients. A group of researchers in Milan, Italy, concluded that a clinical test of melatonin's effect on tamoxifen therapy was necessary. Electromagnetic fields (EMF) have been linked to tumours. If the pineal gland is removed in rats the incidence of tumours is increased. EMFs may influence mel production in the pineal gland. Gliomas have been linked to EMFs. (11) Inhibition of cancer growth by mel has been observed. Melatonin is most effective when given in the evening. There are data which indicate that mel antagonises the mitogenic effects of oestrogens (Blask et al., 1991; 1992; Wilson et al., 1992). (1) Inhibition of antioxidants by reducing agents such as glutathione eliminates the oncostatic effects of mel in certain human breast cancer cell lines. (Blask et al., 1994) As stated above mel has been found to be the most effective scavenger of highly toxic free radicals (Tan et al., 1994), which induce DNA damage. (1) Melatonin may augment the anti tumour activity of IL-2 (Interleukin 2) by inhibiting tumour growth factor production. A pilot study was done using low dose IL-2 plus mel in 14 patients with untreatable endocrine tumours. The results suggest that low dose IL-2 and mel may be a well tolerated therapy for advanced endocrine tumours. (12) Melatonin was added to IL-2 therapy for advanced solid neoplasms resistant to IL-2. Melatonin may enhance IL-2 antitumour immune effect. 40mgs mel was given every day,starting 7 days prior to IL-2. Objective tumour regression was noted in 3/14. (lung,kidney and liver tumours) (13) Studies show that some types of cancer are stimulated when the pineal gland has been surgically removed, especially ovarian and breast cancers. In rats and mice, melatonin appears to slow the growth of prostate and breast cancer and leukemia. Studies focusing on melatonin's role in fighting breast cancer provide some of the best evidence for its protective role: it imitates tamoxifen, a potent anti-estrogen used as standard breast cancer therapy.
Hypermelatonism <ul><li>Seasonal affective disorder (SAD) </li></ul><ul><li>Extreme fatigue and lack of energy </li></ul><ul><li>Increased need for sleep </li></ul><ul><li>Carbohydrate cravings </li></ul><ul><li>Weight gain </li></ul><ul><li>Reduced work productivity </li></ul><ul><li>Withdrawal from social contacts </li></ul><ul><li>Exposure to light improve </li></ul>
Clinical features of CRS <ul><li>Disruption of sleep </li></ul><ul><li>Decreased attention span </li></ul><ul><ul><li>Decreased work efficiency </li></ul></ul><ul><ul><li>Work- and non-work related accidents </li></ul></ul><ul><li>Irritability </li></ul><ul><li>Headaches </li></ul><ul><li>Fatigue </li></ul><ul><li>Substance abuse </li></ul><ul><li>Depression </li></ul><ul><li>Reduced Immunity </li></ul><ul><li>Cardiovascular and </li></ul><ul><li>Gastrointestinal disorders </li></ul>
Melatonin in insomnia <ul><li>Circadian rhythm disturbance most effective </li></ul><ul><li>Insomnia with psychological diseases slight improvement </li></ul><ul><li>Insomnia with structural disease no response </li></ul>
Advantage of melatonin <ul><li>Nontoxic </li></ul><ul><li>No tolerance </li></ul><ul><li>No hangover </li></ul><ul><li>No suppression of REM sleep </li></ul>
Administration <ul><li>0.1mg to 200mg </li></ul><ul><li>As little as 0.3 - 0.5 mg is usually effective as a sleep aid. </li></ul><ul><li>Regular low dosage use for sleep should be limited to one month. </li></ul><ul><li>Start slowly and increase till achieve normal sleep and no early morning drowsiness </li></ul>
Pharmacokinetics <ul><li>Absorption: 60-150min </li></ul><ul><li>Elimination half life: 45-60min </li></ul><ul><li>Metabolism in liver and brain </li></ul>
Melatonin in various age groups <ul><li>Age Group Teens - 20's: Should take Melatonin only occasionally for insomnia. </li></ul><ul><li>Age Group 30 - 50: Can use it more frequently. </li></ul><ul><li>Age Group over 60: Daily use is recommended. </li></ul>
Caution <ul><li>Psychotics </li></ul><ul><li>Manic depression </li></ul><ul><li>Immune system disorders: autoimmune and malignant disorders </li></ul><ul><li>Diabetes and endocrine diseases </li></ul><ul><li>Hypertension and cardiovascular disease </li></ul><ul><li>Children and young reduces sperm count </li></ul><ul><li>Pregnancy and breast feeding </li></ul>
Safety profile <ul><li>LD-50 not known </li></ul><ul><li>Hypothermia </li></ul><ul><li>There is little evidence to support the safety of long-term use. </li></ul>
Drug interaction <ul><li>Not well known </li></ul><ul><li>Anti depressant may increase melatonin level </li></ul><ul><li>Estrogen reduces melatonin level and </li></ul><ul><li>Melatonin reduces estrogen level </li></ul>
Natural way to increase melatonin <ul><li>Early to bed and early to rise ……….. </li></ul><ul><li>Food: Oats, sweet corn, rice, barley, tomatoes and bananas </li></ul><ul><li>Vitamin B3, B6 (dried apricots, barley, whole wheat, tuna and turkey, rice, bananas, lentils, shrimp and carrots) </li></ul>
Natural way to increase Melatonin <ul><li>Meditate regularly </li></ul><ul><li>Avoid too much caffeine and alcohol, and stop smoking. </li></ul><ul><li>Anti-oxidant supplements keeps pineal gland healthy </li></ul>
1.Extend life........… 2.Prevent pregnancy 3.Protect from free - radical damage.… 4.Boost the immune system.....… 5.Prevent cancer...... Melatonin Claims!
Melatonin extend life <ul><li>Melatonin secretion reduces with aging in 80% population </li></ul><ul><li>Cross transplantation of pineal gland </li></ul><ul><li>Aging is due to oxidative injury to cell wall and DNA </li></ul><ul><li>Melatonin is a strong antioxidant </li></ul>
Melatonin and Reproduction <ul><li>Melatonin controls growth hormone level </li></ul><ul><li>Precocious puberty have low melatonin while delayed puberty have high </li></ul><ul><li>Higher levels of melatonin are associated with male infertility and with the cessation of menstruation in women who exercise heavily or suffer badly from stress </li></ul>
Immunomodulation <ul><li>Melatonin activated monocytes... and enhance their ability to destroy nonself cells. </li></ul><ul><li>Melatonin influenced the release of IL-1 proteins that control aspects of blood-cell production and the immune response. </li></ul><ul><li>Melatonin could restore the function of T-helper cells and IL2 in immunocompromised mice. </li></ul>
Melatonin as antioxidant <ul><li>In vitro melatonin is more effective than glutathione in scavenging the highly toxic (OH) radical </li></ul><ul><li>More efficient than vitamin E in neutralizing the peroxyl radical. </li></ul><ul><li>It also stimulates the main antioxidant enzyme of the brain, glutathione peroxidase. </li></ul><ul><li>In vivo melatonin is a potent antioxidant </li></ul>
Melatonin in Cataract <ul><li>Glutathione depletion by Glutathione synthesis inhibitor buthione sulfoxemine (BSO) produces cataract in young mice </li></ul><ul><li>Melatonin administration prevent cataract formation by antioxidant effect </li></ul>
Melatonin in Cancer <ul><li>Increased incidence of ovarian and breast cancer after pinealectomy </li></ul><ul><li>Melatonin suppresses growth of prostate and breast carcinoma </li></ul><ul><li>Anti cancer effect may be due to anti Prolectine, estrogen and growth hormone effect </li></ul><ul><li>Melatonin changes expression of cell membrane estrogen receptor </li></ul><ul><li>Melatonin may enhances anti tumor activity of IL2 by inhibiting tumor growth factor production in endometrial carcinoma </li></ul>
More melatonin relationship <ul><li>Fibromyalgia: reduced melatonin </li></ul><ul><li>Epilepsy: high dose may be effective </li></ul><ul><li>Trypanosomiasis: Circadian rhythm disturbance </li></ul><ul><li>Pain: to induce painless sleep </li></ul><ul><li>Tinnitus: to induce sleep </li></ul><ul><li>Hypercholesteremia: reduces LDL receptor </li></ul><ul><li>Antistress </li></ul>
This billion year old chronobiotic molecule will change our approach to medicine for the next millenium Thank you