Melatonin Deficiency and Excess

A deficient production of melatonin can result in anxiety and mood disorders, lowered basal body temperature insomnia, elevated estrogen/progesterone ratio, and immune suppression associated with cancer. Excess melatonin is associated with seasonal affective disorder (SAD), lowered estrogen/progesterone ratio, low thyroid and adrenal function, and hypotension.

Melatonin Associated Disorders

Because melatonin has a pivotal role in regulating body temperature, the sleep/wake cycle, female reproductive hormones, and cardiovascular function, the effect of disrupted secretion rhythms is widespread, manifesting in a variety of physical and psychological disorders.

  • Anxiety, stress, depression
  • Seasonal Affective Disorder
  • Sleep Disorders
  • Delayed Sleep Phase Syndrome
  • Immunological Disorders
  • Cardiovascular Disease
  • Cancer


Behavior Changes and Mood Disorders

Abnormalities of melatonin circadian function have been closely linked to a variety of behavioral changes and mood disorders. Determining the circadian secretion rhythm of melatonin can assist the clinician in diagnosing the type of mood disorder.
In general, studies have reported decreased nocturnal melatonin levels in patients suffering from depression.43-45 One investigation of major depression in children and adolescents found that melatonin levels were significantly lower in depressed subjects with psychosis than in depressed subjects without psychosis.46 Subnormal levels of melatonin accompanied by a delayed circadian rhythm have also been reported in patients with panic disorder.45
In a fascinating study on geomagnetic storms and depression, British researchers found that male hospital admissions with a diagnosis of depression rose 36.2% during periods of geomagnetic activity as compared with normal periods. The investigators hypothesized that this increase may have been caused by a phase advance in the circadian rhythm of melatonin production.47
In Seasonal Affective Disorder (SAD) melatonin secretion tends to be elevated. Since full spectrum light reduces the rate of melatonin secretion, light therapy can be very effective in treating patients with SAD.48-49

Body Temperature Regulation

In humans, melatonin is closely connected with changes in body temperature. The most striking example is the reciprocal relationship found in circadian profiles, where the lowest body temperature correlates closely with the peak level of melatonin. The ovulatory rise in temperature during the menstrual cycle is also associated with a decline in melatonin secretion levels. There is a possible causal relationship between the two phenomena, since exogenous melatonin can acutely depress body temperature in humans.50
Melatonin’s effect on body temperature may be one of the keys of its ability to enhance sleep. Body temperature follows a circadian rhythm, rising during the day and falling at night. The daily temperature variation in the human body is only about 1 degree, but this small difference has a dramatic influence on sleep. In general, a falling body temperature induces sleep, while a rising body temperature provokes wakefulness. It has been demonstrated that an individual will fall asleep most quickly and stay asleep the longest when lights are out, and the body temperature undergoes its most rapid decline.51

Sleep Disorders

Patients with delayed sleep phase insomnia cannot sleep until the early hours of morning, and often end up sleeping through much of the day. This condition has been treated successfully with exposure to bright light in the early morning to induce phase advances of the clock. An evening dose of 5 mg of melatonin at 11:00 p.m. has also been shown to advance sleep time significantly.52 A combination of both methods — timed application of bright light in the morning and a dose of melatonin in the evening –seems to be the most effective therapy for treating melatonin rhythm disturbances.
Melatonin has not only been shown to advance sleep time, but to increase sleep duration as well.53 It is also effective in reducing the symptoms of jet lag.54 One study examined the effectiveness of melatonin in treating the sleep disorders in 100 children, who had a wide variety of physical problems including blindness, mental retardation, autism, and central nervous system diseases. Melatonin therapy was found to benefit over 80% of these children, and was lauded as a “safe, inexpensive, and very effective treatment of sleep-wake cycle disorders.”55 In general, smaller doses of melatonin appear to be just as effective as larger doses in inducing and sustaining sleep.56
Patients with sleep disorders are often given a prescription for a benzodiazepine, a family of drugs that includes Dalmane, Doral, Halcion, ProSom, Restoril, Valium, Xanax, and many others. Although these medications can be very effective, particularly in cases of anxiety-related insomnia, they have many limitations and adverse side affects, including anxiety, depression, and memory loss (anterograde amnesia).57-59 Melatonin enhances REM and slow-wave sleep patterns with little or no adverse reactions.


There is good evidence for photoperiod dependence and/or melatonin responsiveness in the initiation and evolution of certain cancers, particularly hormone-dependent cancers. Administration of melatonin significantly improved survival time and quality of life in patients with brain metastases due to solid neoplasms.60 When used after first-line chemotherapy (cisplatin) for treating non-small cell carcinoma (NSC) of the lung, melatonin also successfully prolonged the survival time for patients with metastatic NSC lung cancer.61
Because of its powerful oncostatic effects and its estrogen-blocking ability, melatonin demonstrates particular promise in the treatment of breast cancer. Numerous studies have reported an inverse correlation between melatonin levels and the growth of estrogen-receptive positive tumors.62-66 Used in conjunction with tamoxifen to modulate cancer endocrine therapy, melatonin shows marked ability to modulate estrogen receptor expression and inhibit breast cancer cell growth. Moreover, researchers surmised that melatonin may induce objective tumor regressions in metastatic breast cancer patients refractory to tamoxifen alone.67

Immune System

When properly administered, melatonin has general stimulatory effects on immune system functions; its positive anti-cancer effects may stem from this strengthening of the immune response.68 One theory is that melatonin acts as an anti-stress hormone via the brain opioid system, with consequent up-regulation of the immune system.69,70
Many researchers believe that T-derived cytokines are the main mediators of the immunological effect of melatonin. Specific high affinity binding sites for 125I-melatonin have been discovered on T-helper-type 2 lymphocytes in the bone marrow and in various lymphoid tissues.71,72

Multiple Sclerosis

Multiple Sclerosis (MS) is the most common of the demyelinating diseases of the central nervous system. The clinical course and prognosis of the disease is variable, although it typically tends to progress in a series of relapses and remissions. In most cases, a patient with MS undergoes a slow and steady deterioration of neurological function.
Recently, the pineal gland has been implicated in the pathogenesis and clinical course of MS. When melatonin levels decline, an exacerbation of MS symptoms is seen.73,74 Remission effects in MS are thought to relate to the stimulatory influence of melatonin on the immune system.
In one study, 32 MS patients were randomly selected from patients consecutively admitted to a neurology service in a hospital for exacerbations of their symptoms. Nocturnal levels of melatonin and the activity of the pineal gland were monitored over the course of each patient’s illness. The study revealed a progressive decline in melatonin levels over the duration of the illness. Since patients with chronic progressive MS had a lower mean melatonin level compared to those with a relapsing-remitting course of the disease, an analysis of melatonin levels may be crucial for understanding the pathophysiology of MS and, specifically, the course of its progression.75

Antioxidant Activity

Free radicals, especially the hydroxyl radical, can be extremely damaging to cells. Melatonin has both water and fat soluble properties, making it one of the only known antioxidants in nature that can protect all parts of a cell. Since melatonin has the unique ability to navigate any body barrier with ease (including the blood-brain barrier and the placental barrier76), it can protect virtually every cell in the body.
Recent evidence suggests that melatonin plays a critical role in free radical scavenging activity, preserving macromolecules such as DNA, protein, and lipid from oxidative damage.77,78 In fact, melatonin has been proven more powerful than both glutathione and mannitol in neutralizing hydroxyl radicals and may protect cell membranes more effectively than vitamin E.79,80 Remarkably, it is five hundred times more efficient at protecting cells from radiation than dimethyl sulfoxide (DMSO).81

Cardiovascular Disease

A decrease in melatonin causes increased nighttime sympathetic activity, which in turn appears to increase the risk for coronary disease. One study found that patients with coronary heart disease had nocturnal melatonin levels five times lower than in healthy controls. Investigators surmised that lower levels of melatonin may act to increase circulating epinephrine and norepinephrine, which have been implicated in damage to blood vessel walls. Atherogenic uptake of LDL cholesterol is accelerated by these amines at pathophysiological concentrations.82
Research conducted on laboratory rodents has shown that melatonin treatment exerts the beneficial effect of increasing the HDL/total LDL cholesterol ratio, perhaps by enhancing endogenous cholesterol clearance mechanisms.83 Specific binding sites for the melatonin agonist 2-[125I] iodomelatonin have been discovered in the heart (and lungs) of various animals.84 In addition, melatonin seems to inhibit platelet aggregation. Platelet aggregation plays a significant role in the progression of cardiovascular disease.85

Ovulation and Pregnancy

Recently melatonin has stimulated the interest of researchers for its potential use as an oral contraceptive. Researchers have established a negative correlation between melatonin and sex steroids, independent of gonadotrophin activity.86 Increased secretion of melatonin in winter appears to suppress or inactivate the hypothalmic-pituitary-gonadal reproductive axis, which in many species results in a limited, seasonal period of reproduction.87 This natural form of contraception occurs via the hypothalamic GnRH pulse generator. It is postulated that a melatonin/ovarian steroid contraceptive could re-activate this anovulation mechanism in humans, and one melatonin-based contraceptive is already undergoing Phase III clinical trials.88 Long term use of such a contraceptive could reduce the risk of breast cancer by preventing the proliferation of epithelial breast cells caused by continuous ovulatory cycles.89
Significant increases in melatonin have been noted in women during the luteal phase of ovulation.90 In animal studies, pharmacological doses of melatonin caused no harmful effects on developing embryos, suggesting that the administration of melatonin may be safe during pregnancy.91

Conventional Medical Treatment [SH]

The pineal gland and melatonin levels are generally not treated by conventional means, unless a rare pineal tumor is detected.

Naturopathic Medical Treatment and Prevention [SH]

Melatonin Deficiency

Melatonin production is increased by darkness; therefore, artificial light (or any type of electromagnetic radiation), after sundown should be minimized. Daytime exercise and light exposure will promote a regular circadian rhythm of melatonin.

Clinical Nutrition
Vitamin B-6 (Pyridoxal-5-Phosphate): Vitamin B-6 is a cofactor in melatonin synthesis from L-tryptophan.

L-Tryptophan: L-tryptophan is a precursor amino acid to serotonin and melatonin.

5-Hydroxy-Tryptophan (5HTP): 5HTP is intermediate in the tryptophan to serotonin/melatonin pathway.

Melatonin: Bio-identical hormone replacement can be administered.

Melatonin Excess

SAD is common in temperate climates, especially those with a high level of cloud cover. Therefore, regular daytime exposure to light (2500 lux/20 min per day in the morning) has been shown to improve the symptoms of SAD. Normal circadian rhythms should be promoted by following natural day/night light patterns and avoiding, if possible, night shift work. As stress can potentiate melatonin secretion, stress reduction and management of stress are important to the improvement of SAD.92

Clinical Nutrition
Cravings for sweets and other high glycemic foods are common with SAD, but these foods should be avoided. Although these simple carbohydrates may lift the mood temporarily, their consumption is often followed by a blood sugar drop (hypoglycemia), which puts extra strain on the adrenal glands. In addition, weight gained as a result can aggravate SAD. Caffeine and other stimulants are in the same category, and alcohol exacerbates SAD by acting as a depressant. Furthermore, supplements or medications that increase melatonin may exacerbate SAD. Support of thyroid and adrenal function typically improves the symptoms of SAD. 93


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