Life Extension Magazine January 2004

Melatonin and Cancer Treatment

By Eileen M. Lynch, PhD


In 1992, the Life Extension Foundation introduced a melatonin supplement because of the broad-spectrum protective effects that this hormone had shown against age-related disease.1 Some of this research even suggested that melatonin supplementation may extend the human life span.2 Indeed, melatonin is so intricately involved in cell regulatory processes that scientists are now studying it as an adjunctive cancer treatment.3,4

These days, most people are likely to associate melatonin with a hormone that helps people sleep better or prevents jet lag.5,6 Few people realize that melatonin is a cancer-killing hormone7,8 that can enhance the human immune system,9,10 protect against the toxic side effects of chemotherapy4,11 and radiation therapy,12,13 and improve wound healing after cancer surgery.14,15 Even fewer are aware of ongoing clinical trials in which melatonin is being used to help cancer patients better manage their disease symptoms,16 improve their quality of life,17 and even increase their survival rates.4,11

Although the evidence demonstrating melatonin’s anti-cancer effects18 cannot be overstated, melatonin’s impact on cancer treatment remains largely unappreciated. This is likely because pharmaceutical companies have little to gain by advertising the anticancer efficacy of melatonin. In Europe, where melatonin is not even readily available, many clinical trials of melatonin have been conducted.19,20 US pharmaceutical companies, however, have shown little interest in even hosting, let alone funding, such critically important and potentially lifesaving clinical trials.

Life Extension Supports Clinical Trial
The Life Extension Foundation is collaborating with Cancer Treatment Centers of America on the first prospective, randomized clinical trial utilizing melatonin in patients with advanced lung cancer. Life Extension is providing, at no charge, high-dose melatonin and placebo supplements for this ongoing clinical trial, which will be the first in the US to examine the effect of melatonin supplementation therapy on quality of life and overall survival rates for patients with metastatic non-small-cell lung cancer.

Figure 1. Structure of Melatonin (C13H16N2O2)

Life Extension and the Cancer Treatment Centers of America hope to determine whether patients with advanced lung cancer suffer abnormal circadian rhythms and whether this affects their melatonin levels. The researchers hope that this trial will confirm the favorable clinical results documented by Lissoni and colleagues, whose recent European clinical studies indicate that in patients with metastatic non-small-cell lung cancer, five-year survival and overall tumor regression rates were higher in patients concomitantly treated with melatonin than in those treated with chemotherapy alone.4 While no patient treated with chemotherapy survived after two years, five-year survival was achieved in 3 of 49 patients treated with chemotherapy and melatonin. The researchers hope that similarly promising results could eventually convince mainstream medical practitioners to administer melatonin in combination with standard cancer treatment regimens to patients in earlier stages of cancer treatment.

Numerous, mostly European clinical studies already have examined melatonin’s therapeutic benefits to patients with different types of cancer who either did not respond to standard oncological therapies11,19 or were eligible only for supportive care (advanced cancer deemed untreatable by conventional standards).21,22 A literature search of the PubMed database found 806 publications on “melatonin and cancer.” Fifty-two articles were found concerning clinical studies utilizing melatonin in cancer patients. In this article, we will highlight and summarize some of the key studies concerning the use and mechanisms of melatonin as an adjuvant cancer therapy.

What Is Melatonin?
Melatonin (known scientifically as the indoleamine N-acetyl-5-methoxytryptamine) is a hormone with neurotransmitter modulatory activity.23 It is produced from the amino acid tryptophan in minute quantities by the pineal gland when the eyes detect no light (i.e., in darkness or blindness, or during sleep). Melatonin also is produced by the retina24 and, in vastly greater amounts, by the gastrointestinal system.25 In fact, 400 times more melatonin can be found in the gastrointestinal system than in the pineal gland or bloodstream,26 where levels typically range from 0.1 to 10 nmol/L. Melatonin receptors are present in central nervous tissues,27 peripheral tissues,28 and steroidogenic tissues,29 including myometrial tissues of both pregnant and non-pregnant women.SPAN class=wwwMagTextRefNumber>30 Maternal melatonin crosses the placenta.31

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

Melatonin’s Anti-Cancer Mechanisms
Melatonin can kill directly many different types of human tumor cells.3,41 It is a naturally produced cytotoxin, which can induce tumor cell death (apoptosis).7,42 In instances where the tumor has already established itself in the body, melatonin has been shown to inhibit the tumor’s growth rate.43,44 Melatonin exhibits natural oncostatic activity and inhibits cancer cell growth.45 In patients in whom cancer already has become a noticeable physical burden and produces overt symptoms, melatonin has been shown to alleviate numerous cancer symptoms46 and to inhibit development of new tumor blood vessels (tumor angiogenesis),47 which in turn inhibits the cancer from spreading further (metastasis).48 Melatonin can retard tumor metabolism and development by lowering the body temperature;35 it is a natural inducer of hypothermia. Furthermore, as an inducer of antioxidants49 and itself a weak preventive antioxidant,37 melatonin hinders tumor cells from participating in free radical damage to normal cells and consequently limits oxidative damage to DNA,40 lipids,50 amino acids, and proteins.40

In the unfortunate circumstance in which cancer has already overwhelmed the body’s innate cancer-fighting capabilities, including the anti-cancer activity of naturally produced melatonin (levels of which are reduced in most cancer patients), supplemental melatonin may be beneficial.17,43 Melatonin plays a critical role in the host defense system against cancer’s progression by activating the cytokine system,51 which exerts growth-inhibiting properties,10 and by stimulating the cytotoxic activity of macrophages and monocytes.52

Administration of supplemental melatonin has been shown to be beneficial even in the supportive care of advanced and end-stage cancer patients: it lessens tissue wasting and diminishes weight loss, fatigue, weakness, and depression;17,21,43,47,53 enhances immune function;10 improves wound healing;54 and improves quality of life and survival rates.4 Furthermore, melatonin improves common symptoms found in both patients with advanced cancer and those undergoing chemotherapy; it counteracts anemia55 and lymphocytopenia,14,21 stimulates platelet production,21 enhances appetite,16 and diminishes cancer pain56 (including bone pain) through its natural analgesic properties.57 These are substantial benefits considering that approximately half of all patients diagnosed with cancer die because of poor symptom management.58

Life Extension Magazine January 2004

Melatonin and Cancer Treatment

By Eileen M. Lynch, PhD


Melatonin and Cancer Surgery
In peri- and post-operative cancer surgery, melatonin may prove beneficial in wound healing through its natural anti-inflammatory properties.14,59 Melatonin reduces tissue destruction during inflammatory reactions60 by limiting hypoxia-reoxygenation-induced damage,61 scavenging free radicals, and reducing the upregulation of pro-inflammatory cytokines,60 such as the interleukins and tumor necrosis factor-alpha. Furthermore, surgery induces immunosuppression, which could adversely affect tumor-host interactions in cancer patients having their tumors surgically removed. As melatonin inhibits the activation of the acute inflammatory response, it may inhibit immunosuppression while contributing to an immune reaction against the tumor.14 Moreover, melatonin can reverse the perception of pain sensation (hyperalgesia) that is secondary to inflammation associated with wound healing.56

In cancer patients undergoing surgical removal of gastrointestinal tract tumors, preoperative neuroimmunotherapy with melatonin and interleukin-2 (IL-2) was capable of neutralizing the surgery-induced reduction in white blood cell counts (lymphocytopenia).14 Melatonin thus may prove to be beneficial to cancer patients who elect surgical removal of their tumors, by improving wound healing, inhibiting tissue damage, reducing pain sensation and weakness, counteracting reduced blood cell counts and anemia, and preventing immunosuppression.

Melatonin and Radiation Therapy
Radiation requires the presence of oxygen to generate free radicals to kill tumor cells. It is well established, however, that most human tumors are poorly oxygenated (hypoxic) because of blood perfusion and diffusion limitations,62 intermittent blood flow in the tumor microcirculation,63 and the occurrence of anemia in cancer patients (reduced hemoglobin indicates reduced oxygen levels).64,65 In fact, radiation therapy itself usually induces anemia, which is associated with a poor prognosis in cancer patients.66 Melatonin stimulates platelet production (thrombopoiesis)67 and has been shown to effectively treat cancer patients with low platelet counts and anemia.68

Moreover, melatonin has an anti-serotonergic effect, which means that it may block the inhibition of blood flow by serotonin.26 This consequently may increase blood flow and allow restoration of the microcirculation, which is compromised in the tumor microenvironment.69 Melatonin may improve the blood supply to the tumor, increasing tumor oxygen levels and thus increasing radiation-induced tumor cell death (by overcoming radio-resistance).70 In addition, melatonin is lipid soluble and can presumably cross the blood-tumor barrier as it does the blood-brain barrier.71 Melatonin may further increase the delivery of radiation (and chemotherapeutic drugs) to poorly oxygenated regions within the tumor microenvironment, consequently increasing the effectiveness of these anti-cancer modalities. Radiation, which frequently causes inflammation of the mucosa (mucositis), may substantially reduce melatonin levels in the body13 by damaging the mucosa of the gastrointestinal tract where melatonin is known to be localized.26

A radioneuroendocrine approach utilizing radiotherapy with melatonin supplementation in brain glioblastoma patients showed that the likelihood of survival at one year was significantly higher in those who received melatonin with radiotherapy versus radiotherapy alone.12 It recently has been suggested that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia.72 Therefore, melatonin supplementation may prolong the survival of patients undergoing radiotherapy.3 Melatonin also may provide relief from the inherent detrimental side effects of radiation treatment73 (including toxicity to the heart, kidneys, and nerves—cardiotoxicity, nephrotoxicity, and neurotoxicity, respectively), immune suppression, pain, anemia, fatigue, and sleep disturbances.12 Melatonin is a safe and effective facilitator of tissue repair processes, required for recovery from radiation-induced injury,74 and thus offers a promising co-treatment approach for patients undergoing radiation therapy for cancer.

Summary of Studies Using Melatonin
Lissoni’s Phase II Randomized Clinical Trial Results


One-Year Survival


Tumor Type

Patient Number

Basic Therapy

Melatonin Dose



Level Of Significance

Metastatic Non- Small-Cell Lung



20 mg

5-year survival 6%

5-year survival 0%


Metastatic Non- Small-Cell Lung


Supportive Care Only

10 mg

5-year survival 6%

Under 1%




Conventional Radiotherapy

10 mg


Under 1%


Metastatic Breast



20 mg




Brain Metastases


Conventional Radiotherapy

20 mg




Metastatic Colorecta



40 mg




Metastatic Non- Small-Cell Lung



40 mg




Adapted from Life Extension (March 2002). Originally compiled by Cancer Treatment Centers of America.

Melatonin and Chemotherapy
Chemotherapy, through immunosuppressive and cytotoxic actions, exerts detrimental effects on patients’ physiological anti-cancer defense mechanisms. Melatonin, by improving immune status,52,75 has been shown to prolong survival and increase performance status in those undergoing chemotherapy. In conjunction with various chemotherapy regimens, melatonin has provided patients with a significant advantage over chemotherapy alone by increasing five-year survival rates, improving quality of life, and increasing the therapeutic effectiveness of many chemotherapeutic agents,76 while lessening or eliminating their negative and potentially detrimental side effects on normal healthy cells and tissues.4,77,78 Melatonin reduced chemotherapy-induced cardiotoxicity, neurotoxicity, nephrotoxicity, thrombocytopenia (reduced platelet counts), stomatitis (inflammation of mouth), and asthenia (weakness), and improved response in cancer patients.79,80

Melatonin should be seriously considered in combination with extremely toxic chemotherapy regimes—such as anthracyclines (adriamycin),81 cyclosporine, cytarabine,78 IL-2, cisplatin,55,79 5-fluorouracil,75,82 and methotrexate78,82—to reduce the incidence of their well-established side effects,80 which include but are not limited to mucositis and heart and liver toxicity.75 Melatonin recently has been shown to prevent methotrexate-induced liver and kidney toxicity in animals.83 It should be remembered that fasting reduces melatonin levels, typically within two days,84 suggesting that nausea, vomiting, and reduced appetite—side effects of chemotherapy—may reduce melatonin levels.

Melatonin and Chronotherapy
Because of the circadian rhythm dictated by the body’s melatonin levels, some types of chemotherapy work best if administered at an appropriate time of day, and are thus termed “chronotherapy.”3 The daily rhythm of melatonin exerts a “chronobiotic” effect and, as a circadian mediator, melatonin delivers the circadian signals to melatonin targets, including the internal body clock (in the suprachiasmatic nucleus).85 Chronotherapy is associated with maximum patient tolerability, tumor susceptibility, and attempts to improve the efficacy of treatment and the quality of patients’ lives. It takes advantage of asynchronies in growth rate between normal and tumor cells that are regulated by the circadian rhythm, thus minimizing damage to the patient and maximizing drug toxicity to tumor cells.

The growth of tumor cells may intrinsically follow a tumor-specific rhythm. It may be possible to modulate this rhythm by manipulating cancer patients’ melatonin levels.86 The local effect produced on the circadian clock could thus modulate the circadian rhythm.87 Slow-growing tumors could more likely be controlled by the patients’ circadian clock, whereas fast-growing or advanced-stage tumors may have altered circadian rhythms even though they are not temporally disorganized masses. High doses of melatonin are necessary to induce a phase-shifting effect on the circadian rhythm.88 Melatonin thus may have a unique ability to control the biological clock, consequently suppressing malignant growth and increasing the efficacy of cancer therapies. Chronotherapy has been shown to increase the survival time in children with acute lymphoblastic leukemia.89

Life Extension Magazine January 2004

Melatonin and Cancer Treatment

By Eileen M. Lynch, PhD


Melatonin and Hormonal Therapy
Melatonin levels in cancer patients have been correlated with tumor aggressiveness and progression.90,91 A high percentage of women with estrogen-receptor-positive breast cancer have low plasma melatonin levels.92 Conversely, melatonin inhibits human breast cancer cell growth45 and reduces tumor spread and invasiveness in vitro.48 Indeed, it has been suggested that melatonin acts as a naturally occurring anti-estrogen on tumor cells, as it down-regulates hormones responsible for the growth of hormone-dependent mammary tumors.93

Melatonin differs from the classic anti-estrogens such as tamoxifen in that it does not seem to bind to the estrogen receptor or interfere with the binding of estradiol to its receptor.94 Moreover, melatonin can increase the therapeutic efficacy of tamoxifen95 and biological therapies such as IL-2.96 How melatonin interferes with estrogen signaling is unknown, though recent studies suggest that it acts through a cyclic adenosine monophosphate (cAMP)-independent signaling pathway.93 It has been proposed that melatonin suppresses the epidermal growth factor receptor3 and exerts its anti-proliferative effects by inducing differentiation97 as proposed for melanoma cells.98

Regardless of the mechanism, in tumorigenesis studies melatonin reduced the incidence and growth rate of breast tumors and slowed breast cancer development.99 Furthermore, prolonged oral melatonin administration significantly reduced the development of existing mammary tumors in animals.100 In a metastatic hormone-refractory prostate cancer patient, oral melatonin (5 mg/day) induced disease stabilization for six weeks.44

Melatonin Dosage for Cancer Patients

While the optimal dose of melatonin for treating different types of cancer has not yet been established, the many clinical studies by Lissoni and colleagues have shown that doses of 10-50 mg of melatonin nightly are beneficial to cancer patients.

Those recently diagnosed with slow-growing or early-stage cancer may wish to consider supplementing with 3 to 6 mg melatonin nightly; the latter dose may be reserved for early-stage cancer patients who suffer from disturbed sleep patterns. Because most clinical studies have shown that patients with late-stage, advanced, or untreatable cancer, or those with cancer metastasis, benefit from supplementation with 20 mg of melatonin, such patients may wish to consider supplementing with between 6 and 50 mg of melatonin nightly, depending on plasma melatonin levels.

Physicians should be strongly encouraged to prescribe substitutional melatonin therapy to cancer patients with depressed melatonin levels.

Night Light, Melatonin, Meditation, and Cancer Incidence
Low levels of melatonin have been associated with breast cancer occurrence and development. Women who work predominantly at night and are exposed to light, which inhibits melatonin production and alters the circadian rhythm, have an increased risk of breast cancer development.101 In contrast, higher melatonin levels have been found in blind and visually impaired people, along with correspondingly lower incidences of cancer compared to those with normal vision, thus suggesting a role for melatonin in the reduction of cancer incidence.102

Light at night, regardless of duration or intensity, inhibits melatonin secretion and phase-shifts the circadian clock, possibly altering the cell growth rate that is regulated by the circadian rhythm.103 Disruption of circadian rhythm is commonly observed among cancer patients104,105 and contributes to cancer development and tumor progression.106 Cancer alters neuroendocrine system function in such a way that melatonin levels are lower in patients with non-small-cell lung cancer.107 Indeed, the circadian rhythm of melatonin is also altered in advanced gastrointestinal malignancies, such as colorectal, gastric, and pancreatic cancer, with respect to healthy humans.108

Deregulation of many circadian clock functions in the human body—including blood pressure, temperature, hormones, sleep-wake pattern, immune function, and digestive activity—has been used as an independent prognostic factor of survival time and tumor response for patients with certain metastatic cancers.109 The circadian rhythm alone is a statistically significant predictor of survival time for breast cancer patients.110

Several studies have shown that the circadian clock is involved in tumor suppression at the systemic, cellular, and molecular levels, and that cancer should no longer be treated as a local disorder. For instance, the circadian clock regulates the immune response. Disruption of circadian rhythms could therefore lead to immunosuppression, which could disrupt cancer cell immunosurveillance and promote tumor development; however, melatonin as a circadian mediator can target the endogenous clock86 and has been shown to inhibit immunosuppression.111

The phenomenon of light at night regulating melatonin levels may explain the spontaneous tumor regression reported to occur through meditation alone in cancer patients (when the eyes are closed and detect no light).112-114 The regular practice of meditation is associated with increased physiological levels of melatonin.115,116

Pharmacological doses of supplemental melatonin can resynchronize individuals shown to have disrupted circadian rhythms,36,117 such as night-shift workers.118 Thus, cancer patients with endogenously depressed melatonin levels may benefit from both meditation and substitutional melatonin therapy, to improve quality of life119 while potentially inhibiting tumor growth and spread.

Melatonin and Advanced Cancer
Numerous clinical studies by Lissoni and colleagues have shown that melatonin adjuvant therapy favorably influences the course of advanced cancer, leading to an improved quality of life and increased survival.17,21 In cancer patients with untreatable advanced solid tumors, melatonin significantly lowered the frequency of catabolic wasting (cachexia), weakness (asthenia), low platelet (thrombocytopenia), and white blood cell counts (lymphocytopenia) compared to patients who received supportive care only. Melatonin improved disease stabilization and increased survival percentages at one and five years.4,21

Melatonin deficiencies in advanced cancer patients may be due to altered circadian rhythm (disturbed sleep patterns), cancer-related anorexia-cachexia, and reduced food intake as melatonin is produced by the enterochromaffin cells in the gastrointestinal tract in response to feeding.25 Melatonin supplementation in turn increases appetite,26 diminishes tissue wasting,21,46 and restores sleep continuity in those with cancer.5,71,120 Administration of melatonin to patients with advanced cancer who have only short expected survival times results in some cases in disease stabilization and improvement of performance status.17,43,119

Melatonin Supplementation and Cancer
Extrapolating the reduced melatonin levels observed in aging humans121,122 to the cellular level, one might expect to find less melatonin at the cellular level in tumors32,107 compared to normal healthy cells if tumor cells “age” (because of their increased growth rate) more rapidly than normal healthy cells. The potentially lower melatonin levels in tumor cells could possibly be normalized by melatonin supplementation, which in turn would be expected to lead to a negative growth advantage in the tumor microenvironment and therefore inhibit tumor growth. Melatonin levels are depressed in individuals with cancers of different origins during the phase of primary tumor growth,110 whereas normal melatonin levels may be found when remission occurs.123

Life Extension Magazine January 2004

Melatonin and Cancer Treatment

By Eileen M. Lynch, PhD


In summary, results of the numerous clinical studies in patients undergoing standard anticancer therapies—including chemotherapy, immuno-hormonal therapy, radiation therapy, and cancer surgery—suggest that individuals with cancer should consider melatonin supplementation under a physician’s supervision. While melatonin may be obtained through diet and enter the bloodstream, sources of natural melatonin production, such as food intake, gastrointestinal bacteria, and bile, may be reduced in cancer patients. Taken together, these factors, in conjunction with the short half-life of melatonin, provide a good basis for recommending melatonin supplementation as an adjuvant therapy for cancer.

With the current level of evidence on the multidisciplinary anticancer actions of melatonin, Life Extension believes that physicians should be strongly encouraged to prescribe melatonin to patients with certain tumor types on diagnosis or during early stages of tumor development. Continued research and clinical trials are imperative to further define melatonin’s role in the management of cancer’s physical and psychological symptoms and in the adjuvant treatment of cancer patients. Sadly, due to a lack of commercial opportunities, we are unlikely to see further clinical trials with melatonin in the US, other than those sponsored by foundations such as Life Extension.

Much remains to be learned about how practical therapeutics will be achieved with melatonin supplementation. Despite the many practical hurdles to the use of melatonin in the adjuvant treatment of cancer patients, particularly in the US, we remain hopeful that the overwhelming proof of melatonin’s efficacy will eventually drive its use in clinical applications.

Contraindications and Dosage
One study reported no contraindications to melatonin use.158 Because of unknown risk, pregnant and nursing women should take melatonin only under the close supervision of a physician or not at all.158 Some researchers have suggested that people with allergies, asthma, autoimmune diseases, and immune-system cancers, such as leukemia and lymphoma, should use melatonin with caution. Clinical studies have shown, however, that in leukemia and lymphoma patients, simultaneous administration of melatonin with IL-2 is beneficial in providing disease stabilization and in prolonging survival time.53

Who’s at Risk for Melatonin Deficiency?

  • Apart from those confronted with cancer, melatonin-deficient individuals may include:
  • the elderly, geriatrics, and those with age-related disease117,139,145
  • shift workers, individuals exposed to light at night, and insomniacs39,146
  • airline pilots, flight attendants, and frequent transcontinental flyers 6,147
  • individuals with occupations involving high electromagnetic field exposure, including telephone or electric-line workers148
  • those with pineal disease,149 pinealectomised individuals (those without a pineal gland),150 or those with suprachiasmatic nucleus involvement117
  • quadriplegics151
  • post-gastric26 or post-spinal-cord surgery patients151,152
  • anorexics, bulimics, and those with poor appetite or subject to frequent vomiting136 or with irritable bowel syndrome, diarrhea, or ulcerative colitis25
  • individuals undergoing total parenteral nutrition (intravenous nutrition),153 and those who fast chronically84
  • those who suffer from delayed sleep phase syndrome, circadian rhythm variations, fibromyalgia, depression, or anxiety (treated by benzodiazepines)72,136, 154
  • females who suffer cramping (uterine contractile disturbances) associated with menstruation,30 as melatonin has been shown to block prostaglandin production155 and depress spontaneous uterine contractility156
  • individuals on blood pressure medication, such as beta-blockers, statins, or calcium channel blockers.157 Most medications prescribed to lower blood pressure also inadvertently reduce serum melatonin levels, including beta-blockers, calcium channel blockers, and calcium antagonists. An estimated 40% of individuals who take beta-blockers have sleep disorders that may be easily remedied by taking melatonin. It has been suggested that, in clinical trials, melatonin should be combined with statins to reduce the free-radical-mediated side effects of these cholesterol-lowering drugs.158

Studies in humans have shown melatonin toxicity to be remarkably low with no serious negative side effects even at high doses (3 to 6.6 g) administered over a period of 35 days.159,160 Nevertheless, minor reactions to melatonin supplementation such as sleepiness, vivid dreams, headache, abdominal pain, and nausea have been reported to occur occasionally in a small proportion of individuals.158 Excess melatonin production has rarely been seen except in polycystic ovary disease.161 More recently, an observational study found elevated serum melatonin levels in individuals with nocturnal asthma.162

Sources of Melatonin
Melatonin is present in all living organisms, including microalgae (green algae), bacteria, fungi, plants, small crustaceans (certain prawns and crayfish), fish, animals, and humans.163 Natural sources of melatonin, not standardized to provide a defined concentration, and with possible contaminants, also include medicinal plants such as feverfew (Tanacetum parthenium), St. John’s wort (Hypericum perforatum), and huang-qin (Scutellaria baicalensis),122,164 sometimes reaching levels of several nanograms per gram165 and possibly contributing to the therapeutic efficacy of the respective herbs.

High melatonin concentrations are found in seeds and some fruits such as tart cherries, bananas, and tomatoes.166,167 Melatonin also is found in food sources such as oats, rice bran, sweet corn, wheatgrass juice, and ginger. It has been shown that dietary melatonin (from plant sources) directly elevates the circulating level of melatonin in the body,168 as does smoking marijuana.169

The building blocks for natural melatonin production in the body include sufficient amounts of vitamin B6, vitamin B3 (niacinamide), and most important, the amino acid tryptophan, which is found in high quantities in foods such as nuts (soy, almonds, and peanuts,), seeds (pumpkin and watermelon), spirulina, beans, and tofu.

Who Should Supplement with Melatonin?

Melatonin is widely accepted for the treatment of sleep disorders and circadian rhythm disturbances,132,133 and is particularly effective for certain types of insomnia and sleep disorders in the elderly.134 Melatonin can facilitate the discontinuation of commonly prescribed sleeping medications, such as benzodiazepine therapy.135, 136 The “chronobiotic” effect of melatonin has been used to help re-synchronize individuals shown to have disrupted circadian rhythms (for example, blind people),88 in “delayed sleep phase” syndrome, night-shift work, and jet lag.118 In fact, the best clinical indication for melatonin is for alleviating jet-lag symptoms, particularly if taken at the bedtime of the arrival destination.118 In children, melatonin has been reported to be beneficial for treating colic, diarrhea, sepsis,50 and asphyxia.71,137

  • In advanced age, melatonin supplementation should be considered for the following reasons:
  • Melatonin production declines with age,121 and it has been shown that the aged have lower blood levels of melatonin. Elderly women have higher levels of melatonin compared to elderly men, which may be one reason why women live longer than men.
  • Aged individuals with early neuropathological changes in the temporal cortex, where the Alzheimer’s disease process starts, have lower cerebrospinal fluid levels of melatonin.138
  • The preventive antioxidant activity of melatonin may counteract free-radical-mediated degenerative diseases typical of the aged.139-141 Melatonin has been shown to be beneficial in the treatment of Alzheimer’s disease.142,143
  • If aging is indeed a consequence of accumulated free radical damage, then the unique electro-reactive properties and intracellular distribution of melatonin should be advantageous in deferring the signs of aging.117
  • Melatonin has beneficial effects on sleep disorders,144 which frequently afflict the aged.134

Melatonin Availability
Melatonin is available either as an over-the-counter drug or food supplement in the US, Argentina, Poland, and China. Although theLife Extension Foundation’s melatonin supplements are not registered as drugs, their purity has been certified and verified by an independent laboratory for the purposes of the ongoing lung cancer clinical trial. Unfortunately, this is not the case with many of the other readily available melatonin supplements, as certification is not mandated for food substances or additives.

For now, melatonin remains a relatively inexpensive nutritional supplement not yet controlled by the FDA or any other corporate or regulatory body. Interestingly, there has been mention of categorizing melatonin as a vitamin, which could be beneficial in compelling the medical establishment to finally recognize its importance. On the other hand, many pharmaceutical companies have started to patent therapeutic uses of melatonin: a Dutch company has patented a composition for intranasal melatonin administration, a French company has patented a melatonin agonist for the purpose of treating depression and sleep disorders, and an Israeli company has patented a method for treating or preventing symptoms of tardive dyskenisia by melatonin administration.

When to Take Melatonin
Melatonin should probably be taken 30 minutes to one hour before sleeping. Slow-release melatonin preparations may benefit those with various types of insomnia, as the oral bioavailability of melatonin is approximately 15%.170 Exposure to light at night, however, regardless of the duration or intensity of the light, can fully suppress or decrease melatonin levels.171

Life Extension Magazine January 2004

Melatonin and Cancer Treatment

By Eileen M. Lynch, PhD


Reprint of a letter from Cancer Treatment Centers of America

November 6, 2003

Mr. William Faloon
Life Extension Foundation
3600 West Commercial Blvd.
Fort Lauderdale, FL 33309

Re: Status of Protocol CTCA 01-07: A Multi-Center Randomized, Double-Blind, Trial Evaluating the Chronotherapeutic Role of Melatonin in the Treatment of Stage IIIB and IV Non-Small Cell Lung Carcinoma

Dear Mr. Faloon:

On behalf of Cancer Treatment Centers of Americaâ, I’d like to take this opportunity to say “thank you” for your donation of the thousands of capsules of melatonin for our clinical trial investigating the effects of melatonin, given at the appropriate circadian phase, in patients with non-small cell lung cancer. Indeed, the support of the Life Extension Foundation has made this landmark study possible. I’d also like to take a moment to update you on the progress of our study.

Our participating centers have enrolled thirty-one (31) patients onto the trial since December 2002, and we are looking forward to a steady increase in the number of patients enrolled in the foreseeable future.

To implement this program, your donation of high quality 20 mg doses of melatonin saved us considerable expense and effort. As you know, both federal and local IRB regulations require that we obtain an independent assay of any chemical agent that will be used in a human clinical trial. To fulfill these requirements, randomly selected capsules of melatonin and placebos were sent for analysis (HPLC and gas chromatography) to the Roswell Park Cancer Institute (an National Cancer Institute-Designated Comprehensive Cancer Center). As expected, the Life Extension Foundation’s products achieved all specifications on purity and dose.

Your product donations are now helping us discover more about the role of melatonin in cancer treatment. Indeed, this will be the first prospective randomized cancer clinical trial in the United States to investigate: (1) whether lung cancer patients produce a nocturnal pulse of melatonin prior to therapy; (2) what fraction of patients with advanced lung cancer suffer abnormalities in their circadian activity/rest rhythm, and 3) whether or not melatonin therapy, delivered at the appropriate circadian phase, improves the quality of life and overall survival of NSC lung cancer patients.

Thank you once again for Life Extension Foundation’s continued and generous support. We look forward to keeping you updated on the progress of this landmark investigation.

Best Wishes,

Christopher G. Lis, MPH
Vice President
Research and Development


1. Sandyk R. Possible role of pineal melatonin in the mechanisms of aging. Int J Neurosci. 1990;52:85-92.

2. Dilman VM, Anisimov VN, Ostroumova MN, Khavinson VK, Morozov VG. Increase in lifespan of rats following polypeptide pineal extract treatment. Exp Pathol Jena. 1979;17:539-545.

3. Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: Cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Topics in Med Chem. 2002;2:113-132.

4. 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;35:12-15.

5. Cajochen C, Krauchi K, Wirz-Justice A. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrin. 2003;15:432-437

6. Herxheimer A, Petrie KJ. Melatonin for preventing and treating jet lag. Cochrane Database Syst Rev. 2001;1:CD001520.

7. Winczyk K, Pawlikowski M, Guerrero JM, Karasek M. Possible involvement of the nuclear rzr/ror-alpha receptor in the antitumor action of melatonin on murine colon 38 cancer. Tumour Biology. 2002;23:298-302.

8. Scott AE, Cosma GN, Frank AA, Wells RL, Gardner HS, Jr. Disruption of mitochondrial respiration by melatonin in mcf-7 cells. Toxicol & Applied Pharmacol. 2001;171:149-156.

9. Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F. Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Can & Clin Onc. 1989;25:789-795.

10. Neri B, de Leonardis V, Gemelli MT, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res. 1998;18:1329-1332.

11. Lissoni P, Barni S, Ardizzoia A, et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology. 1992;49:336-339.

12. Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology (Huntington). 1996;53:43-46.

13. Karbownik M, Reiter RJ. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med. 2000;225:9-22.

14. Lissoni P, Brivio F, Brivio O, et al. Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients. J Biol Regulators & Homeostatic Agents. 1995;9:31-33.

15. Lissoni P, Brivio O, Brivio F, et al. Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma. J Pineal Res. 1996;21:239-242.

16. Inui A. Cancer anorexia-cachexia syndrome: Current issues in research and management. CA: Cancer Journal for Clinicians. 2002;52:72-91.

17. Lissoni P, Barni S, Tancini G, et al. Clinical study of melatonin in untreatable advanced cancer patients. Tumori. 1987;73:475-480.

18. Vijayalaxmi, Thomas CR Jr, Reiter RJ, Herman TS. Melatonin: From basic research to cancer treatment clinics. [review]. J Clin Oncol. 2002;20:2575-2601.

19. Barni S, Lissoni P, Paolorossi F, Crispino S, Archili C, Tancini G. A study of the pineal hormone melatonin as a second line therapy in metastatic colorectal cancer resistant to fluorouracil plus folates. Tumori. 1990;76:58-60.

20. Ghielmini M, Pagani O, de Jong J, et al. Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer. Br J Cancer 1999; 80:1058-1061.

21. Lissoni P. Is there a role for melatonin in supportive care? Supportive Care in Cancer. 2002;10:110-116.

22. Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer. 1994;73:699-701.

23. Simonneaux V, Ribelayga C. Generation of the melatonin endocrine message in mammals: A review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Pharmacol Rev. 2003;55:325-395.

24. Kvetnoy I. Extrapineal melatonin in pathology: New perspectives for diagnosis, prognosis and treatment of illness. Neuroendocrinol Lett. 2002;23:92-96

25. Bubenik GA. Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. Biol Signals & Receptors. 2001;10:350-366.

26. Bubenik GA. Gastrointestinal melatonin: Localization, function, and clinical relevance. Digest Dis & Sci. 2002;47:2336-2348.

27. Weaver DR, Reppert SM. The mel1a melatonin receptor gene is expressed in human suprachiasmatic nuclei. Neuroreport. 1996;8:109-112.

28. Ekmekcioglu C, Haslmayer P, Philipp C, et al. Expression of the mt1 melatonin receptor subtype in human coronary arteries. J Recept Signal Transduct Res. 2001;21:85-91.

29. Woo MM, Tai CJ, Kang SK, Nathwani PS, Pang SF, Leung PC. Direct action of melatonin in human granulosa-luteal cells. J Clin Endocrinol Metab. 2001;86:4789-4797.

30. Schlabritz-Loutsevitch N, Hellner N, Middendorf R, Muller D, Olcese J. The human myometrium as a target for melatonin. J Clin Endocrinol Metab. 2003;88:908-913.

31. Klein DC. Evidence for the placental transfer of 3 h-acetyl-melatonin. Nat New Biol. 1972;237:117-118

32. Grin W, Grunberger W. A significant correlation between melatonin deficiency and endometrial cancer. Gyn & Obst Invest. 1998;45:62-65.

33. Khoory R, Stemme D. Plasma melatonin levels in patients suffering from colorectal carcinoma. J Pineal Res. 1988;5:251-258.

34. Barni S, Lissoni P, Crispino S, et al. Neuroimmunomodulation in cancer patients: Correlations between melatonin and beta-endorphin blood levels and t helper/suppressor ratio. Int J Biol Markers. 1988;3:82-86.

35. Dawson D, Gibbon S, Singh P. The hypothermic effect of melatonin on core body temperature: Is more better? J Pineal Res. 1996;20:192-197.

36. Kumar V. Melatonin: A master hormone and a candidate for universal panacea. Indian J Exp Biol. 1996;34:391-402.

37. Fowler G, Daroszewska M, Ingold KU. Melatonin does not “directly scavenge hydrogen peroxide”: Demise of another myth. Free Radic Biol Med. 2003;34:77-83.

38. Antunes F, Barclay LR, Ingold KU, et al. On the antioxidant activity of melatonin. Free Radic Biol Med. 1999;26:117-128.

39. Anisimov VN. The light-dark regimen and cancer development. Neuroendocrinology Letters. 2002;23:28-36.

40. Karbownik M, Reiter RJ. Melatonin protects against oxidative stress caused by delta-aminolevulinic acid: Implications for cancer reduction. Cancer Investigation. 2002;20:276-286.

41. Riabykh TP, Nikolaeva TG, Bodrova NB. Effects of biorhythm regulator melatonin on DNA synthesis in short-term cultures of human malignant tumors. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk. 2000:30-33.

42. Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ. Melatonin and cell death: Differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci. 2003;60:1407-1426

43. Lissoni P, Barni S, Cattaneo G, et al. Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology. 1991;48:448-450.

44. Shiu SY, Law IC, Lau KW, Tam PC, Yip AW, Ng WT. Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed mt1 receptor subtype. J Pineal Res. 2003;35:177-182.

45. Cos S, Sanchez-Barcelo EJ. Melatonin, experimental basis for a possible application in breast cancer prevention and treatment. Histology & Histopathology. 2000;15:637-647.

46. Mantovani G, Maccio A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs. 2001;61:499-514.

47. Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A, Maestroni GJ. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuroendocrinol Lett. 2001;22:45-47.

48. Cos S, Fernandez R, Guezmes A, Sanchez-Barcelo EJ. Influence of melatonin on invasive and metastatic properties of mcf-7 human breast cancer cells. Cancer Research. 1998;58:4383-4390.

49. Srinivasan V. Melatonin oxidative stress and neurodegenerative diseases. Indian J Expt Biol. 2002;40:668-679.

50. Gitto E, Karbownik M, Reiter RJ, et al. Effects of melatonin treatment in septic newborns. Pediatr Res. 2001;50:756-760.

51. Lissoni P, Giani L, Zerbini S, Trabattoni P, Rovelli F. Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe vera in untreatable advanced solid neoplasms. Natural Immunity. 1998;16:27-33.

52. Currier NL, Sun LZ, Miller SC. Exogenous melatonin: Quantitative enhancement in vivo of cells mediating non-specific immunity. J of Neuroimmun. 2000;104:101-108.

53. Lissoni P, Bolis S, Brivio F, Fumagalli L. A phase ii study of neuroimmunotherapy with subcutaneous low-dose il-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies. Antican Res. 2000;20:2103-2105.

54. Maestroni GJ. Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer. Adv Expt Med & Biol. 1999;467:217-226.

55. Lissoni P, Malugani F, Bukovec R, et al. Reduction of cisplatin-induced anemia by the pineal indole 5-methoxytryptamine in metastatic lung cancer patients. Neuroendocrinol Lett. 2003;24:83-85.

56. Raghavendra V, Agrewala JN, Kulkarni SK. Melatonin reversal of lipopolysacharides-induced thermal and behavioral hyperalgesia in mice. Eur J Pharmacol. 2000;395:15-21.

57. Shaji AV, Kulkarni SK. Central nervous system depressant activities of melatonin in rats and mice. Indian J Exp Biol. 1998;36:257-263.

58. Bruera E, Neumann CM. The uses of psychotropics in symptom management in advanced cancer. Psycho-Oncology. 1998;7:346-358.

59. Lissoni P, Rovelli F, Meregalli S, et al. Melatonin as a new possible anti-inflammatory agent. J Biol Regulators & Homeostatic Agents. 1997;11:157-159.

60. Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX. Melatonin and its relation to the immune system and inflammation. Ann N Y Acad Sci. 2000;917:376-386.

61. Reiter RJ, Tan DX. Melatonin: A novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res. 2003;58:10-19.

62. Vaupel P, Kelleher DK, Hockel M. Oxygen status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol. 2001;28:29-35.

63. Hill SA, Pigott KH, Saunders MI, et al. Microregional blood flow in murine and human tumours assessed using laser doppler microprobes. Br J Cancer Suppl. 1996;27:S260-263.

64. Auclerc G, Meric JB, Pommeyrol A, Rixe O, Khayat D. Anemia in cancer patients before treatment. Bull Cancer. 2003;90 Spec No:S128-132.

65. Thomas GM. Raising hemoglobin: An opportunity for increasing survival? Oncology. 2002;63 Suppl 2:19-28.

66. Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist. 2002;7:492-508.

67. Lissoni P, Bucovec R, Bonfanti A, et al. Thrombopoietic properties of 5-methoxytryptamine plus melatonin versus melatonin alone in the treatment of cancer-related thrombocytopenia. J Pineal Res. 2001;30:123-126.

68. Lissoni P, Cazzaniga M, Tancini G, et al. Reversal of clinical resistance to lhrh analogue in metastatic prostate cancer by the pineal hormone melatonin: Efficacy of lhrh analogue plus melatonin in patients progressing on lhrh analogue alone. Eur Urology. 1997;31:178-181.

69. Vaupel P, Hockel M. Blood supply, oxygenation status and metabolic micromilieu of breast cancers: Characterization and therapeutic relevance. Int J Oncol. 2000;17:869-879.

70. Hockel M, Schlenger K, Mitze M, Schaffer U, Vaupel P. Hypoxia and radiation response in human tumors. Semin Radiat Oncol. 1996;6:3-9.

71. Bubenik GA, Blask DE, Brown GM, et al. Prospects of the clinical utilization of melatonin. Biol Signals & Receptors. 1998;7:195-219.

72. Delagrange P, Atkinson J, Boutin JA, et al. Therapeutic perspectives for melatonin agonists and antagonists. J Neuroendocrin. 2003;15:442-448.

73. Jatoi A, Thomas CR, Jr. Esophageal cancer and the esophagus: Challenges and potential strategies for selective cytoprotection of the tumor-bearing organ during cancer treatment. Semin Radiat Onc. 2002;12:62-67.

74. Sorenson JR. Cu, fe, mn, and zn chelates offer a medicinal chemistry approach to overcoming radiation injury. Curr Med Chem. 2002;9:639-662.

75. Lissoni P, Tancini G, Barni S, et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Supportive Care in Cancer. 1997;5:126-129.

76. Cerea G, Vaghi M, Ardizzoia A, et al. Biomodulation of cancer chemotherapy for metastatic colorectal cancer: A randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. Anticancer Res. 2003;23:1951-1954.

77. Granzotto M, Rapozzi V, Decorti G, Giraldi T. Effects of melatonin on doxorubicin cytotoxicity in sensitive and pleiotropically resistant tumor cells. J Pineal Res. 2001;31:206-213.

78. Reiter RJ, Tan DX, Sainz RM, Mayo JC, Lopez-Burillo S. Melatonin: Reducing the toxicity and increasing the efficacy of drugs. J Pharm & Pharmacol. 2002;54:1299-1321.

79. Lissoni P, Vaghi M, Ardizzoia A, et al. A phase ii study of chemoneuroimmunotherapy with platinum, subcutaneous low-dose interleukin-2 and the pineal neurohormone melatonin (p.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. In Vivo. 2002;16:93-96.

80. Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Can. 1999;35:1688-1692.

81. Rapozzi V, Zorzet S, Comelli M, Mavelli I, Perissin L, Giraldi T. Melatonin decreases bone marrow and lymphatic toxicity of adriamycin in mice bearing tlx5 lymphoma. Life Sci. 1998;63:1701-1713.

82. Kajdaniuk D, Marek B, Kos-Kudla B. Influence of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil on plasma melatonin and chosen hormones in breast cancer premenopausal patients. J Clin Pharm & Therap. 2001;26:297-301.

83. Jahovic N, Cevik H, Sehirli AO, Yegen BC, Sener G. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res. 2003;34:282-287.

84. Bogdan A, Bouchareb B, Touitou Y. Ramadan fasting alters endocrine and neuroendocrine circadian patterns. Meal-time as a synchronizer in humans? Life Sci. 2001;68:1607-1615.

85. Vanecek J. Cellular mechanisms of melatonin action. Physiol Rev. 1998;78:687-721.

86. Pevet P, Bothorel B, Slotten H, Saboureau M. The chronobiotic properties of melatonin. Cell Tissue Res. 2002;309:183-191.

87. McArthur AJ, Gillette MU, Prosser RA. Melatonin directly resets the rat suprachiasmatic circadian clock in vitro. Brain Res. 1991;565:158-161.

88. Deacon S, Arendt J. Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans. Brain Res. 1995;688:77-85.

89. Fu L, Lee CC. The circadian clock: Pacemaker and tumour suppressor. Nat Rev Cancer. 2003;3:350-361.

90. Kajdaniuk D, Marek B, Kos-Kudla B, et al. Does the negative correlation found in breast cancer patients between plasma melatonin and insulin-like growth factor-i concentrations imply the existence of an additional mechanism of oncostatic melatonin influence involved in defense?[comment]. Med Sci Monitor. 2002;8:CR457-461.

91. Callaghan BD. Does the pineal gland have a role in the psychological mechanisms involved in the progression of cancer? Medical Hypotheses. 2002;59:302-311.

92. Brzezinski A. Melatonin in humans. New Eng J Med. 1997;336:186-195.

93. Torres-Farfan C, Richter HG, Rojas-Garcia P, al. e. Mt1 melatonin receptor in the primate adrenal gland: Inhibition of adrenocorticotropin-stimulated cortisol production by melatonin. J Clin Endocrinol Metab. 2003;88:450-458.

94. Sanchez-Barcelo EJ, Cos S, Fernandez R, Mediavilla MD. Melatonin and mammary cancer: A short review. Endocr Relat Cancer. 2003;10:153-159.

95. Lissoni P, Barni S, Meregalli S, et al. Modulation of cancer endocrine therapy by melatonin: A phase ii study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer. 1995;71:854-856.

96. Lissoni P, Barni S, Tancini G, et al. Role of the pineal gland in the control of macrophage functions and its possible implication in cancer: A study of interactions between tumor necrosis factor-alpha and the pineal hormone melatonin. J Biol Regul & Homeostatic Agents. 1994;8:126-129.

97. Cos S, Verduga R, Fernandez-Viadero C, Megias M, Crespo D. Effects of melatonin on the proliferation and differentiation of human neuroblastoma cells in culture. Neurosci Lett. 1996;216:113-116.

98. Souza AV, Visconti MA, De Lauro Castrucci AM. Melatonin biological activity and binding sites in human melanoma cells. J Pineal Res. 2003;34:242-248.

99. Subramanian A, Kothari L. Suppressive effect by melatonin on different phases of 9,10-dimethyl-1,2-benzanthracene (dmba)-induced rat mammary gland carcinogenesis. Anticancer Drugs. 1991;2:297-303.

100. Rao GN, Ney E, Herbert RA. Effect of melatonin and linolenic acid on mammary cancer in transgenic mice with c-neu breast cancer oncogene. Breast Cancer Res & Treat. 2000;64:287-296.

101. Schernhammer ES, Laden F, Speizer FE, et al. Night-shift work and risk of colorectal cancer in the nurses’ health study. J Natl Cancer Inst. 2003;95:825-828.

102. Feychting M, Osterlund B, Ahlbom A. Reduced cancer incidence among the blind.[comment]. Epidemiology. 1998;9:490-494.

103. Travlos GS, Wilson RE, Murrell JA, Chignell CF, Boorman GA. The effect of short intermittent light exposures on the melatonin circadian rhythm and nmu-induced breast cancer in female f344/n rats. Toxicologic Pathology. 2001;29:126-136.

104. Mormont MC, Levi F. Circadian-system alterations during cancer processes: A review. Int J Cancer. 1997;70:241-247.

105. Roenneberg T, Lucas RJ. Light, endocrine systems, and cancer--a view from circadian biologists. Neuroendocrinol Lett. 2002;23 Suppl 2:82-83.

106. Schernhammer ES, Laden F, Speizer FE, et al. Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study.[comment]. J Natl Cancer Inst. 2001;93:1563-1568.

107. Mazzoccoli G, Carughi S, De Cata A, et al. Neuroendocrine alterations in lung cancer patients. Neuroendocrinol Lett. 2003;24:77-82.

108. Muc-Wierzgon M, Nowakowska-Zajdel E, Zubelewicz B, et al. Circadian fluctuations of melatonin, tumor necrosis factor-alpha and its soluble receptors in the circulation of patients with advanced gastrointestinal cancer. J Exp Clin Cancer Res. 2003;22:171-178.

109. Mormont MC, Waterhouse J, Bleuzen P, et al. Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clin Cancer Res. 2000;6:3038-3045.

110. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92:994-1000

111. Lissoni P, Mandala M, Brivio F. Abrogation of the negative influence of opioids on il-2 immunotherapy of renal cell cancer by melatonin. Eur Urology. 2000;38:115-118.

112. Meares A. Regression of cancer after intensive meditation. Med J Australia. 1976;2:184.

113. Meares A. Regression of cancer of the rectum after intensive meditation. Med J Australia. 1979;2:539-540.

114. Meares A. Remission of massive metastastis from undifferentiated carcinoma of the lung associated with intensive meditation. J Am Soc Psychosomatic Dentistry & Medicine. 1980;27:40-41.

115. Massion AO, Teas J, Hebert JR, Wertheimer MD, Kabat-Zinn J. Meditation, melatonin and breast/prostate cancer: Hypothesis and preliminary data. Med Hypotheses. 1995;44:39-46.

116. Coker KH. Meditation and prostate cancer: Integrating a mind/body intervention with traditional therapies. Sem in Urol Onc. 1999;17:111-118.

117. Skene DJ, Swaab DF. Melatonin rhythmicity: Effect of age and alzheimer’s disease. Exp Gerontol. 2003;38:199-206.

118. Claustrat B, Geoffriau M, Brun J, Chazot G. Melatonin in humans: A biochemical marker of the circadian clock and an endogenous synchronizer. Neurophysiol Clin. 1995;25:351-359.

119. Bartsch C, Bartsch H, Karasek M. Melatonin in clinical oncology. Neuroendocrinology Letters. 2002;23:30-38.

120. Etzioni A, Luboshitzky R, Tiosano D, Ben-Harush M, Goldsher D, Lavie P. Melatonin replacement corrects sleep disturbances in a child with pineal tumor. Neurology. 1996;46:261-263.

121. Schulman C, Lunenfeld B. The ageing male. World J Urol. 2002;20:4-10.

122. Karasek M, Reiter RJ. Melatonin and aging. Neuroendocrinol Lett. 2002;23 Suppl 1:14-16

123. Bartsch C, Bartsch H, Fuchs U, Lippert TH, Bellmann O, Gupta D. Stage-dependent depression of melatonin in patients with primary breast cancer. Correlation with prolactin, thyroid stimulating hormone, and steroid receptors. Cancer. 1989;64:426-433.

124. Ying SW, Niles LP, Crocker C. Human malignant melanoma cells express high-affinity receptors for melatonin: Antiproliferative effects of melatonin and 6-chloromelatonin. Eur J Pharm. 1993;246:89-96.

125. Petranka J, Baldwin W, Biermann J, Jayadev S, Barrett JC, Murphy E. The oncostatic action of melatonin in an ovarian carcinoma cell line. J Pineal Res. 1999;26:129-136.

126. Kobayashi Y, Itoh MT, Kondo H, et al. Melatonin binding sites in estrogen receptor-positive cells derived from human endometrial cancer. J Pineal Res. 2003;35:71-74.

127. Ram PT, Yuan L, Dai J, et al. Differential responsiveness of mcf-7 human breast cancer cell line stocks to the pineal hormone, melatonin. J Pineal Res. 2000;28:210-218.

128. Marelli MM, Limonta P, Maggi R, Motta M, Moretti RM. Growth-inhibitory activity of melatonin on human androgen-independent du 145 prostate cancer cells. Prostate. 2000;45:238-244.

129. Moretti RM, Marelli MM, Maggi R, Dondi D, Motta M, Limonta P. Antiproliferative action of melatonin on human prostate cancer lncap cells. Oncology Reports. 2000;7:347-351.

130. Chuang JI, Chang TY, Liu HS. Glutathione depletion-induced apoptosis of ha-ras-transformed nih3t3 cells can be prevented by melatonin. Oncogene. 2003;22:1349-1357.

131. Guha A. Ras activation in astrocytomas and neurofibromas. Can J Neurol Sci. 1998;25:267-281.

132. Bruls E, Crasson M, Van Reeth O, Legros JJ. Melatonin. Ii. Physiological and therapeutic effects. Revue Medicale de Liege. 2000;55:862-870.

133. Cardinali DP, Brusco LI, Lloret SP, Furio AM. Melatonin in sleep disorders and jet-lag. Neuroendocrinol Lett. 2002;23:9-13.

134. Olde Rikkert MG, Rigaud AS. Melatonin in elderly patients with insomnia. A systematic review. Z Gerontol Geriatr. 2001;34:491-497.

135. Wagner J, Wagner ML, Hening WA. Beyond benzodiazepines: Alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother. 1998;32:680-691.

136. Rohr UD, Herold J. Melatonin deficiencies in women. Maturitas. 2002;41:S85-104.

137. Fulia F, Gitto E, Cuzzocrea S, et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: Reduction by melatonin. J Pineal Res. 2001;31:343-349.

138. Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF. Early neuropathological alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res. 2003;35:125-130.

139. Reiter RJ, Tan DX, Mayo JC, Sainz RM, Lopez-Burillo S. Melatonin, longevity and health in the aged: An assessment. [review] [48 refs]. Free Rad Res. 2002;36:1323-9.

140. Pappolla MA, Chyan YJ, Poeggeler B, et al. An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: Implications for alzheimer’s disease. J Neural Transm. 2000;107:203-231.

141. Raghavendra V, Kulkarni SK. Possible antioxidant mechanism in melatonin reversal of aging and chronic ethanol-induced amnesia in plus-maze and passive avoidance memory tasks. Free Radic Biol Med. 2001;30:595-602.

142. Brusco LI, Marquez M, Cardinali DP. Melatonin treatment stabilizes chronobiologic and cognitive symptoms in alzheimer’s disease. Neuroendocrinol Lett. 2000;21:39-42.

143. Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in alzheimer type dementia. J Nippon Med Sch. 2003;70:334-341.

144. Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001;86:4727-4730.

145. Monti JM, Cardinali DP. A critical assessment of the melatonin effect on sleep in humans. Biol Signals Recept. 2000;9:328-339.

146. Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int. 1992;9:380-392.

147. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;2:CD001520.

148. Caplan LS, Schoenfeld ER, O’Leary ES, Leske MC. Breast cancer and electromagnetic fields--a review. Ann of Epidemiology. 2000;10:31-44

149. Jan JE, Tai J, Hahn G, Rothstein RR. Melatonin replacement therapy in a child with a pineal tumor. J Child Neurol. 2001;16:139-140.

150. Beskonakli E, Palaoglu S, Renda N, Kulacoglu S, Turhan T, Taskin Y. The effect of pinealectomy on immune parameters in different age groups in rats: Results of the weekly alteration of the zinc level and the effect of melatonin administration on wound healing. J Clin Neurosci. 2000;7:320-324.

151. Zeitzer JM, Ayas NT, Shea SA, Brown R, Czeisler CAICCA. Absence of detectable melatonin and preservation of cortisol and thyrotropin rhythms in tetraplegia. Journal of Clinical Endocrinology & Metabolism. 2000;85:2189-2196.

152. Kneisley LW, Moskowitz MA, Lynch HG. Cervical spinal cord lesions disrupt the rhythm in human melatonin excretion. J Neural Transmission. 1978;Suppl.:311-323.

153. Volodina TV, Ol’shevskii EG, Abramov Iu V, et al. Effect of parenteral administration of melatonin on the biochemical composition of the rat granulation tissue. Vopr Med Khim. 2001;47:393-404.

154. Siegrist C, Benedetti C, Orlando A, et al. Lack of changes in serum prolactin, fsh, tsh, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients. J Pineal Res. 2001;30:34-42.

155. Gimeno MF, Landa A, Sterin-Speziale N, Cardinali DP, Gimeno AL. Melatonin blocks in vitro generation of prostaglandin by the uterus and hypothalamus. Eur J Pharmacol. 1980;62:309-317.

156. Drogovoz SM, Ryzhenko IM. The tocolytic activity of melatonin. Eksp Klin Farmakol. 1993;56:23-25

157. Cagnacci A, Arangino S, Angiolucci M, Maschio E, Melis GB. Influences of melatonin administration on the circulation of women. Am J Physiol Regul Integr Comp Physiol. 1998;274:R335-338.

158. Karasek M, Reiter RJ, Cardinali DP, Pawlikowski M. Future of melatonin as a therapeutic agent. Neuroendocrinol Lett. 2002;23:118-121.

159. Papavasiliou PS, Cotzias GC, Duby SE, Steck AJ, Bell M, Lawrence WH. Melatonin and parkinsonism. Jama. 1972;221:88-89.

160. Seabra ML, Bignotto M, Pinto LR, Jr., Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29:193-200.

161. Luboshitzky R, Qupti G, Ishay A, Shen-Orr Z, Futerman B, Linn S. Increased 6-sulfatoxymelatonin excretion in women with polycystic ovary syndrome. Fertility & Sterility. 2001;76:506-510

162. Sutherland ER, Martin RJ, Ellison MC, Kraft M. Immunomodulatory effects of melatonin in asthma. Am J Respiratory & Critical Care Med. 2002;166:1055-1061.

163. Hardeland R, Poeggeler B. Non-vertebrate melatonin. J Pineal Res. 2003;34:233-241.

164. Murch SJ, Simmons CB, Saxena PK. Melatonin in feverfew and other medicinal plants. Lancet. 1997;350:1598-1599.

165. Reiter RJ, Tan DX, Burkhardt S, Manchester LC. Melatonin in plants. Nutr Rev. 2001;59:286-290

166. Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ. Detection and quantification of the antioxidant melatonin in montmorency and balaton tart cherries (prunus cerasus). J Agric Food Chem. 2001;49:4898-4902.

167. Manchester LC, Tan DX, Reiter RJ, Park W, Monis K, Qi W. High levels of melatonin in the seeds of edible plants: Possible function in germ tissue protection. Life Sci. 2000;67:3023-3029.

168. Tan DX, Manchester LC, Hardeland R, al. e. Melatonin: A hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res. 2003;34:75-78.

169. Lissoni P, Resentini M, Mauri R, et al. Effects of tetrahydrocannabinol on melatonin secretion in man. Horm Metab Res. 1986;18:77-78.

170. Hartter S, Ursing C, Morita S, al e. Orally given melatonin may serve as a probe drug for cytochrome p450 1a2 activity in vivo: A pilot study. Clin Pharmacol Ther. 2001;70:10-16.

171. Brainard GC, Rollag MD, Hanifin JP. Photic regulation of melatonin in humans: Ocular and neural signal transduction. J Biol Rhythms. 1997;12:537-546.