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
- 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
- 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.
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 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