Long considered a jet-setter’s best friend owing to its ability to ameliorate jet lag, melatonin is synonymous in many peoples’ minds with insomnia remedies. But a growing body of science indicates that this mysterious compound, produced by nearly everything that lives, has benefits well beyond better sleep.

Recent studies have shown that supplemental melatonin can reduce tumor volume and improve survival in patients with advanced stages of breast, lung and other forms of cancer. There is also fresh data showing that it can improve overnight blood pressure control and prevent early morning pressure surges in hypertensive patients who do not show the normal nocturnal pressure drop. Advocates believe melatonin has a role to play in the management of many common diseases.

Produced by the pineal gland, melatonin (also known as N-acetyl-5-methoxytryptamine) is actually an aromatic amino acid hormone synthesized from serotonin via a dual enzyme process in the pineal. Its most obvious function is to regulate circadian rhythms and sleep cycles. In this sense, it is a “master” hormone, governing diurnal secretion of other hormones. It also plays a role in temperature regulation and immune system function.

Endogenous melatonin production rises and falls over a 25-hour daily cycle, with the peak and trough levels showing considerable individual variation. In general, production tends to decline as people age. Peak melatonin production occurs in the late teen years, and heads downhill after age 20. An individual in his or her 60s typically shows daily peaks that are half of what they were when he or she was 20 (Brzezinski A. N Engl J Med. 1997; 336: 185–195).

This relatively simple compound is one of nature’s most ubiquitous signaling molecules. “Melatonin is found in every life form on the planet. Single celled algae make it, redwood trees make it, and all forms of animal life make it,” said Tim Birdsall, ND, Vice-President for Integrative Medicine, Cancer Treatment Centers of America (www.cancercenter.com), a pioneering network of cancer centers that is knitting together conventional and holistic approaches to cancer care.

Improving Cancer Survival

Speaking at the annual meeting of the American Holistic Medical Association in Minneapolis last June, Dr. Birdsall said melatonin has become one of CTCA’s mainstay nutraceuticals for the management of patients with solid tumors, especially cancers of the lung, breast, and malignant melanomas.

“Its effect is due to modulation of cytokines. Cancer cells produce cytokines that suppress the immune system, reduce appetite, and increase metabolic rate, all of which promote both tumor growth and cachexia. Melatonin funnels the conversion of cytokines into pathways that are immune-stimulating rather than immune-suppressing. I don’t think it is a hormonal effect, but rather a cytokine effect,” explained Dr. Birdsall.

While it is certainly not a replacement for chemotherapy, radiation or other conventional cancer treatments—and Dr. Birdsall stressed that natural therapies seldom are—melatonin can definitely improve clinical outcomes and survival rates. He cited a study by researchers at the division of radiation oncology at Ospedale San Gerardo, Milan, Italy, in which 100 patients with metastatic non–small cell lung cancer, treated with etoposide and cisplatin (a standard chemo-combo in Europe), were randomized to receive melatonin, 20 mg per day at bedtime, or no additional therapy, and followed for 5 years.

Three of 49 melatonin-treated patients (6%) were still alive at the 5-year mark, versus none of the 51 patients in the control group. In fact, none of the patients in the control group even made it to the 2-year point. The Italian researchers also found that the chemotherapy was better tolerated in patients treated with melatonin. The study confirms, “in a considerable number of patients and for a long follow-up period, the possibility to improve the efficacy of chemotherapy in terms of both survival and quality of life by a concomitant administration of melatonin,” they reported (Lissoni P, et al. J Pineal Res. 2003; 35(1): 12–15).

“Tumor response rates were better, five year survival was better, and chemotherapy was better tolerated in the melatonin group,” Dr. Birdsall said. “I’ve had patients with brain metastases from lung cancer who responded to melatonin.”

Dr. Lissoni’s team also reported in a separate trial that melatonin attenuates the severity of cisplatin-induced anemia in lung cancer patients. “Hematopoiesis is under a neuroendocrine control, namely mediated by the pineal gland.” They studied the effect of 5-methoxytryptamine, 1 mg per day, in cisplatin-treated patients with metastatic lung cancer. While the supplement was unable to prevent chemo-induced red cell and hemoglobin declines, the degree of anemia was considerably lower in the patients receiving the 5-MTT compared with those on cisplatin alone (Lissoni P, et al. Neuro Endocrinol Let. 2003 Feb–Apr; 24(1–2): 83–85).

Melatonin level and cancer risk appear to be correlated, though there is not enough data to determine if there is a causal relationship in either direction. Investigators at the department of internal medicine, San Giovanni Rotondo Regional General Hospital, compared 17 healthy elderly subjects with 17 age-matched individuals with stage I–II lung cancer, and 17 others with stage III–IV lung cancer. They found that melatonin levels were consistently lower in the cancer patients versus the controls, and that serum cortisol levels were increased. Moreover, cortisol secretion seemed to lose its circadian rhythmicity with the decline in melatonin (Mazzoccoli G, et al. Med Sci Monit. 2005; 11(6): CR284–288).

“Numerous interactions exist among the nervous, endocrine, and immune systems, mediated by neurotransmitters, hormones, and cytokines. Melatonin may modulate the integrated functions of a unique neuro-immune-endocrine system. Neoplastic diseases may be linked to progressive loss of integration among these systems,” they reported.

Dr. Birdsall noted that Cancer Treatment Centers is sponsoring a 3-arm clinical trial to test the effects of melatonin in 90 patients with lung cancer. All will be treated with standard chemotherapy, but will be randomized to receive 20 mg melatonin in the morning and a placebo in the evening, melatonin in the evening and placebo in the morning, or 20 mg melatonin at both times. One objective is to try and distinguish the direct immunomodulatory effects of melatonin from the positive impact of better sleep.

He said that in his experience, melatonin at doses in the range 20–40 mg per day, is very safe, though this is considerably higher than the 0.5–10 mg range used by people treating sleep problems. Even at the higher doses, melatonin will not likely interfere with any drugs the patients may be taking.

“As far as we can tell, it has no interactions, and we have really looked closely at this. We have seen some patients who are able to get off Ambien or other sleep meds, which is a good thing.” He added that there could potentially be “long term hormonal implications, especially for women. But to date, we have not seen this.”

Melatonin & Breast Cancer

Victoria Maizes, MD, Executive Director of the Program in Integrative Medicine, University of Arizona, Tucson, has found melatonin to be a valuable ally in helping women deal with breast cancer.

During a talk on nutritional strategies for prevention and treatment of breast cancer at Columbia University’s Nutrition and Health conference last Spring, Dr. Maizes stressed that melatonin has multiple biochemical effects that can influence breast cancer, including direct anti-estrogenic effects.

“It interferes with the effects of endogenous estrogens, and also interferes with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors.” Supplemental melatonin can decrease circulating levels of estradiol, which is a good thing for many women with breast cancer.

According to researchers at the Department of Physiology and Pharmacology, University of Cantabria, Santander, Spain, melatonin acts simultaneously at several different levels along estrogen signaling pathways. It “selectively neutralizes the effects of estrogens on the breast and the local biosynthesis of estrogens from androgens, one of the main objectives of recent anti-tumor pharmacological therapeutic strategies” (Cos S, et al. Cancer Detect Prev. 2006; 30(2): 118–128).

In a landmark study published in 1999, Lissoni’s group in Milan showed that at doses of 20–40 mg per day, which Dr. Maizes admitted is “definitely on the high but tolerable side,” melatonin increased survival in a cohort of women with metastatic breast cancer (Lissoni P, et al. Eur J Cancer. 1999; 35(12): 1688–1692).

Other studies have shown that the hormone prevents the wasting associated with advanced cancer, and increases the efficacy of tamoxifen and other chemotherapies, while reducing their toxicity.

Melatonin may also have direct anti-tumor effects, as suggested by rat experiments by David Blask and colleagues at the Chrono-Neuroendocrine Oncology Laboratory, Bassett Research Institute, Cooperstown, New York. Dr. Blask has identified multiple mechanisms by which melatonin, at physiological levels, can inhibit growth of a variety of tumors. It inhibits neoplastic cells’ ability to form cyclic AMP and uptake linoleic acid, resulting in impaired cell proliferation (Blask DE, et al. Endocrine. 2005; 27(2): 179–188).

While direct anti-tumor effects are certainly welcome, Dr. Maizes stressed that one should not underestimate the impact of sleep dysregulation on cancer risk, or the potential value of restoring healthier sleep cycles. “Disruption of circadian rhythms may, in fact, increase the risk of breast cancer incidence and mortality, and breast cancer patients tend to have low levels of melatonin.”

Many researchers across the globe have studied the relationship between melatonin levels, sleep dysregulation and breast cancer risk. Though the data thus far have been mixed, the issue is well worth considering, especially in women in poor overall health or who have other risk factors for breast cancer.

“Women who work late shifts and also eat badly are really facing a double-whammy,” said Dr. Maizes. (For thorough reviews on the potential connection between low melatonin and breast cancer, see Bartsch C, Bartsch H. Cancer Causes Control. 2006; 17(4): 559–571; and Sanchez-Barcelo EJ, et al. Endocr Relat Cancer. 2003; 10(2): 153–159.)

Is Melatonin a Natural Anti-Hypertensive?

According to a joint Israeli-Turkish study, supplementation with melatonin can improve nocturnal blood pressure control and prevent early morning pressure surges in hypertensive patients who are “non-dippers” (i.e., they do not show normal night-time pressure drop).

Speaking at the 16th European Meeting on Hypertension, Yehonatan Sharabi, MD, said people with impaired nocturnal pressure regulation are at markedly increased risk of end-stage target organ damage. The exact etiology of the non-dipper phenomenon is unclear, but the Israeli investigators believe low melatonin levels may be a factor. Prior studies showed that non-dippers have a decreased output of urinary 6-sulphatoxy-melatonin, the main metabolite of melatonin.

Collaborating with researchers at the Departments of Cardiology and Pharmacology at Gazi University, Ankara, Turkey, Dr. Sharabi and his colleagues at the Chaim Sheba Medical Center, Tel Hashomer, Israel, studied 38 non-obese people with “garden variety” hypertension, but for the fact that they did not show the normal nighttime pressure drops. All were already on one or more antihypertensive medications and generally well controlled, though they did have early morning pressure surges.

The 38 patients had a mean age of 64. Most were on two or more antihypertensive drugs, and had stable daytime pressure control. Following a 2-week run-in phase, the subjects underwent baseline 24-hour ambulatory pressure monitoring, and were then randomized either 2 mg controlled-release melatonin per day, taken 2 hours before bedtime, or placebo. The investigators repeated the 24-hour monitoring after 4 weeks.

The melatonin patients had mean morning pressures of 141/78 mmHg, and mean nighttime pressures of 136/72 mmHg; the placebo group was very similar with means of 143/77 mmHg and 137/72 mmHg.

While there were no major changes in daytime systolic pressure following melatonin treatment, Dr. Sharabi noted a significant 7 mm reduction in nighttime systolic and 3 mm reduction in nighttime diastolic pressures. Patients in the placebo group didn’t show any change. He said that the nighttime pressure fall was a most welcome finding.

“The time interval from 1–5 a.m. seemed to be the period of maximal melatonin effect on blood pressure, and this is very important given the incidence of early morning cardiovascular events.”

Compliance with the melatonin protocol was very high, and there were no observed adverse events or drug interactions.

Interestingly, melatonin seemed to be most effective in patients on angiotensin-converting enzyme inhibitors or diuretics. Dr. Sharabi said other researchers have suggested melatonin could potentially increase blood pressure when combined with calcium channel blockers. However, a number of patients in this study were on CCBs, and there was no pressure increase.

The mechanisms by which melatonin regulates blood pressure are not entirely clear; it may have multiple beneficial effects on the cardiovascular tree. There is some data showing that prolonged use of melatonin increases carotid arterial compliance. It also inhibits sympathetic nervous system activity, while activating the parasympathetic system. There may actually be direct endothelial effects as well. “We know there are receptors for melatonin in the arterial walls.”

The only caveat regarding the use of melatonin in the hypertension context is with regard to elderly patients at risk for orthostatic hypotension. According to Chester Ray, PhD, a researcher at Penn State College of Medicine, melatonin can interfere with nervous system responses that compensate for the orthostatic effect. In elderly people or those already prone to orthostatic hypotension, this could be problematic. These patients should probably not take supplemental melatonin unless there’s a really strong rationale for doing so.