Q&A: How to safely use melatonin for optimal health

Melatonin is associated with mechanisms linked to the root cause of a range of health issues that occur throughout the body, according to Deanna Minich, PhD, CNS, IFMCP.

Minich, a nutrition scientist and expert in food and dietary supplements, and colleagues, recently published a review article in Nutrients, about the emerging clinical research on the uses and safety of supplemental melatonin. We spoke with Minich about her findings and what they mean for integrative practitioners.

Integrative Practitioner: How do you define melatonin?

Minich: Melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous molecule, an indoleamine, made by humans, animals, and plants. Humans ingest it in small amounts from the many food sources it is contained in such as fruits, vegetables, nuts seeds, and grains. We also produce it endogenously by the pineal gland and by the enterochromaffin cells in the gut from the amino acid, tryptophan. The gut mucosa locally produces melatonin in response to meals. It is 400 times the amount of melatonin produced by the pineal gland in response to darkness.

Melatonin is located in several tissues, such as the liver, kidney, brain, retina, thyroid, thymus, and reproductive organs. It’s also found in almost all bodily fluids such as breast milk, cerebrospinal fluid, saliva, and urine. The mitochondria are the primary site of melatonin production within the cell.

Endogenous melatonin levels vary throughout the lifespan. Newborns do not produce melatonin until about three months of age, but they can get it from their mother’s milk if breastfed. Levels are highest during childhood and start to decline with the onset of puberty until the end of life. Adults 55 years and older have the lowest circulating melatonin levels.

With respect to function, melatonin serves multiple roles. In addition to being a hormone and chronobiotic, melatonin is a potent amphiphilic (both water- and fat-soluble) antioxidant, free radical scavenger, chemopreventative, anti-inflammatory agent, and mitochondrial regulator. Because of its ability to travel across tissues, it can work effectively in many organs, with the capacity for one molecule of melatonin to scavenge up to ten free radicals. Of note, even the metabolites of melatonin have antioxidant properties.

Integrative Practitioner: What causes a melatonin imbalance, and what symptoms does it result in?

Minch: Melatonin imbalance is often associated with circadian rhythm dysfunction, which can happen because of changes in sleep patterns, such as travel and jet lag, shift work, and even exposure to artificial blue light at night.

Since melatonin is the “hormone of darkness,” produced in the absence of light, overabundant exposure to artificial light at nighttime can lead to health issues. Our research group has proposed a new term in the scientific literature, “darkness deficiency,” to refer to this type of overexposure to artificial light and underexposure to darkness. We hear so much about getting adequate sunlight to produce healthy amounts of vitamin D in the skin, but not as much about the importance of darkness to stimulate synthesis of melatonin from the pineal gland. With the rise in technology and more people on computers, phones, and devices into the night, we will most likely see greater dysfunction and imbalance with melatonin.

Melatonin balance can include trouble falling asleep and not feeling refreshed upon waking, which can lead to symptoms such as daytime fatigue, irritability, and trouble concentrating. Individuals may find themselves relying on caffeine for an energy boost or increasing sugar and carbohydrate intake to help maintain energy levels.

Integrative Practitioner: What are the traditional uses of supplemental melatonin?

Minich: Most people know melatonin for its role in the circadian rhythm. Due to its influence on the day-night cycle, it has come to be known for its connection to sleep, specifically in the context of sleep-wake disorders, jet lag, and shift work.

One aspect of how melatonin helps promote sleep is by lowering core body temperature. It can also be applied as a chronobiotic in which it can shift the timing of one’s circadian rhythm, particularly useful in those individuals who have delayed sleep-wake phase disorder, or an internal body clock set to later than social norms.

Melatonin supplementation has also been utilized therapeutically for cognitive conditions such as dementia. Since the 1990s, there has been a more exploratory track of investigation into its role in specific cancers. Higher doses than those used traditionally for sleep, most commonly in the range of 10-20 mg, and sometimes much higher, have been administered under clinical supervision to offset the symptoms related to chemotherapy. Examples of cancers where this has been done include non-small cell lung cancer, thrombocytopenic cancer, and colorectal cancer.

Integrative Practitioner: What are some of the newer uses of supplemental melatonin?

Minich: Newer uses of supplemental melatonin are diverse and span the gamut of body systems. With the rise of interest in longevity, there has been more interest in its therapeutic benefit for healthy aging and mitochondrial function. Perhaps the most recently recognized application is its efficacy in promoting immune health. During the COVID-19 pandemic, melatonin supplementation was recommended alongside other immune-active nutrients such as vitamin D and zinc. It was suggested that its anti-inflammatory properties could help with the cytokine storm and even viral infections through its potential role in phase separation.

Along the lines of its relationship to immune health is the emerging research on autoimmune conditions such as multiple sclerosis and Hashimoto’s thyroiditis. While ongoing supplemental melatonin is discussed for chronic diseases, there is also a potential benefit to help override the acute effects of oxidative stress from athletic performance and even environmental toxin load and exposures.

Scientific research indicates recent investigations into women’s health, specifically preeclampsia, fertility, endometriosis, and PCOS, in addition to bone health. Although lesser known, there is interest for melatonin supplementation in other areas of health, including the cardiovascular system, with application to hypercholesterolemia, hypertension, metabolic syndrome, endothelial dysfunction, and possibly for glycemic control, based on personalized gene variants. Other areas include migraines and headache, tinnitus, attention-deficit hyperactivity disorder (ADHD), and autism.

With the gut as a central hub of melatonin production, it is perhaps not surprising that there is a connection between melatonin and gut health. A relation between gut health and melatonin is being explored particularly in relation to GERD, ulcers, and IBS, with investigations into melatonin and its interaction with the gut microbiome and dietary polyphenols. There is an emerging correlation between gut dysbiosis, decreasing endogenous melatonin, and functional cognitive impairment. Sleep disturbance is associated with dysbiosis. Animal studies indicate that administering melatonin to sleep-deprived animals might offset dysbiosis through its anti-inflammatory activity and ability to reduce oxidative stress. With the popularized view that “all health starts in the gut” held by many types of practitioners, it will be of interest to see what future research findings hold for melatonin supplementation in this regard considering these preliminary correlations.

Integrative Practitioner: What’s the difference between phytomelatonin and synthetic melatonin? Is one form more effective than the other?

Minich: Most people do not realize that 99 percent of supplemental melatonin is synthetic, derived from chemical synthesis, often involving petrochemicals. This manufacturing process is not only environmentally toxic, producing pollution, but could theoretically result in contaminants in the final product. Therefore, there is a great need for an effective, safe, and high-quality source of melatonin.

Phytomelatonin is melatonin from plant sources. There are only a few phytomelatonin supplements on the market. A word of caution that the manufacture of plant-derived melatonin may also involve extracts and chemicals; therefore, it is best to inquire with the manufacturer as to their processes. A proprietary form of phytomelatonin on the market (commercially known as Herbatonin) is not extracted with chemicals. It is in its original plant cell matrix that includes the bioidentical melatonin and other supportive phytochemicals like beta-carotene, lutein, and chlorophyll.

In a published research study from Henry Meissner, PhD, MSc, and colleagues, phytomelatonin (Herbatonin) was compared with synthetic melatonin, and found it to be superior in its mechanisms of action, including the following:

• Up to 470 percent greater anti-radical activity (DPPH)
• 100 percent more efficient at reducing cellular reactive oxygen species (ROS in a skin cell line)
• 300 percent higher antioxidant potential (ORAC)
• 646 percent more effective at blocking inflammation (COX-2)

Finally, unpublished preliminary observations by Meissner suggest that phytomelatonin may have preferential absorption over several hours as the body digests the melatonin within the cell matrix, resulting in a natural extended release over several hours without the effect of morning grogginess or other untoward symptoms.

Integrative Practitioner: What are the appropriate clinical uses of melatonin based on the evidence?

Minich: Based on the evidence, there are many factors to consider when dosing melatonin supplements. First and foremost, the individual's age is foundational since children have the highest endogenous levels decreasing from puberty onwards. If we were to replenish these levels to that of middle-aged adults, the physiological dose would be 0.3 milligrams (mg). The preponderance of data indicates that circadian rhythm imbalance is one of the leading reasons for supplementation with melatonin. This imbalance could be due to travel and jet lag, shift work, delayed sleep-wake disorder, or even overexposure to artificial light at night.

The circadian rhythm and sleep disturbances can affect other health conditions such as cognitive impairment, dysbiosis, cardiometabolic diseases, and reproductive health. Mitochondrial health and aging are relevant areas of exploration that would also seem to benefit from melatonin supplementation based on its actions; however, more clinical studies are needed to establish proper dosing regimens. The clinician should evaluate each individual for their particular condition to see how melatonin supplementation can fit into a complete nutrition and lifestyle protocol. 

Integrative Practitioner: What are your recommended doses for melatonin based on which condition is being treated?

Minich: Dosing melatonin needs to be personalized to the individual due to their need and how their bodies metabolize melatonin based on liver enzymes. For example, some people may metabolize melatonin supplements slowly and need to time their dose earlier than others or take less. In contrast, others may be fast metabolizers and need to time and dose accordingly. From a clinical perspective, the “more is better” approach is not always best and can lead to side effects such as grogginess upon waking, vivid dreams, and headaches.

Cornerstone research by Richard Wurtman, MD, and colleagues at the Massachusetts Institute of Technology (MIT) tested a pharmacologic dose (3 mg) and a physiological dose (0.3 mg) and found favorable effects with the lower dose.

Thus, it would be prudent to apply the same principle as with other hormone therapies: always start with the lowest dose for the shortest duration. Based on the published data, that dose would be the physiological dose of 0.3 milligrams unless there are indications for more tailored amounts, such as jetlag and cancer, as per clinician recommendations. The clinician may also want to consider the patient’s age, overall health, use of medications, other supplements, and metabolism. 

Editor’s note: This interview was edited and condensed.