MELATONIN DOSING

A generally accepted guideline is to use the lowest effective dose of melatonin as the most appropriate course (1).

 

Larger doses do not always confer greater health benefits. The upper limits of a lethal dose of melatonin have not been clinically established. A recent systematic review and meta-analysis of safety studies on high-dose melatonin (≥10 mg/day) in adults concluded that there are limited studies from which to draw any solid conclusion about its safety profile (2).

 

In clinical applications, too much melatonin or various extended-release formats have been documented to produce side effects such as amnesia or a “melatonin hangover” the next day, finding it harder to fall asleep, or sleeping well for three to four hours and then waking up and not being able to go back to sleep (3). Those with certain genotypes, such as polymorphisms in the melatonin receptor 1B (MTNR1B) gene, may require monitoring of hemoglobin A1C if they take supplemental melatonin (3,4).

 

Within clinical medicine, it has also been more anecdotally discussed whether high doses over the long-term can negatively impact the body’s melatonin production, with individuals potentially becoming dependent over time. While a theoretical concern, there is a lack of significant scientific evidence that this dependence can develop, and if it does, under which conditions and individuals may be most susceptible.

 

There have also been reports of vivid dreams or nightmares while using melatonin supplements (5). Since the average human adult produces between 0.1 mg and 0.9 mg of melatonin daily (6), this range is known as physiological doses. This can be referred to as "micro-dosing" in some media outlets. Amounts above this range are known as pharmacological doses. Much has been written about melatonin’s therapeutic value, but the doses used in studies tended to be supraphysiological or based on previous studies that did not have an explicit rationale for choosing the amount. Therefore, some dogma about dosing melatonin has developed in scientific research and clinical medicine.

 

In a pivotal study by Zhdanova et al. (7), multiple doses were compared: a physiological dose (0.3 mg), a pharmacological dose (3 mg), and a low physiological dose of 0.1 mg. They found the best objective data at 0.3 mg of melatonin. Sleep data were obtained by polysomnography. The physiological dose (0.3 mg) restored sleep efficiency and elevated plasma melatonin levels to normal during early adulthood. The pharmacological dose (3 mg), like the lowest dose (0.1 mg), also improved sleep; however, it induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours. Interestingly, the control group (not insomniacs) also had low melatonin levels, but melatonin did not improve sleep. The low dose in the study did not raise melatonin levels into the normal range. It is an intriguing point that we need to lower our body temperature to sleep well but doing so excessively can disrupt sleep. Melatonin’s action of lowering body temperature is important to monitor and may give significant clues to the appropriate dosage. Symptoms like needing more blankets, or excessive movement, may indirectly suggest an imbalance of melatonin.

 

The dose of melatonin was patented up to 1 mg based on this earlier research (8), excluding dietary supplement manufacturers from selling this dose and thus, using higher doses. It can be postulated, in part, that the earlier historical use of higher-dose melatonin levels may have been associated with the inability to operate freely with known efficacious doses of melatonin in supplemental format.

 

Lissoni et al.’s cancer research from over twenty years ago demonstrated that 20 mg given intramuscularly followed by oral daily doses of 10 mg was effective in arresting tumor growth and improving quality of life markers (9). Higher oral doses (50 mg daily) were given in a subsequent study with immunotherapy to 14 patients with advanced hepatocellular carcinoma(10). Other studies since these pivotal publications have used this dose as a reference (11–14). Little research has been conducted on lower doses to determine if they are as effective in cancer patients or if the physiological dose of 0.3 mg can be used for prevention. Hopefully, future studies will delve into these questions.

 

In 2002, Lewy et al. found that physiological doses (0.5 mg) may offer benefits that pharmacologic doses (20 mg) do not (15,16). They observed the effects of the dosage of melatonin in blind humans who often have disrupted circadian rhythms due to the pineal gland not receiving appropriate stimulation from the retina. They concluded that too much melatonin may negatively affect the melatonin phase-response curve (15). The phase-response curve describes how an intervention given at various times in relation to the individual’s sleep period will influence their circadian rhythm, i.e., whether the intervention will cause a phase delay, advance, or no phase shift. This point supports the concept that too much melatonin may not benefit a person. It also begs the question, “How much is too much?” It will be difficult to answer this question for the masses as hormone production, genetics, and timing of secretion are complex variables to assess for the individual. In addition, the bioavailability of the form or product used can play a part.

 

Anecdotally, clinical use of supplemental melatonin has commonly ranged between 1–3 mg as a daily dose; however, some find that the dose is determined by the product type, with lower doses being just as effective in some instances. Melatonin is quickly broken down by the body and should be dosed at the appropriate, personalized level for each patient. Controlled-release formulations have been discouraged in older adults due to the possibility of prolonged melatonin levels and unknown implications thereof (1). Because it is rapidly metabolized, melatonin might be used more regularly daily by those who need it, rather than every second or third day. In other words, if a person has symptom relief from 1 mg of melatonin, they may not experience the same benefit with 3 mg of melatonin every third day. Products containing a dose of 3–5 mg are often chosen because they are perceived as a good value but supplementing with more melatonin than physiologically required is not always better if the dose is incorrect.

 

For this reason, starting at the physiological dose of 0.3 mg and increasing if necessary is often recommended except for specific conditions where higher doses are therapeutically prescribed, such as jet lag, shift work, or cancer.

 

Jet Lag and Shift Work

For jet lag, recent studies are lacking in detailing the most efficacious dose. Most research on the use of melatonin for jet lag is from 10–20 years ago or longer. Melatonin may not be effective for everyone but could be well-suited for those individuals with a history of jet lag and/or for those flying across ≥ five time zones to the East (17). Upon arriving in a new time zone, it is advised to follow the new time zone sleep cycle, taking the oral melatonin supplement thirty to sixty minutes before desired sleep on the first night and continuing for the following three to four nights, gradually reducing the dose. In one study, the fast-release formula was more effective than the slow-release preparation(18). Some studies used a protocol in which melatonin supplementation was initiated three days before travel started (19,20). Supplemental melatonin is intended for short-term use: 3–6 days after arrival at destination.

 

Similarly, study findings are inconsistent for shift work. Older clinical studies with smaller subject numbers found no difference (21,22) or modest differences(23) in sleep outcomes compared with placebo. A meta-analysis (24) found essentially no benefit from melatonin.

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Melatonin and Children

The use of melatonin in children is now widely accepted for various disorders, but since the studies range so widely in dosing, a critical analysis is required for each child. Dyssomnia, ADHD, and ASD have been studied and reviewed, all confirming effectiveness and safety of melatonin. It should be noted that studies were of various lengths, with some as short as two weeks, and the longest-lasting study was six months. Only one questionnaire-based study investigated long-term melatonin use in children with ADHD and chronic insomnia and, by its design, was based on subjective symptom reports. In an average of 3.7 years of follow-up from previous clinical trial participation of pharmacological doses of melatonin, 65% of children were still using melatonin as prescribed in the study, but only 9% were able to discontinue use (25). Neither the parents nor children monitored their melatonin use but relied on the initial study proposal, so dosing varied widely. Compliance nearly four years later was at 65%, presumably due to the satisfaction of use.

 

Dosing parameters may vary according to factors such as the child’s medical problems, severity, type of sleep problems, or the associated neurological pathology. Indiscriminate, long-term dosing may lead to unnecessary dependence and even perturbations in puberty onset when nocturnal levels of melatonin tend to decline (26). More discriminating research is warranted to understand the implications of exogenous melatonin in children, pre-teens, and teens. Based on what is currently known and the easily administered formats provided in the market (e.g., gummies, chewables), it would seem prudent to exercise caution. The authors would like to emphasize that the dramatic increase in the use of supplemental melatonin in children is unwarranted because they endogenously produce more melatonin than adults (27). Furthermore, it seems that the research has mistakenly been construed and applied to healthy children rather than children with particular needs, such as autism or ADHD.

 

Metabolism of melatonin

Finally, to underscore the discussion of dosing in both pediatrics and adults, it is important to understand that melatonin is metabolized via the liver primarily by the enzyme CYP1A2 (28). The slow metabolism of this enzyme has clinical applications. A melatonin clearance test is reasonable but difficult to implement practically. Therefore, loss of response after several weeks may suggest a patient’s tolerance of melatonin and necessary dose reduction. In one report, clinicians observed that the initial response to melatonin had disappeared weeks after starting treatment, and that the favorable response returned with dose reduction (29).

 

Conclusion

In conclusion, what is optimal dosing of melatonin with the current understanding? Based on the review of current literature, it would seem that the administration of melatonin, as with other exogenous hormones like estrogen (30), would be at the lowest dose for the shortest period of time. Moreover, with melatonin specifically, the physiological kinetics and circadian rhythm need consideration, ideally taking a physiological dose (0.3–0.5 mg) of melatonin with sustained release properties and going into darkness a minimum 30 min before desired sleep, thereby mimicking the physiological kinetics based on light and dark patterns as well as the typical endogenous trajectory of immediate and then sustained release over four to five hours The caveat to this dosing recommendation is in relation to the use of melatonin for acute treatment for cancer or other health conditions that may require higher dosing or other forms of delivery (e.g., intramuscular, intravenous, etc.).

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Authors: Deanna Minich, Ph.D., Melanie Henning, ND, Catherine Darley, ND, Mona Fahoum, ND, Corey B. Schuler, DC, James Frame

Reviewer: Peer-review in Nutrients Journal

Last updated: September 22, 2022

 

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