Melatonin: Part 2

New Melatonin Research: Part 2   Now, continuing to follow up on the links embedded in the video that launched this investigation, we will examine some other high-dose melatonin studies done with humans, rather than rodents.   Neuroprotection   Back to studies on neurological disorders. Here we have a clinical safety study on patients with ALS (also called Lou Gehrig’s disease) in which they were given 300 mg daily for up to two years.   “Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.” (Source)   Sepsis   The following study is both disturbing and exciting. It concerns using melatonin to treat neonatal sepsis, which is an infection in the bloodstream of newborn infants less than 28 days old. (“It continues to remain a leading cause of morbidity and mortality among infants, especially in middle and lower-income countries.”) Infants with this condition were given two 10 mg doses of melatonin daily for 2 days.   “Three of 10 septic children who were not treated with melatonin died within 72 h after diagnosis of sepsis; none of the 10 septic newborns treated with melatonin died. To our knowledge, this is the first study where melatonin was given to human newborns.” (Source)   While this study is not of a super high dose, it is worth sharing in part just to get this information out there, and to appreciate that 20 mg given to a newborn is a very high dose based on their body weight compared to an adult.   1,000 mg Daily   Finally, with regards to high doses, we have another human study seeking to determine the toxicity of melatonin. Five adults were given 1,000 mg of melatonin daily for one month. There were no adverse effects on the basic clinical parameters of blood pressure, ECG, and heart rate, nor was anything negative revealed in their serum chemistry or urine analysis.

  “We studied the effects of prolonged ingestion of melatonin, 1 g per day, on skin color and the serum levels of pituitary hormones in 5 human subjects with hyperpigmented skin. Melatonin lightened hyperpigmented skin of one patient...but had no effect on three patients' skin with idiopathic hyperpigmentation...The subjects all noted increased drowsiness but through studies on the eyes, liver, kidneys, and bone marrow revealed no other evidence of toxicity.“” (Source)   More Melatonin Studies   Following are some interesting studies concerning melatonin, but ones where, in most cases, the doses used are not clearly defined. This material is therefore not here to support the idea of massive doses but rather to further support the argument that melatonin has many, many more functions in the body than simply supporting sleep cycles.   Insight into the roles of melatonin in bone tissue and bone-related diseases (Review), is an overview of countless melatonin studies, though it is focused on the issues mentioned in the title.   This massive review concluded that “melatonin functions as a protector in bone injury, osteoporosis, osteoarthritis and periodontitis by exerting multiple effects”.   Here are but a few highlights from this review:

1. “Melatoninsupplementationiswell-toleratedandcanattenuateperimenopausal symptoms, as well as restore the balance of bone remodeling to avoid bone loss and osteoporosis.”
2. “Estrogendeficiency,themajorcharacteristicofmenopause,contributesto osteoporosis...Melatonin can attenuate osteoporosis induced by estrogen deficiency.”
3. “Salivaandplasmamelatoninlevelsaresignificantlylowerinindividualswith periodontal disease compared to clinically healthy subjects...The gingiva (the “gums”) is one of the external sites of melatonin synthesis, and melatonin receptor 1 has been found in human gingiva, indicating that melatonin may play a receptor-mediating role in the oral cavity.”
4. “Adailydietarysupplementof10mgmelatoninmaybeaneffective complementary treatment for patients with insomnia with generalized chronic periodontitis...improving sleep quality may itself improve the response to periodontal therapy.”
5. “Theprotectiveeffectsofmelatoninonalveolarbonecanalsoacceleratethe process of osteointegration during implant restoration, to obtain a better implantation effect. Melatonin can be used to inhibit the enhancement of oxidative stress in oral tissues in the period immediately following tooth extraction to avoid excessive alveolar bone loss.”

6. “Melatonincanbedetectedinsynovialfluid”(suggestingwhyitiseffectivefor osteoarthritis).
7. “Reducedlevelsofmelatoninhavebeenfoundtobeassociatedwithobesity.”

  The only dose level I could find in this review that is relatively high, is another mouse study: “The daily oral melatonin administration (100 mg/kg body weight) has been reported to increase bone formation to prevent ovariectomy-induced bone degeneration in mice.”   As with most such medical studies based on natural substances they suggest more research, which is valid in this case since “there is no consensus on the optimal route, dosage and time of melatonin administration”, and “a few studies have reported adverse effects.”   One of the claims made in the video that initiated this material on super high doses of melatonin, was that melatonin supports mitochondrial health. Elsewhere, on a Facebook post, someone suggested that if you are groggy in the morning after using melatonin then you need to take more. That this sensation is an indication your mitochondria are detoxifying and you need more melatonin to repair your mitochondria. I could find no scientific verification of this idea, and in fact, I have always taught that this feeling means you are taking too much and you should roll back your dose to an amount more suited to your biological age.   Age-Based Requirements for Melatonin   According to the premier scientific researcher on melatonin, Dr. Walter Pierpaoli, the following is the average melatonin requirements for different age groups: Ages 40 to 44 - .5 to 1mg; ages 45 to 54 – 1 to 2mg; ages 55 to 64 – 2 to 2.5mg; ages 65 to 74 – 2.5 to 5mg; ages 75 and over – 3.5 to 5mg.   Mitochondria   Though I could find no support for this idea that grogginess means you need more, I was able to confirm that melatonin is important for mitochondrial function. Which is good news for those with diseases linked to mitochondrial dysfunction, including Chronic Fatigue Syndrome and Fibromyalgia. (In case you are unaware, the mitochondria produce ATP in our cells, which provides us with bodily energy.)   In fact, “malfunctioning mitochondria have been linked to diabetes, heart disease, Alzheimer's disease, Parkinson's disease and even normal aging”. (Source)

  As the title of this study indicates, Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics, there can be no doubt that there is a relationship between the two.   “Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin.”   Now let’s look at another rodent study, one involving melatonin and mitochondria.   “Melatonin, a mitochondria-targeted molecule that is known for being a potent ROS (i.e. free radical) scavenger, promotes ATP synthesis via the elevation of COX expression and activities. Melatonin administered to aged rats at 10 mg/kg per day in drinking water prevented the 30% age-related decline in COX activity while abolishing concomitant elevation of H2O2 in brain mitochondria of aged rats compared to controls.” (H2O2 - hydrogen peroxide - is a free radical byproduct and a neurotoxin when it gets into the brain.) (Source)   GERD   Given the widespread nature of reflux disease, I felt I should include this information on how melatonin can benefit this condition.   The potential therapeutic effect of melatonin in gastro-esophageal reflux disease is a study that concludes with this: “The present study showed that oral melatonin is a promising therapeutic agent for the treatment of GERD. It is an effective line of treatment in relieving epigastric pain and heartburn. This observation is in agreement with Klupiñska et al who found that in patients with GERD and recurrent duodenal ulcers, melatonin concentration was lower than in healthy subjects and concluded that high or relatively correct secretion of melatonin is sufficient to prevent peptic changes in esophageal and duodenal mucosa.”   Warnings   Melatonin can interact with certain medications including blood thinners, diabetes medications, and immunosuppressants. If you are on any of these drugs consult with a medical professional (or do more research) before using any high dose regimen of melatonin. As well, it appears that birth control pills will increase the body’s production of melatonin, and when used in conjunction with a melatonin supplement may result in higher than expected levels in the body. (Source)

  As we discovered in Part One, melatonin is involved in the reproduction functions of our bodies, so its interaction with birth control pills kind of makes sense. However, this link is something to pay attention to if one is seeking to become pregnant.   For example, when melatonin was given to a group of women in combination with progestin (a synthetic progesterone hormone), it inhibited ovarian function in women so much so that the researchers believed that this combination could be used in the future as an effective oral contraceptive. (In fact, “a melatonin-based contraceptive is at present undergoing phase III clinical trials”. Source)   That being said, the amount given to the women in this study combining melatonin and progestin, was pretty high: “MEL was administered in a dosage of 300 mg to 12 women for 4 months [to 8 women daily (days 1-30) and to 4 women on days 5-17 of the cycle]. MEL was also combined with the synthetic progestin norethisterone (NET).” (Source)   Therefore, it is likely safe for a woman seeking to become pregnant to use 1 or 2 mg of melatonin if it is necessary for sleep support. But, again, do more research if this is your concern.   Endogenous vs Exogenous   Now one thing mentioned in the video suggesting 1,000 mg daily, that I could find no confirmation for, is the idea that you can take as much as you want without affecting your body’s own production of melatonin.   Conventionally, it is believed that if you take high amounts of a substance, especially like a hormone, from an outside source (exogenous), you will shut down your body’s internal production of that substance (endogenous). This is most obvious with things like steroids, whereby one who uses too much synthetic testosterone will stop producing their own naturally, once they stop ingesting it from an external source.   However, according to the Texas Health website: “If you’re worried that taking melatonin often enough will suppress your body’s natural production of it, you can breathe a sigh of relief because several studies have found that taking melatonin will not affect your body’s ability to make it on its own.”   One of the aforementioned studies had this to say: “A melatonin treatment trial using a 50 mg daily bedtime dose for 37 days to a blind subject resulted in no change in the endogenous melatonin profile. We conclude that circulating melatonin can shift the phase, but does not alter the amplitude, of pineal melatonin secretion.”

  Nonetheless, I am in favor of erring on the side of caution, thus I would suggest as I always do, that if you are going to use high amounts of melatonin you do it for only five days a week.