The glymphatics are the lymphatics of the brain and with a restful night’s sleep we remove potentially neurotoxic products like beta-amyloid, tau proteins, alpha-synuclein and neurofibrillary tangles which are responsible for neurological diseases such as dementia, Alzheimer’s, Parkinson’s, and M.S. respectively. In a study “Protection of Metal Toxicity by Melatonin – Recent Advances” published in Research Gate, melatonin was shown to be a powerful chelating agent against heavy metals such as mercury, lead, aluminum, cadmium, and arsenic. Melatonin also protects the heart, kidneys, thyroid, and reproductive organs through its natural anti-oxidative mechanisms.
Melatonin is not just in the pineal gland. It is produced in the mitochondria in every cell throughout our body including our skin, then stored in the pineal gland during the day, before being released at night. All animals and even plants produce melatonin. It is ubiquitous in nature. Research is showing that melatonin acting as an antioxidant is also associated with our immune system and our ability to resist infections, gut health, cardiovascular system, sex hormones, aging skin, and blood sugar problems. It also could be a key factor in the risk of cancer and the bodies failure to respond to chronic infections such as Lyme disease, Epstein Barr, and long Covid. Could it be that those people with chronic health issues have impaired mitochondria and an impaired ability to manufacture melatonin? It appears so.
Russel Reiter, MD, PhD has been researching melatonin for decades. Dr. John Lieurance, a chiropractor took his research and expanded it into a book that I will summarize here. In his book Melatonin-Miracle Molecule, he states while most people respond to physiological doses of 1-10 mg of melatonin there are people who may need supra-physiological doses of melatonin for sleep and other chronic health issues that range in the 40-250 mg range. Unlike other hormones like thyroid hormone for instance, taking melatonin exogenously does not reduce the body’s production of melatonin. Dr. Lieurance said that there have been studies where dosages given to animals as high as the equivalent of 150,000 milligrams for a 150 lb. human, had no toxic effect on them.
One of the main ways in which melatonin is helpful is by balancing the two parts of the autonomic nervous system. The sympathetic nervous system is like an accelerator of a car and the parasympathetic nervous system is like the brakes. Living in our modern society creates experiences that cause sympathetic stress, and we lack the ability to “rest and digest” which is the responsibility of the parasympathetic nervous system. Melatonin may be the biggest key to strengthening the parasympathetic nervous system. As we age, we fail to produce melatonin as much as when we were younger. Therefore, supplementing melatonin can have a great impact on digestion, and improving heart rate variability. Improving heart rate variability could also impact anxiety levels. One animal study in 2017 revealed that melatonin can increase levels of GABA in parts of the brain. GABA has a calming effect on the body and reduces anxiety. In humans a study in 2015 showed melatonin was comparable to benzodiazepines for reducing anxiety before a surgical procedure. With the gut having as much as four hundred times the melatonin in it than the nervous system and pineal gland, you could see how it may have a profound impact on our digestive health. This came from a study “Gastrointestinal melatonin: Localization, function, and clinical relevance” published in the Digestive Diseases and Sciences in 2002 and The Journal of Physiology and Pharmacology in 2008.
Melatonin is produced in our cell’s mitochondria. Mitochondria are so plentiful in our bodies that some people estimate they make up one-third of our body weight. Mitochondria play a critical role in how efficiently we produce energy in the form of ATP from glucose. Mitochondria are the cells “batteries,” and the cells hold onto the melatonin to buffer the stress of inflammation from chemicals, infections, and EMF’s (electro-magnetic fields). Without melatonin it appears that there is a build-up of PDK enzyme (pyruvate dehydrogenase kinase) where pyruvate fails to convert into Acetyl CoA in the Krebs cycle occurring within the cell’s mitochondria. The pyruvate is then shuffled out of the mitochondria into the cytoplasm where it converts into ATP through a much less efficient process called aerobic glycolysis. This aerobic glycolysis lags the Krebs cycle by yielding only 4 ATP vs 36 ATP molecules resulting in a 90% loss of the cells ability to make energy. The most sensitive organs toward mitochondrial dysfunction are the brain and heart because they have the most metabolically active need for ATP production. Aerobic glycolysis, also called the Warburg effect is associated with cancer development.
In a research study published in the International Journal of Molecular Science in 2013, a paper titled “Modulation by Melatonin of the Pathogenesis of Inflammatory Autoimmune Disease talked about how melatonin could be effective in several inflammatory diseases. Another study published in The Immunology Letters in 2003 showed how melatonin was able to rejuvenate age associated degenerated thymus tissue. The thymus is important for our immune system’s production of T lymphocytes and NK (natural killer) cell activity. In 2017 a study in the International Journal of Molecular Sciences studied patients suffering from hepatitis and how melatonin was able to reduce fatigue, body aches and weakness along with normalizing elevated liver enzymes. In 2014, Immunology published a study “Melatonin reduces airway inflammation in ovalbumin-induced asthma”. This study showed that melatonin decreased the number of inflammatory cells, airway hyperresponsiveness, and immunoglobulin IgE, and interleukin 4,5,14 and inflammatory cytokines showing a role for melatonin for treating asthma. Lungs are highly vulnerable to damage caused by inflammation and infections as we know recently from Covid 19 infections. According to the journal Life Sciences in 2020 melatonin due to its antioxidant properties can bind to receptors on the lungs called NLRP3 inflammasomes and could blunt the damage caused by toxins and infections.
Aside from its antioxidant ability, melatonin is a pleiotropic molecule with both pro-inflammatory and anti-inflammatory properties. This adaptogenic ability can influence a wide variety of immune cells. It can reduce excess immune responses from autoimmune diseases and improve immune responses in immunocompromised people. Autoimmune diseases can show up as an organ specific disease such as Type 1 diabetes in the pancreas, or a systemic disease such as lupus in the connective tissue, M.S., or A.L.S. in the nervous system, or Rheumatoid arthritis in the joints. In one study high dose (300 mg/day) rectal suppository melatonin reduced oxidative stress by measuring serum protein carbonyls in ALS patients, showing that melatonin had neuroprotective abilities through antioxidation.
A study in Cardiolgia in March 2012 titled “Melatonin and Cardiovascular Disease: Myth or Reality?” showed that melatonin was able to reduce the risk of atherosclerosis by decreasing the levels of LDL or bad cholesterol and increasing HDL the good cholesterol. It also showed that melatonin reduced blood pressure because of melatonin’s ability to reduce stress hormones such as epinephrine.
I was unaware of the broad spectrum of health issues that melatonin could influence as well as the potential usefulness and safety of using high dose melatonin for problems beyond sleep. Since oral melatonin may be absorbed at a lowered rate supplementation at higher doses seems logical given its safety profile but only if lower doses were first determined to be ineffective. Supplementation of L-tryptophan might help too or eating more foods high in tryptophan. See chart below: