Articles and research related to functional medicine for gut, brain, and immune health
Melatonin for immune, GI, and brain health (part 1)
June 22, 2020
Melatonin, a neurohormone available in supplement form, is best known for its use in initiating sleep. Our own endogenous melatonin plays a key role in regulating our 24-hour sleep-wake cycle. Of course, the body doesn’t usually make a substance to do just one thing. Similar to many plant medicines, substances made in the body can have multiple actions in different places in the body. They can also have a modulating effect, meaning they can exhibit opposite actions depending on what the body needs, for example increasing or decreasing inflammation. Melatonin has been shown to exhibit modulating effects on our immune function in the GI tract, the brain, and elsewhere in the body
WHERE ITS MADE:
We commonly hear that melatonin is made in the pineal gland of the brain in response to changes from light to dark. Its production increases when it is dark outside and gradually declines in the early hours of the morning slowly waking us up for the day. But melatonin is made in other parts of the body as well. More than 400-500 times as much is made in immune cells in the GI tract called enterochromaffin cells. It is reasonable to conclude that the health of our GI tract influences its secretion, including what we eat and what we digest and absorb. Another function of melatonin that has been widely discussed is that it has antioxidant properties. Some research shows that the primary site of melatonin production is in the mitochondria, where its antioxidant capabilities protect the mitochondria.
https://www.nature.com/articles/s41419-019-1556-7
INFLAMMATION, ALLERGY, AUTOIMMUNITY, and HISTAMINE:
In addition to its circadian rhythm and antioxidant effects, melatonin modulates many immune system responses. It is unlike many other hormones, in that it is made in many non-endocrine cells in the body. It is involved in both T cell and antibody responses. It can be pro-inflammatory against pathogens, disease-causing organisms, by increasing inflammatory cytokines. However, it can also exhibit anti-inflammatory actions in the presence of an over-response to pathogens, as recent studies have shown with COVID-19 and cytokine storm or an overproduction of cytokines. Melatonin is anti-inflammatory in response to slow developing, low grade inflammation such as neurodegeneration seen in normal aging and Alzheimer’s. It is also anti-inflammatory in situations of acute, high grade inflammation such as sepsis and traumatic brain injury.
It’s ability to modulate inflammatory cytokines is also evident in allergic and autoimmune responses. It balances the Th1 and Th2 responses to bacteria/viruses and parasites/allergens, respectively. Studies of people with atopic, or allergic, eczema show that it helps decrease IgE antibody response to allergens. People with allergic rhinitis – seasonal or environmental allergies with primarily nasal symptoms – have lower levels of endogenous melatonin. Melatonin regulates histamine-release from mast cells. Histamine is also involved in our sleep-wake cycle, increasing in the early morning hours when melatonin levels are decreasing. New studies are looking at melatonin as a possible treatment for allergic rhinitis, as well as in addressing other high histamine conditions. Melatonin regulates Th17 cells and inhibits TNF alpha that lead to autoimmune tissue destruction. TNF alpha inhibition is the mechanism of action of many pharmaceutical medicines for autoimmune conditions, but these also carry an increased risk of certain infections and cancers. Healthy levels of melatonin in the body may have a preventative effect against development or worsening of allergy, excess histamine, and autoimmunity. It has been widely studied for its benefits in preventing and treating certain cancers, such as colorectal cancers. It can mitigate the side effects of treatments like chemotherapy and radiation and help decrease cancer growth.
https://pubmed.ncbi.nlm.nih.gov/16217132/
https://www.sciencedirect.com/science/article/abs/pii/S1359610119300449
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159806/
https://www.researchgate.net/publication/339025705_Melatonin_and_Allergic_Rhinitis
https://pubmed.ncbi.nlm.nih.gov/19963060/
IBS, GI MOTILITY, REFLUX, MICROBIOME:
Melatonin has numerous actions in the gastrointestinal tract. Studies of supplemental melatonin’s impact on patients with Irritable Bowel Syndrome (IBS) show that a 3 mg dose has a pain-relieving effect. Visceral abdominal pain is a hallmark symptom of IBS.
Melatonin is thought to play a role in modulating GI motility. Initial research suggests, at low doses it increases intestinal motility, while high doses may decrease gut motility. Melatonin receptors are found in the muscular layers of the intestines, responsible for GI motility. The presence of melatonin in the gut activates these receptors and can have both contractile and relaxing effects on the smooth muscle of the GI tract. It appears to act as a modulator of gut motility in response to an excess or deficient motility response
Melatonin has been studied in patients with GERD, who have lower levels of endogenous melatonin than people without GERD. It again exhibits multiple helpful actions, protecting the esophageal mucosa from stomach acid and also regulating the muscle tone of the lower esophageal sphincter preventing refluxing of stomach acid into the esophagus. One 40-day study compared treatment of GERD with Omeprazole (a commonly prescribed medication for GERD) to a supplement with melatonin, l-tryptophan, methionine (melatonin precursors), vitamin B6, folic acid, vitamin B12 (co-factors to making melatonin), and betaine.
- Within 1 week, 99% of patients taking the supplement with melatonin improved, 66% taking Omeprazole improved.
- At the end of the 40 days 100% taking the supplement reported no symptoms, 60% taking Omeprazole had no symptoms.
- Those with remaining symptoms were given the supplement with melatonin for 40 days and 100% of them had resolution of their symptoms.
Like us, the microbes in our intestines operate on a 24-hour circadian rhythm of rest and activity, regulated in part by our melatonin secretion. Research on night shift workers and people experiencing jet lag, show that our gut microbes do best when our eating times are more predictable, since they are helping to digest some of our food. Regular mealtimes may help our beneficial microbes to predict their own eating times and can affect their growth and movement. Newer studies show that some types of bacteria show patterns of “swarming” behavior – spread and growth – in response to melatonin levels in the intestines.
Melatonin in GI tract also exerts its antioxidant and microbiome regulation functions in studies of intestinal inflammation. It may have preventative or even treatment effects in GI inflammation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949259/
https://pubmed.ncbi.nlm.nih.gov/27919824/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198018/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821302/#B26
https://pubmed.ncbi.nlm.nih.gov/18616070/
https://www.sciencedaily.com/releases/2014/10/141016123522.htm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709092/
https://www.hindawi.com/journals/bmri/2018/2607679/
NEUROINFLAMMATION, PANS/PANDAS, ASD, DOWN SYNDROME:
Melatonin’s immune-modulating effects also occur in the brain, regulating the activation of microglia, immune cells in the brain, to protect our neurons from injury and inflammation. Many studies focus on patients with traumatic brain injury and on typically aging brains, as well as the brains of people with Alzheimer’s disease. Our endogenous melatonin levels decrease in later life, possibly contributing to oxidation and other effects in the aging brain.Melatonin’s regulation of our brain’s inflammatory response is also beneficial in people with Autism and PANS/PANDAS. In people with autoimmune reactions, susceptibility to infections, and GI inflammation, it can have numerous benefits. Melatonin has been studied in people with Autism with high levels of oxidative stress and GI symptoms, for its antioxidant and anti-inflammatory properties. People with autism show a genetic tendency toward lower melatonin levels. Many people with Down Syndrome also have lower levels of endogenous serotonin and melatonin with higher levels of kynurenic acid excreted in their urine. Increased levels of this organic acid suggest “tryptophan steal”, a process in which tryptophan is shunted away from making adequate amounts of serotonin and melatonin, to create kynurenic acid. Inflammation and/or infection may underlie this process. Melatonin given as an antioxidant nutrient shows benefit for people with autism and Down Syndrome who experience high levels of oxidative stress. As a supplement, it is often used to help with initiation of sleep, but it may improve sleep quality by addressing underlying causes of sleep disruption from abdominal pain to excess inflammation and oxidative stress. It is also worth noting that many people without these diagnostic labels, but with other symptoms affecting their nervous system (brain, mood, behavior), their hormonal system, their immune system, or their GI system, have underlying inflammation and may have lower levels of melatonin.
https://onlinelibrary.wiley.com/doi/full/10.1111/jpi.12525
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096870/
https://pubmed.ncbi.nlm.nih.gov/20480727/
LONG TERM USE:
Systematic reviews of melatonin research in people of various ages from newborns to elders, taking melatonin in different dosages and forms, for different lengths of time suggest that clinical use of endogenous melatonin is not only safe but is associated with a wide variety of better health outcomes. Now that its use has been more widespread over the last several years, most commonly for children with neurodevelopmental conditions involving disturbed sleep, some studies are beginning to examine longer term supplementation. Continued improvements are often seen, even with several years of use. As a clinician, I think it is important to note that my goal for any patient is not to remain on melatonin supplements indefinitely, but to address the underlying causes of their own endogenous melatonin production being disrupted. Because that process can take some time, it is heartening to see studies of melatonin use up to 2-4 years showing a low side effect profile, no tolerance, and good efficacy in promoting better sleep, physical health, behavior, and learning.
In one study of children with autism with sleep disturbances, 2 years of use showed continued favorable results and while a 2-week break showed some decline in sleep quality, during that time their sleep quality was still improved over their baseline before beginning supplementation.
Studies of melatonin use in people with sleep onset delay insomnia (trouble falling asleep) show that long term, regular use of exogenous melatonin supplements affect our own melatonin release by advancing it by as much as 3 hours. The amount of our own melatonin released is not lessened by taking supplemental melatonin. Taking lower doses a few hours before bedtime for a short period of time can reset your circadian rhythm and advance the time you fall asleep by up to 3 hours. There is some evidence that exogenous melatonin use also may increase the storing of our endogenous melatonin, making it more available to us.
Because melatonin production is influenced by our morning exposure to light and our evening exposure to darkness, adjustments to our sleep hygiene that create optimal conditions for melatonin production include morning walks or time outside, and evening avoidance of bright light, in particular screens which emit blue light.
Melatonin production is also dependent on availability of its amino acid precursor, tryptophan, as well as many vitamin co-factors. This means our melatonin levels are influenced by our dietary intake, as well as our digestion and absorption of nutrients in the GI tract. Most plant foods contain some amount of melatonin, but foods that have been shown to contain notable amount of melatonin are tomatoes, olives, barley, rice, and walnuts.
In conclusion, improving intake, digestion, and absorption of proteins and vitamins needed to make our own melatonin, along with improving sleep hygiene are essential to supporting the numerous beneficial functions of melatonin in the body. Supplementing while addressing root causes, is not only safe, but can be very effective in helping with better sleep, as well as immune, brain, and GI function. Creating a regular daily rhythm of sleep, wake, and eating patterns is most beneficial to our health.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798185/
https://www.aappublications.org/news/2020/04/01/healthbriefmelatonin
https://www.sciencedirect.com/topics/neuroscience/6-hydroxymelatonin
Melatonin for immune, GI, and brain health (part 2)
July 29, 2020
INFLAMMATORY BOWEL DISEASE:
Several studies have been done looking at the beneficial effects of melatonin for patients with Irritable Bowel Disease (IBD). In one small study using melatonin supplements in combination with medication, biopsies of the patients’ s large intestine were examined after 30 days of medication alone or medication and melatonin. Signs of inflammation were gone in 78% of the patients receiving the treatment with melatonin included (55% with medication only). One month after treatment with medication and melatonin, 89% patients with Ulcerative Colitis regained healthy colonic mucus membrane layers (50% with medication only). Melatonin clearly helped to improve the structure and function of the mucosal lining of their affected GI tract areas. This is significant not just for people with IBD, but for the potential benefits in less severe forms of GI inflammation seen in many chronic health conditions.
https://pubmed.ncbi.nlm.nih.gov/21516743/
INTESTINAL MOTILITY:
Our endogenous melatonin plays a role in helping to regulate GI motility. It is produced by enterochromaffin cells (EC cells) in the GI mucosa (mucus lining) and the deeper, submucosal layer. It acts on the nerves and muscles of the intestines, modulating muscle contraction and relaxation. Smaller doses increase transit, while high doses slow transit. This bidirectional effect may have benefit for patients with chronic constipation due to slow gut motility and/or for patients with loose stools and increased gut transit time, leading to impaired nutrient absorption.
Studies have shown that removing the pineal gland of the brain (where much of our melatonin is produced) effects the Migrating Motor Complex, the pattern of nerve impulses that occur between meals and create the squeezing motion in the GI smooth muscle that moves food through the intestines. Mammal studies suggest that giving exogenous melatonin appears to restore this function. This may be significant for patients with Small Intestinal Bacterial Overgrowth as well, suggesting lower melatonin levels as a possible contributing factor in impaired gut motility.
Many pathogenic bacteria or viruses in the intestines produce toxins known as LPS (lipopolysaccharides) that can create disturbances in our gut motility (i.e. acute food poisoning and many chronic GI infections). Melatonin in the GI tract has been shown to reverse these effects. This again suggests the importance of ruling out low melatonin levels in the gut as a contributing factor and emphasizing regular sleep/wake habits and exposure to daylight and darkness as means to maintain our melatonin.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198018/
LIVER AND GALL BLADDER FUNCTIONS:
Impairments in liver and gall bladder function are often seen in people with ASD and Down Syndrome, as well as PANS/PANDAS, among other conditions. The gall bladder helps to drain waste products from liver into our intestines to be eliminated. As in other areas of the body, melatonin’s antioxidant effect, as well as its ability to modulate inflammatory responses, are seen in liver and gall bladder functioning. It has also been shown to protect the liver against acetaminophen-induced liver failure and to improve bile flow.
In one controlled trial animal study of cholestasis, or reduced bile flow, melatonin treatment lowered elevated lab markers (ALT, AST, alkaline phosphatase, and bilirubin) and protected against liver cell damage in part by regulating the production and use of L-tryptophan and glutathione.
Melatonin has been found in human bile, which itself is a pro-oxidant in the liver and intestines, so melatonin may act as an antioxidant to prevent damage to the intestinal lining from our own bile. Here again in the body, it is protective to our tissues and helps to modulate other body functions (oxidation, inflammation) in order to maintain balance and healthy functioning throughout the body.
It has been studied as an adjuvant to (UV) phototherapy for jaundice in neonates (along with vitamin d and riboflavin).
https://pubmed.ncbi.nlm.nih.gov/23272189/
https://www.spandidos-publications.com/10.3892/ijmm.2018.3859
https://pubmed.ncbi.nlm.nih.gov/10622237/
LIVER TOXINS:
Melatonin’s many antioxidant functions make it protective to the liver in the presence of toxins such as:
- The heavy metal cadmium – found in the soil and has been widely dispersed by mining. It is also found in fertilizers, so we are exposed to it through soil contact, as well as plant foods
- Pollutants like benzene – a widely used industrial pollutant found in synthetic fibers, plastics, dyes, detergents, drugs
- Mycotoxins such as aflatoxin b1 found in grains and other foods susceptible to molds
While it is impossible to avoid exposure to many of these substances, healthy levels of melatonin help our body to process and eliminate them. For people with genetic impairments to their detoxification pathways, ensuring optimal levels may be of extra benefit, although this has not been well researched.
Many studies show melatonin’s benefits for people with cancer. It repairs liver damage from several cancer and autoimmune medications (such as methotrexate) as well as damage from radiation treatments. It lessens the liver toxicity of some neuropsychiatric drugs (anti-epileptics, anxiolytics – trazadone, diazepam). It increases glutathione levels in the liver, protecting liver cells and biliary cells from damage.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412268/
THYROID:
The relationships between thyroid function and melatonin are still not fully clear. Melatonin’s antioxidant properties help to maintain healthy oxidation levels needed for thyroid hormone balance. In addition, melatonin has been found to be beneficial in many autoimmune conditions due to its balancing of immune pathways, so it may be helpful in autoimmune thyroid conditions such as Graves’ or Hashimoto’s, however, it may increase thyroid hormone production, making it more useful in hypothyroidism, than in hyperthyroidism. Further studies are needed to confirm this relationship. One study of 51 patients with Hashimoto’s as well as symptoms of anxiety, depression, and sleep disturbance examined the role of melatonin along with thyroid replacement medication.
- 2 groups studied – 1 taking thyroid replacement alone, 1 taking thyroid replacement plus melatonin
- Greater improvements in TSH (lower) and FT4 (higher), as well as better improvement in depression symptoms were seen in the melatonin group than with thyroid replacement alone (which still lowered thyroid hormones somewhat and helped with anxiety).
Melatonin is also made in the C cells of the thyroid. It helps to regulate synthesis of thyroid hormones and is itself regulated by TSH. Rat studies giving exogenous melatonin show increases in T4 hormone expression.
In the pineal gland, melatonin production is regulated by norepinephrine, a stress hormone, so finding ways to manage stress responses and create calm can help maintain our melatonin levels. Numerous evidence-based practices such as deep breathing and Mindfulness can be beneficial for children, as well as adults. Since healthy neurotransmitter production relies on nutrients like amino acids and vitamin and mineral co-factors, GI health is also key to making our own melatonin for sleep/wake rhythm. While working on all of these, supplemental melatonin may be of help for some people.
https://pubmed.ncbi.nlm.nih.gov/26579570/
https://www.endocrine-abstracts.org/ea/0026/ea0026p394
POTENTIAL DOWNSIDES:
While there is so much evidence that our own melatonin does a great deal of good in so many areas of the body, many people wonder about any harmful effects of taking supplemental melatonin. As with any supplement, talking with a healthcare practitioner familiar with functional medicine and/or Naturopathic medicine is recommended. There are some studies suggesting melatonin may have a pro-oxidant effect for some people with asthma, but this relationship has not been proven, and melatonin is still being considered as a treatment for asthma, given its beneficial effects on the immune and respiratory systems.
Different people respond differently to different amounts of melatonin, so the best dosages are individualized. This may be due to our own individual levels of endogenous melatonin already present. Levels may be tested in the blood or dosages can be started low and increased to find the minimum effective dose. The most common melatonin side effects reported include:
- Headache
- Dizziness
- Nausea
- Drowsiness
Other, less common melatonin side effects for some people might include short-lasting feelings of depression, mild tremor, mild anxiety, abdominal cramps, irritability, reduced alertness, confusion or disorientation, and abnormally low blood pressure (hypotension). Because melatonin can cause daytime drowsiness, don’t drive or use machinery within five hours of taking the supplement. While it is not discussed in the medical literature, I have seen some patients experience increased night waking or early morning waking when taking melatonin. This illustrates the need for individualizing treatment with melatonin and addressing the whole person and their GI, immune, and nervous system functioning in the context of their unique medical history.
Another issue to keep in mind is that melatonin supplements can interact with various medications, including:
- Anticoagulants and anti-platelet drugs
- Anticonvulsants
- Contraceptive drugs
- Diabetes medications
- Medications that suppress the immune system (immunosuppressants)
https://link.springer.com/article/10.1007%252FBF01845499
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