Melatonin - the Hormone of Both Sun and Darkness - Protects Your Health and Can Save Your Life
The Healthcare Wars, Part 5
This is a long-form guest article written by one of my highly productive penpals during the pandemic, M. Langen. He is a great researcher of good will, though as per liability protection, know that he is not licensed to give health advice (as per all such stupid disclaimers). So, while this article has over 200 citations, it is up to you as to how to view the information (which is always a good thing). Personally, I am thankful for his writing and sharing. As M is not a native speaker, he appreciates constructive critique of his writing in English.
“While circulatory melatonin may be the “Hormone of Darkness”, subcellular melatonin may be the “Hormone of Daylight”. - Scott Zimmerman and Russel Reiter (23)
This article should be considered an urgent public health alert.
Calling melatonin “sleep hormone” is just as wrong as calling vitamin D “bone vitamin”. Even though melatonin actually supports sleep and many studies have shown that it can be used as a safe method to improve efficacy, duration and quality of sleep (1)(2), it is so much more than only a sleep aid. Melatonin is a key regulator of health with an almost infinite number of functions. It is one of the strongest antioxidants. It has, for example, strong immunomodulatory, anti-inflammatory, antiseptic, anticancer, antihypertensive, anticoagulant, lipid-lowering, antidiabetic, anti-anxiety, anti-fatigue, antiviral, antibacterial, antiparasitic, anti-epileptic, neuro-protective, athero-protective, cardio-protective, liver-protective, ocular-protective, bone-protective, lung-protective, intestinal-protective and pain-relieving effects.
Thousands of studies demonstrate the strong health-promoting effects of melatonin. I invite you to read this article which summarizes the most important and most recent results of melatonin research and provides an overview of diseases and conditions that may be prevented or treated by this hormone. Most of the presented results are so new and/or still so widely unknown among the public that you will be one of the first people to learn about them. They are highly fascinating and the available data makes clear that millions of annual deaths from various causes could be prevented by melatonin.
In fact, the older people get, the lower the endogenous melatonin synthesis in the pineal gland at night. Since melatonin is one of the master regulators of health, this progressive decline is likely one of the most important reasons for the fact that older people are more susceptible to various diseases, including unfavorable outcomes of several diseases (like infections). Synthesis of melatonin gradually declines, starting in the late twenties and already reaching a very low level in the fifties. People above 60 only produce extremely low amounts in the pineal gland, thus they have very low nocturnal melatonin levels compared with younger people (3).
In a review, published in 2020, the authors noted:
“From an evolutionary point of view, vitamin D and melatonin appeared very early and share functions related to defense mechanisms (...) A deficiency of these molecules has been associated with the pathogenesis of cardiovascular diseases, including arterial hypertension, neurodegenerative diseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bone diseases, metabolic syndrome, and diabetes, among others. During aging, the intake and cutaneous synthesis of vitamin D, as well as the endogenous synthesis of melatonin are remarkably depleted, therefore, producing a state characterized by an increase of oxidative stress, inflammation, and mitochondrial dysfunction (...) vitamin D and melatonin might share a synergistic effect in the protection of proper mitochondrial functioning.” (4)
Some new studies actually confirmed that vitamin D and melatonin have synergistic effects. You need sufficient amounts of both of them to protect your health.
Besides the age-related declining synthesis of melatonin, there are additional factors that reduce your melatonin status and, in this way, increase your health risks! These factors include exposure to artificial light at night, a lack of sunlight/infrared exposure during the day, insufficient intake of melatonin-containing foods, a lack of exercise or a diet low in tryptophan, which is the precursor of melatonin.
In fact, many believe melatonin is a hormone or molecule of darkness. This is an interesting half-truth. In reality, it is both: it is a molecule of both sunlight and darkness! For two reasons:
1. Studies have shown that bright light exposure during the day leads to a stronger melatonin synthesis in the pineal gland at night.
“Our results showed that nocturnal melatonin secretion was increased by exposure to bright light in the daytime” (5), the authors of an RCT concluded.
This is also the reason why bright light therapy during the morning or during the day improves sleep at night (21).
2. Exposure to near infrared radiation (NIR), which is an important part of sunlight, leads to an increase of intracellular melatonin. NIR from sunlight actually penetrates the skin and reaches tissues, bones, muscles and organs and increases the production of melatonin in the mitochondria of various cells in the body. Unlike the melatonin that is synthesized in the pineal gland at night which circulates in the blood, much of the extrapineal melatonin that is produced in various cells all over the body does not seem to enter the blood but remains in the cells of origin to protect them directly from harm/oxidative stress. In a new review, published in 2023, the authors concluded:
“...the avoidance of light at night and exposure to sun during the day are equally important to improve melatonin production…” (22)
Thus, if you want to have enough melatonin, you have to spend much or most of your day outside rather than in a house and you need to avoid artificial light at night. This is actually the “more normal” form of living. However, modern life is different. People spend more than 90% of their time indoors and the modern artificial lights in houses/buildings do not emit NIR. Most windows also block NIR from entering the building. In addition to that, at night, many people are still exposed to artificial lights which not only provide no NIR, but also reduce the synthesis of melatonin in the pineal gland.
Isn't it amazing how people nowadays do the opposite of what they should do to stay healthy? Not to forget all the other disease-promoting factors like unhealthy (fast) food, lack of exercise, stress, harmful medical interventions and drugs etc. We do not need to be surprised at all about the extremely high rates of chronic diseases.
“Incandescent sources introduced in the 1800s emitted 90% of their energy in the NIR. Starting in the 1950s, CFL and more recently LED lighting and displays, provide zero NIR. Coupled with Low E glass that blocks NIR from entering our homes, we now spend 93% of our time indoors exposed to zero NIR. This represents the largest reduction to solar exposure in human history. It is important that we understand the impact of eliminating 90% of the solar spectrum, which has had effects on biological processes such as melatonin production. Simultaneously, heavily modulated artificial light at night not found in nature has been introduced into the human environment. This has likely resulted in the increase in a wide range of diseases” (22), leading melatonin scientists described in 2023. It is highly likely that many younger people also do not have enough melatonin for that reason.
Of note, human-visible wavelengths (400 to 700 nm) and ultraviolet (UV) wavelengths (300 to 400 nm) account for almost half of the sunlight´s energy. UV-B (280 to 320 nm), is responsible for the vitamin D synthesis. NIR (700 to 1100 nm) accounts for the other half of the sun´s radiation (179)(180). Depending on the latitude (the higher the latitude, the worse) on cloudy days and/or in winter months, exposure to NIR may not be as high as on cloud-free days and/or during summer months, making it more difficult to produce enough melatonin intracellularly. Thus, besides the widely known problem with vitamin D deficiency, people may also have a high risk of not synthesizing sufficient amounts of intracellular melatonin in the winter, which increases health risks. A NIR lamp may be one of the possible ways to improve the melatonin status, especially in winter or during periods of low sun exposure. More about this in the end of the article.
In addition to the melatonin that is produced in the pineal gland at night, a high amount of the total melatonin in the body originates from extrapineal sources. These sources include:
-the intracellular synthesis (in mitochondria) of all or most cells, which synthesize melatonin in response to NIR or exercise, for example. In order for the cells to be able to produce melatonin, tryptophan must be available. Interestingly, the gastrointestinal tract contains 400 times more melatonin than the pineal gland and, other than many organs and cells in which melatonin is produced, the enterochromaffin cells of the gut do release some melatonin into the circulation after consumption of tryptophan. Once in the blood, melatonin may reach other parts of the body (24).
-low amounts of melatonin in foods like vegetables and nuts, the consumption of which also lead to an increased blood level of melatonin.
-and even the microbiota of the skin, mouth, intestinal tract etc (22).
As described above, the endogenous synthesis in the pineal gland declines during aging. It is likely that the ability of other organs and cells to produce melatonin (from sunlight, for example) also declines with increasing age. The same happens, for example, with the intracellular coenzyme Q10 synthesis. With increasing age, less and less of the antioxidant Q10 is produced within the cells, which is another very important reason why older people have much higher disease risks. It is possible that older people won't produce as much melatonin during exposure to NIR as younger people. Therefore, in order to support and protect health, supplementation might be reasonable in certain circumstances.
The following sections prescribe the overwhelming health benefits, documented in studies, that resulted from supplementation of melatonin. In the end of this article will be described what can be done (besides or in addition to taking a supplement) to improve the melatonin status of the body and cells.
Oxidative stress and inflammatory processes
Oxidative stress and inflammatory processes are involved in the development of or are the cause of almost all diseases and conditions. Melatonin is an extremely strong anti-oxidative and anti-inflammatory molecule.
Meta-analyses of randomized controlled trials (RCT´s) have shown that supplementation of melatonin significantly reduces oxidative stress, and increases the total antioxidant capacity of the body as well as the glutathione and superoxide dismutase levels. In other words, melatonin strongly improves the antioxidative defense system of the body and lowers oxidative processes (25). Intake of melatonin also significantly reduced important inflammatory parameters that are involved in the development of a wide range of diseases, like interleukin 1, interleukin 6 and interleukin 8 (26).
“Exogenous melatonin reduces levels of inflammatory markers and may be useful for prevention and adjuvant treatment of inflammatory disorders. Melatonin is safe with few side effects, which makes it an excellent agent for prevention of inflammatory disorders. Because chronic inflammation increases with aging and inflammation plays a role in the etiology of numerous diseases that affect older populations, melatonin has the potential to be widely used particularly in older adults”, (26) the authors of a meta-analysis concluded.
Infections and immune health
Most of the global annual deaths that are associated with or caused by influenza, pneumonia, Covid-19 etc. occur among older people. The fact that older people produce less melatonin is likely one of the most important reasons for this age-discrepancy. Of course, there are other reasons as well, including deficiencies of vitamin D and other micronutrients, reduced levels of antioxidant defense systems, like glutathione, chronic diseases and chronic inflammatory processes, an unhealthy diet, low exercise levels etc. However, many of these factors are associated with or caused by low melatonin, suggesting that melatonin deficiency may be one of the most important underlying reasons why these factors and comorbidities increase the risk of developing severe symptoms of such infectious diseases. Melatonin is critical. It is one of the most important immune regulators:
“Melatonin is a molecule with multiple activities on a virus infection. These include that it downregulates the overreaction of innate immune response to suppress inflammation, promotes the adaptive immune reaction to enhance antibody formation, inhibits the entrance of the virus into the cell as well as limits its replication (...) Several clinical trials have confirmed that melatonin when added to the conventional therapy significantly reduces the mortality of the severe COVID-19 patients. The cost of melatonin is a small fraction of those medications approved by FDA for emergency use to treat COVID-19. Because of its self-administered, low cost and high safety margin, melatonin could be made available to every country in the world at an affordable cost. We recommend melatonin be used to treat severe COVID-19 patients with the intent of reducing mortality”,
the authors of a review described (7).
Many annual deaths due to infections may be preventable if the melatonin deficiency of the elderly would be restored or if acutely infected patients would be treated with pharmacological doses of this hormone. Of course, more and more younger people also do not produce or get as much melatonin as they should, due to artificial light at night, low exposure to sunlight during the day, lack of exercise or low consumption of melatonin-containing foods etc. Because of such factors, several younger people may also be at higher risk of more severe (infectious) disease outcomes.
Of note, due to this molecule being mainly immunomodulatory and anti-inflammatory, melatonin is likely much stronger in preventing severe outcomes of infectious diseases than in preventing an infection (and a mild form of illness).
Sepsis
Sepsis is a life threatening medical emergency, affecting almost 50 million people per year. It is an overreaction of the immune system (immune hyperactivation) to an infection. Annually, sepsis contributes to or causes the death of more than 11 million people. While many of these deaths occur in low income countries, sepsis is also a leading cause of death in high income countries. In the US alone, it claims 260.000 lives per year. In fact, according to a comprehensive analysis, it was estimated that in 2017, sepsis accounted for or was involved in 19.7% of all global deaths. This means this condition is involved in or responsible for 1 in 5 deaths! (8)
Melatonin may help us solve this tragedy! The results of a new retrospective cohort study with US veterans, including more than 9000 patients with a primary inpatient admission diagnosis for sepsis, showed, after applying propensity score weighted Cox models (a valuable method to rule out confounding factors as far as possible), that melatonin treatment was associated with a 34% lower risk of 30-day overall mortality (HR = 0.665; 95% CI = [0.493–0.897]) (9)
Two double-blind, randomized placebo controlled trials, published in recent years, confirmed that melatonin is an effective treatment for sepsis. Septic patients who received 50 to 60 mg of melatonin per day, orally or intravenously, required less vasopressors, had more ventilator-free-days over a 28-day period, recovered faster and stayed less days in the ICU and in the hospital than those who were unlucky enough to receive a placebo. In addition, melatonin-treated patients had a statistically non-significant 37 bis 45% lower mortality, compared with the placebo-treated patients. Even though the reduction of mortality did not reach statistical significance in these two isolated RCTs (10)(11), due to the relatively small number of patients, it points to the same % risk reduction that was found in the much larger retrospective study which was previously mentioned. Also, efficacy (in the form of faster recovery from sepsis) of melatonin against sepsis has been proved in these RCTs. Thus, in the future, properly powered RCT´s, administering at least 50 mg of melatonin per day, are most likely going to find a significant reduction of mortality as well.
Melatonin has also shown to be an effective treatment for neonatal sepsis and significantly improved the clinical condition of sepsis in neonates from the intervention group, compared to the control group, within 3 days of therapy (RR: 2.212; 95% CI: 1.452 to 3.371; P < 0.0005) (12).
Neonatal sepsis is defined as sepsis that occurs in newborn infants less than 28 days old. It is a leading cause of morbidity and mortality among infants. Interestingly, while melatonin synthesis decreases with age and thus, low melatonin may be a contributing factor to the development of (older) adult sepsis, melatonin production in babies does not start until the first three to five months (13).
This may, in part, explain the especially high susceptibility of infants to severe illness and sepsis.
While breast milk contains melatonin, unfortunately many infants do not receive it. In fact, the absence of breastfeeding seems to be a significant risk factor for neonatal sepsis (14).Timing of initiation is critical as well. A study has shown that, if breastfeeding is started within the first hour of birth, the risk of severe neonatal illness and sepsis can be substantially reduced (15).
While breast milk also contains many additional, extremely important, defense substances, meta-analyses which showed that melatonin treatment is highly effective for neonatal sepsis suggest that this hormone is a critical ingredient in mother´s milk, promoting a healthy and regulated immune system that protects against infections and sepsis. The synthetic milk products (infant formula) that a very high number of infants receive instead of mother´s milk, are highly inadequate as they lack various important substances, including melatonin.
“Recently, we proposed that melatonin should be added to a night-time specific formula feed, in order to bring formula feed closer to the benefits of breast milk (7). The absence of melatonin in formula feeds is a major deviation from the evolutionary forces that underpin the presence of melatonin in night-time breast milk”,
researchers argued in a review (13).
The fact that breastfed individuals have much lower disease risks (both in the short and long term) may also, besides other defense substances, be due to melatonin that participates in the regulation and development of a healthy immune system and gut microbiota.
“Breastfeeding affords protection against a wide variety of medical conditions that may emerge at different time-points over the lifespan, including hospital admissions for respiratory infections and neonatal fever (4), (5), offspring childhood obesity and cancer (6), sudden infant death syndrome (SIDS) (7), as well as an array of other medical conditions, such as cardiovascular disease, obesity, hyperlipidemia, hypertension and types 1 and 2 diabetes (8).” (13)
Note that even though melatonin deficiency may, in part, explain why older adults and neonates are especially susceptible to sepsis, therapeutic high dose melatonin is also highly likely effective for sepsis in other age groups. This is because there is a big difference between normal levels and therapeutic/pharmacologic doses. While a normal or sufficient state of an essential substance like melatonin may reduce, to some extent, the risk of developing certain diseases (no 100% risk reduction), higher doses are often required to overcome or survive acute or chronic conditions. This is, in part, also the case because illnesses may, due to oxidative and inflammatory processes, result in a depletion of certain substances like vitamin C, melatonin etc.
So the need is much higher and therapeutic doses may be required.
If we (carefully) assume, based on the currently available data, that melatonin can reduce the mortality rate of sepsis patients by 35 to 40%, this would indicate that, of the yearly 11 million global sepsis deaths, approximately 4 million could be prevented by melatonin administration.
In order to provide an example: 4 million is the entire population of Los Angeles, the second most populous city in the USA.
While, admittedly, the currently available data may not be sufficient to draw a firm conclusion about the exact number of lives that may be saved, the number of 4 million is most likely an underestimation.
Why?
An RCT with 158 hospitalized Covid-Patients shows that patients who received 10 mg of melatonin per day had a significantly lower risk of developing sepsis.
After 17 days (longest follow-up time for sepsis incidence), 35.5% of the patients in the control group and only 8.5% of the patients in the melatonin group had developed sepsis. The risk of sepsis was reduced by more than 75%. (16)
Thus, if hospitalized patients who are suffering from any infection or who are especially vulnerable to developing sepsis, due to risk factors like old age, having comorbidities, being treated in the ICU, having a weak immune system or, in neonates, a low birth weight, premature birth, an infection of the mothers amniotic fluid etc. would be treated EARLY with melatonin, a very high number of sepsis cases could be prevented and thus it is possible that most sepsis deaths might be preventable with melatonin.
The Covid-Pandemic was truly eye-opening to the fact that early treatment of disease-stages is extremely important. The earlier you treat, the higher the chances of preventing fatal outcomes! Some of the most striking examples:
-0% of the 360 Covid-Patients who were treated by Dr. Accinelli within the first 3 days of their illness with Hydroxychloroquine and Azithromcycin died, compared with a case fatality rate of approximately 10% during the same period in the same country (Peru). Based on the CFR, more than 35 of these 360 patients from Dr. Accinelli should have died (17). However, early treatment prevented deaths completely.
-Dr. Fareed and Dr. Tyson from California who developed their own early treatment protocol for Covid-patients, consisting of hydroxychloroquine, zinc, azithromycin, vitamin D, vitamin C, aspirin and many more antiviral and anti-inflammatory drugs (protocol was individualized for each patient) had a similar success. Their study, written by Mathew Crawford is called “Low Rates of Hospitalization and Death in 4,376 COVID-19 Patients Given Early Ambulatory Medical and Supportive Care. A Case Series and Observational Study” and included the data of the first >4000 patients they had treated until march 2021 was added to their book. Most (90%) of these thousands of patients were treated early, within some days after onset of symptoms. And among those, 0% died. The study included a control group, consisting of more than 20.000 patients from the same county who did not visit their clinics and did not receive their treatment protocol. Among those, 2.3% died from Covid. The early treated patients from Fareed and Tyson thus had a 99.8% lower mortality risk (age-adjusted) p < 0.001 (18).
As of February 2023, they had already treated >18.000 patients early! And still had 0 deaths thanks to early treatment. I had the huge honor of being allowed to translate their book, to help them bring this life saving knowledge to other countries. Unfortunately, most Covid-patients in this world never received such effective early treatment protocols which is the main reason why there were a lot of deaths. Completely unnecessary deaths.
The same should be done with sepsis! Patients who are at risk of developing this life-threatening condition should be treated precautionarily, with melatonin and additional substances that have shown to regulate the immune response. Most sepsis deaths may be preventable in this way!
Besides vitamin C, D, glutathione etc. another treatment that receives too little attention is coenzyme Q10.
For example, in an RCT with septic patients who were still in the early phase of sepsis at baseline, only 35% of the patients in the control group survived, while in the intervention group that received 200 mg of Q10 per day, the survival rate was 80% (p: 0.01). Thus, Q10 treatment reduced the risk of death by approximately 70% (19).
All of these cheap and safe treatments should be combined and administered as early as possible. It is highly likely that this approach would prevent most of the annual sepsis deaths.
Covid-19
Could the age-related decline of the melatonin status be one of the most important reasons for the fact that Covid-19 is much more dangerous for older people? What if melatonin is one of the strongest protective factors? Scientists think so. For example, according to Shneider et al:
“The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don’t suffer from COVID-19 as much as their grandparents and have a much higher melatonin level (...) Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin(...) by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms…” (20)
Or according to Charaa et al:
“Melatonin secretion gradually decreases with age and becomes clear in people over the age of 60. This deprivation is inversely proportional to the increase in mortality due to COVID-19 with age (...) It is assumed that melatonin with its immunomodulatory and antiviral actions plays a protective role against the severity of SARS-CoV-2 infection. Following our review, we concluded that this hypothesis was highly plausible and we proposed a prophylactic treatment protocol against the severity of COVID-19 using a melatonin supplementation.” (27)
Note that these (and other scientific) articles proposing the use of melatonin had already been available in the beginning of the pandemic, in April and May 2020. Still in the same year, the results of a retrospective treatment study with 948 Covid-patients became available, showing that those who received melatonin following intubation had a 87% lower mortality, compared with those who did not receive it (28).
Given the extremely high safety and the low price and the fact that it is available over the counter in many countries, one would expect that health agencies and governments worldwide would recommend all infected patients to treat Covid early with melatonin, of course, in combination with other orthomolecular and conventional treatments that have shown to be effective for viral diseases and/or Covid-19, like vitamin D, zinc, HCQ etc. etc.) to prevent severe symptoms and hospitalizations. However, I can not remember that my government told me to do so. Can you? Dr. Fareed and Dr. Tyson actually informed their government about their success in 2020 and required widespread use of early treatment protocols. However, they have been ignored. The reason for the ignorance should be clear, so it does not have to be explained.
As of February 2023, the results of 18 controlled studies in which the effect of melatonin on Covid-outcomes has been investigated, are available. A meta-analysis of all these studies confirms a very strong treatment effect (199).
RCT´s have shown that patients who received melatonin (relatively) early during their disease course, recovered much faster. For example, in one RCT, patients with mild to moderate Covid received either standard therapy or standard therapy + 6mg of melatonin per day. After 2 weeks, 47% of the patients in the control group had recovered. However, in the melatonin group, 86% had recovered. Also, melatonin led to a significant reduction of inflammation (CRP).
“The result of this study confirmed the effectiveness of melatonin in mild to moderate outpatients with COVID-19”, the authors concluded (29).
A double-blind RCT showed that hospitalized Covid-patients who received 9 mg of melatonin (3x3 mg) per day had a much faster recovery and were able to leave the hospital approximately twice as fast as the patients in the control group (after 4.7 vs. 8.2 days). Thanks to melatonin, symptoms disappeared significantly faster.
“Compared with the control group, the clinical symptoms such as cough, dyspnea, and fatigue, as well as the level of CRP and the pulmonary involvement in the intervention group had significantly improved (p <0.05). The mean time of hospital discharge of patients and return to baseline health was significantly shorter in the intervention group compared to the control group (p <0.05).” (30)
Several meta-analyses have been published, confirming that melatonin is a very effective treatment for these patients (31)(32).
In an RCT with 158 hospitalized patients with Covid-pneumonia, 76 received only standard of care, 82 received standard of care + 10 mg of melatonin per day. In the control group, 17.1% of the patients died. This % hospital fatality rate was approx. in line with the overall worldwide mortality rate of hospitalized Covid-patients (33).
However, in the melatonin group, only 1.2% died (p = 0.001). This means: Melatonin reduced the risk of death by 93% (34).
And even when melatonin treatment started extremely late and was given to extremely sick ICU patients, it still significantly reduced mortality, as was confirmed in a double-blind trial (35).However, it is important to start treatment as early as possible. As the authors of a review explained:
“Many viruses, including the ones that cause a cytokine storm (like Covid-19) tend to decrease melatonin synthesis, which negatively affects the host’s immune system”
(...)
“Due to its demonstrated efficacy as an antioxidant, anti-inflammatory, and immunomodulator, the effects of melatonin can reduce the severity of symptoms and cellular damage induced by viral diseases when started as an early treatment.” (36)
By treating all patients with adequate doses of melatonin (as was already proposed in the beginning of the pandemic but widely ignored), this alone could have prevented a very substantial amount (maybe even most) of the deaths.
And interestingly, since melatonin also prevents or reduces the Covid-induced coagulopathy, it can also prevent the thromboses that have often been a cause of death of these people. Melatonin treatment reduced the risk of thrombosis in hospitalized Covid-patients by more than 50% (34).
However, melatonin and many other highly effective treatments have been widely ignored, which resulted in unnecessary suffering and deaths.
While scientists usually express themselves carefully, you can still hear the strong frustration about the denial of this treatment that leading melatonin scientists clearly expressed in their review in 2022:
“The failure of melatonin to attract attention as a potential treatment for COVID-19 is somewhat disappointing considering a number of scientific/medical papers that have recommended its use. This may relate to a number of factors, including the lack of promotion of its therapeutic use for this disease by any influential group. Numerous already-available pharmaceutical drugs have been repurposed for the potential treatment of COVID-19. Yet, no organization/agency has proposed the use of melatonin even though it is much less expensive (sometimes a 100-fold less costly than the proposed prescription medications), and based on the outcomes of recent published trials {95,96), it has efficacy in treating this condition. After an analysis of 27 publications related to the ability of drugs to successfully treat COVID-19, the authors concluded that melatonin is at least twice as effective as remdesivir or tocilizumab in reducing the inflammatory markers of a coronavirus 2019 infection {132]. Both remdesivir (Veklury) and tocilizumab (Actemra) are FDA authorized for use to treat select COVID patients suffering with a severe infection; both drugs have notable side effects and are given intravenously [133,134]. In contrast, melatonin has a high safety profile and can be taken orally or administered by any other route [16]. Since melatonin is non-patentable and is inexpensive, the incentive of the pharmaceutical industry to support its use is lost. Finally, pharmaceutical drugs are sometimes enthusiastically advanced by individuals who stand to gain financially [135].” (37)
Other infectious diseases
Since melatonin is one of the most important immune regulators with strong anti-inflammatory, antioxidant, antiviral etc. properties, it is reasonable to consider that it could also help treat other infections.
Even though more studies and clinical trials should be performed, the available evidence already indicates that melatonin may also be highly effective for all or many other infectious diseases, including bacterial, viral and parasitic infections. If infectious diseases around the world were treated routinely with (early high dose-adjuvant) melatonin as standard of care, millions of deaths could likely be preventable. Maybe to a similar extent as with high dose vitamin C. The combination of melatonin and vitamin C might even have synergistic effects.
Ebola, one of the deadliest viral diseases, may be defeated by melatonin, as described in a review from Anderson et al:
“Optimizing natural killer (NK) cell responses seems crucial to surviving Ebola virus infection. Melatonin increases NK cell cytotoxicity significantly, suggesting efficacy in managing the Ebola virus. Under conditions of challenge, melatonin increases heme oxygenase-1 (HO-1), which inhibits Ebola virus replication (...)
Melatonin's effects on hemorrhage are mediated primarily by a decrease in pro-inflammatory cytokines. By optimizing the appropriate immune response, melatonin is likely to afford protection to those at high risk of Ebola viral infection, as well as having direct impacts on the course of infection per se.” (38)
Other scientists agreed:
“The capacity of melatonin to prevent one of the major complications of an Ebola infection, i.e. the hemorrhagic shock syndrome, which often contributes to the high mortality rate, is noteworthy.” (39)
Many other data shows the (potential) ability of melatonin to fight other deadly viral diseases which are responsible for thousands or even millions of deaths like venezuelan equine encephalitis virus, viral hepatitis, west nile virus, respiratory syncytial virus (40)(41).
Influenza infections which also cause hundreds of thousands of global deaths per year, can likely be treated with melatonin (42). Although there are no clinical trials yet that investigated the effect of melatonin on influenza outcomes, based on all available data, it is likely that melatonin could also support and accelerate the recovery of influenza patients.
Viral (or vaccine-induced) myocarditis might also be an indication for melatonin, according to the authors of a review published in 2020:
“...melatonin ameliorates cardiac function and represses virus-induced cardiomyocyte apoptosis. Melatonin also repressed ER stress and maintained mitochondrial dysfunction. Sang and co-workers performed an in vivo study to investigate protective effects of melatonin on viral myocarditis and explore possible mechanisms. Melatonin treatment significantly ameliorated the myocardial injuries through improving myocarditis via repressing inflammation (...) Therefore, melatonin should be further considered as a new therapeutic agent for viral myocarditis (Sang et al. 2018).” (6)
There is also data that indicate melatonin may help treat tuberculosis. According to the authors of another review:
“...The results show that in 31 patients with TB (tuberculosis), mean MEL (melatonin) and 6-HMS concentrations were significantly lower than in the control subjects. The treatment of TB patients with MEL might result in a wide range of health benefits including improved quality of life and reduced severity of infection and may be considered as an adjunctive therapy to classic treatment of pulmonary TB.” (40)
What about drug-resistant or multidrug-resistant bacterial infections?
They are a leading cause of death, with more than 1 million fatalities around the globe. These infections are deadlier than malaria or HIV. The 6 leading pathogens responsible for deaths due to antibiotic drug-resistance are Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa (43).
As demonstrated in the following reviews and studies, melatonin has shown to be (potentially) effective for many or most of them:
“In vitro studies have demonstrated that MEL (melatonin) is effective against multidrug-resistant Gram-positive and Gram-negative bacteria, carbapenem-resistant Pseudomona aeruginosa, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus…” (40)
The authors of another review described:
“Klebsiella pneumoniae is a Gram-negative bacterium and the causative agent of several life-threatening nosocomial infections, including pneumonia (...)
Melatonin could alleviate K. pneumoniae infection-induced inflammation in three-dimensional lung spheroids. In conclusion, our study demonstrated that melatonin abrogated K. pneumoniae-induced inflammation and apoptosis in lung cells through AMPK. Our study demonstrated the potential of melatonin for therapy against K. pneumoniae infections including pneumonia.” (44)
Strikingly, melatonin may also help overcome antibiotic drug resistance in gram-negative pathogens like Escherichia coli:
“Colistin, a nonribosomal peptide antibiotic, is one of last-resort antibiotics against multidrug-resistant Gram-negative pathogens (...) However, the mobilized colistin resistance gene (mcr-1) and its variants that encode phosphoethanolamine transferases reduce the negative charge of lipid A and confer a substantial resistance to colistin (7,8). More problematically, the mcr-1 has already spread to over 40 countries/regions covering five of seven continents (9). Therefore, there is an urgent need to identify novel strategies to overcome MCR-mediated acquired colistin resistance in Gram-negative pathogens.”
(...)
Remarkably, although colistin or melatonin alone did not prevent a lethal infection by MCR-1-positive E. coli, a single dose of the combination treatments led to increased survival (...) combinations of colistin and melatonin significantly reduced the bacterial load(...) compared with colistin monotherapy. These data confirmed that melatonin dramatically rescues colistin activity in vivo.
(...)
Interestingly, we found that melatonin effectively reverses MCR-mediated colistin resistance both in vivo and in vitro through multiple modes of action. The discovery of melatonin as a new and safe colistin adjuvant provides a therapeutic regimen for combating Gram-negative bacteria infections.
(...)
In this study, despite the weak antibacterial effect of melatonin at low dosage on bacteria 54, we unexpectedly found that melatonin exhibits the highest potentiation (8 to 32-fold) with colistin in resistant bacteria. Additionally, this activity is independent of bacterial species and resistance gene types. To our knowledge, this study is the first to employ the co-application of melatonin and colistin to treat infectious diseases caused by resistant bacteria.” (45)
It is likely that melatonin would have to be administered in high enough doses, maybe intravenously, to make sure that required concentrations can be reached. Unfortunately, we do not yet know the exact doses that are required for such infections.
Other preclinical research indicates that melatonin may also be effective for various parasitic infections. Several research suggests that it could be an effective treatment for amoebiasis, chagas´ disease, toxoplasmosis, giardiasis, leishmaniasis, southeast asian liver fluke infection, trypanosomatidae cruzi and even malaria. Many of these parasitic infections cause significant global morbidity and mortality. The effects of melatonin include improvement of the host's immune function against parasites and reduction of the harm (and thus likely lower risk of death) done to the host during the infection (46).
With regard to malaria, controversial findings have been reported, with some results showing beneficial and others showing potentially harmful effects of melatonin, suggesting that it has complex actions in malaria. In order to overcome the potentially harmful impact of melatonin and to still being able to benefit from the positive effective, some researchers suggested to, for example, consider a coordinated administration of melatonin antagonists (to interrupt the synchronous maturation of the parasite) and melatonin in high doses to decrease the liver damage during the infection (40).
Even though more research should be conducted to investigate which infectious diseases respond best to or can be treated effectively with melatonin, the existing data suggest that melatonin is likely a highly valuable possibility to reduce global mortality from many infections.
Cancer
Melatonin hates cancer cells and cancer cells hate melatonin.
If you want to grow cancer cells in a petri dish, make sure not to add melatonin.
Many experimental studies have shown that melatonin has strong anti-cancer effects. This includes pancreatic, prostate, breast, colorectal, ovarian, oral, ovarian, brain tumors and cancers etc.
The fact that the older people get, the higher their risk of cancer, may in part be due to the progressive decline of melatonin with increasing age.
Besides older age, modern lifestyle with unhealthy diets, lack of exercise, exposure to artificial light at night and limited exposure to NIR from the sun etc. also result in a reduced melatonin status in both younger and older people.
In a review published in 2017, melatonin researchers noted:
“There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases (...) What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth.” (47)
In another review published in 2021, the authors summarized:
“Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies.” (48)
Even skin cancers like melanoma are targeted by melatonin:
“Collectively, based on in vitro and in vivo studies, melatonin possesses promising anti-cancer properties via its ability to regulate multiple cell signaling pathways such as MAPK and PI3K/Akt/mTOR. In addition, melatonin has been shown to regulate cytoskeleton remodeling during the mitosis phase of the cell cycle, resulting in the inhibition of melanoma growth. Importantly, melatonin exerts synergistic effects in combination with vemurafenib, resulting in the augmentation of vemurafenib efficacy against melanoma”, the authors of a review, published in 2023, concluded (49).
Scientists identified low melatonin levels in cancer patients and assumed a causal association between a reduced melatonin availability and cancer development. For example, the authors of a meta-analysis that investigated the association of melatonin and breast cancer, concluded:
“Our data suggest that low levels of melatonin might be a risk factor for breast cancer.” (200)
It is thus possible that improvement of the melatonin status may reduce the risk of developing cancer. Unfortunately, there are not many prophylaxis studies yet. However, there is at least one. And this is a high quality nationwide cohort study from Sweden, published in 2021.
The authors of this study wanted to investigate whether supplementation of melatonin had an impact on colorectal cancer (CRC) incidence, which is the third most common type of cancer.
The results:
“As far as we know, this retrospective nationwide cohort study is the first population-based study to explore whether the use of melatonin was associated with a reduced CRC risk in older adults. We found a statistically significant inverse association between melatonin use and CRC incidence among older adults. In addition, the reduced risk was associated with an increased cumulative dose of melatonin use, and individuals with the highest doses have a 34% reduced risk of developing CRC. The association was apparent irrespective of CRC location and cancer stage at diagnosis. Our study highlights the possibility of melatonin as a potential chemopreventive agent for the primary prevention of CRC from nationwide real-world data.”
Even though this was not an RCT, the fact that the researchers found a dose-dependent effect (the higher the dose, the lower the risk of cancer), strongly increases the likelihood that the association was causal: Melatonin intake reduced this cancer (50). More studies should be conducted to investigate which other cancers can be prevented with melatonin and what the ideal doses are.
Melatonin (20 mg daily or more) has also been used successfully as a treatment. The newest meta-analysis of RCT´s shows that the tumor remission rate was significantly higher in the melatonin group than in the control group (relative risk [RR] =2.25; 95% CI, 1.86-2.71; P<0.00001; I 2=9%).
The melatonin group also had a significantly higher overall survival rate (RR =2.07; 95% CI, 1.55-2.76; P<0.00001; I 2=55%) (51).
“Based on the above meta-analysis results, it was concluded that MLT, as an adjuvant for the treatment of tumors, can effectively improve the remission rate and overall survival rate of tumor patients…” (51)
Strikingly, patients who received melatonin also had a much lower risk of side effects like thrombocytopenia, neurotoxicity, fatigue, asthenia, and hypotension from radio-chemotherapy (52)(53).
Melatonin was effective in various different cancer forms, including breast, brain, lung, and cancers of the digestive tract (51)(54).
For example, adjuvant melatonin treatment (20 mg daily) has also shown to increase survival among glioblastoma patients (a form of brain cancer). While the control group that received only standard therapy only had a 6% survival rate at 1 year, the melatonin group had a 43% survival rate (55).
Unfortunately, most of the available results are limited to the evaluation of 1-year survival in patients with advanced cancers. However, there are a few studies that investigated a longer timeframe. For example, in an RCT with metastatic non-small cell lung cancer, those who received -in addition to a chemotherapy regimen- melatonin (20 mg daily in the evening) had a much longer survival rate than patients who received the chemotherapy regimen without melatonin.
“Both the overall tumor regression rate and the 5-year survival results were significantly higher in patients concomitantly treated with melatonin. In particular, no patient treated with chemotherapy alone was alive after 2 years, whereas a 5-year survival was achieved in three of 49 (6%) patients treated with chemotherapy and melatonin. Moreover, chemotherapy was better tolerated in patients treated with melatonin. This study confirms, in a considerable number of patients and for a long follow-up period, the possibility to improve the efficacy of chemotherapy in terms of both survival and quality of life by a concomitant administration of melatonin.” (56)
Unfortunately, these patients already had strongly progressed cancers with metastases. This means: Treatment with melatonin started very late.
In order to find the true effect of melatonin, we need to have many more studies that test early treatment! The earlier treatment starts the better. In most available studies, melatonin was administered to patients with advanced cancer. We need early treatment studies with melatonin administration starting from the first day of diagnosis. Most likely, this would result in even better outcomes, including remission or cure rates, and more strongly improved survival.
While melatonin is not the “magic bullet” and does not cure all patients, it is clearly an effective treatment which should be part of an individual integral protocol that aims at solving all causes. Treating cancer exclusively with conventional treatment, with or without melatonin, is not the golden way out. Other highly relevant factors including diet, toxins, micronutrient deficiencies, lack of exercise, disturbed gut microbiota and especially psychological causes of the disease have to be addressed as well. Melatonin may be part of such a comprehensive individualized protocol that starts as early as possible. But it should, just as little as chemotherapy, not be used as a monotherapy.
We do know that, among many other orthomolecular treatments including vitamin C or Q10, daily vitamin D supplementation also significantly reduces the risk of cancer mortality (57).
Based on the available results from meta-analyses of RCT´s, scientists concluded that many thousands of annual cancer deaths may be preventable by routine vitamin D supplementation of older adults.
“Our results support promotion of supplementation of vitamin D among older adults as a cost-saving approach to substantially reduce cancer mortality.” (58)
Interestingly, a study from 2021 indicates that melatonin and vitamin D have synergistic effects in cancer prevention and treatment. For example, an in vitro study suggests that the combination of melatonin + vitamin D is much more effective in the treatment of breast cancer than the single administration of either melatonin or vitamin D alone.
“The effectiveness of combination was manyfold than individual effects and same trend was reflected in their ratio (Bax/BCL-2)(...) This finding is an interesting addition in the literature because it highlights that this combination is not only effective through indirect positive effects on patients health, including better quality of life mediated through melatonin and vitamin D3, but the effect is also direct though attenuating the key genes directly.
(...)
Overall, the role of melatonin and vitamin D3 on induction of apoptosis and inhibition of cancer cell proliferation is multifaceted, but playing a direct role in key molecular players, Bax and BCL-2 (...) In conclusion, the study supports the use of both melatonin and vitamin D3 as an adjuvant therapy along with conventional chemo- and radiation therapy in breast cancer”, the authors concluded (59).
A deficiency of both could contribute to a higher susceptibility of cancer and may especially promote unfavorable outcomes.
Hopefully, we will soon have studies that investigate the prophylactic and curative effects of combined vitamin D and melatonin supplementation. Probably, the effects of this approach will be even stronger than the results of the currently available RCT´s that already show significant benefits with single intake of vitamin D or melatonin.
Of note, while it is well established that sun exposure is protective against many cancers, including colorectal-, prostate-, breast cancer and non-Hodgkin's lymphoma (217). Besides vitamin D, an increased intracellular synthesis of melatonin may, in part, be responsible for this protective effect.
Heart diseases
While cardiovascular diseases are the leading cause of death, melatonin may help protect cardiovascular health and prevent heart diseases and reduce the risk of myocardial infarction and stroke via many different mechanisms, including strong antioxidant, anti-inflammatory, anticoagulant, direct cardioprotective and lipid-lowering effects. In several studies, melatonin has also shown to reduce the progression of atherosclerosis (60)(61).
In fact, in recent years, melatonin has been identified as a new potential therapeutic approach for atherosclerosis, which is the underlying cause of 50% of all deaths in western countries like the US (62).
“Collectively, our study revealed that melatonin prevented atherosclerotic progression via the blockage of NLRP3 inflammasome activation and inflammatory factor secretion, which was a novel mechanism of melatonin against AS (Atherosclerosis). Melatonin induced Sirt3/FOXO3/Parkin-mediated mitophagy and decreased mitochondrial ROS production, thereby attenuating NLRP3 inflammasome activation in macrophages. Taken together, our study provides novel insight into melatonin as a new target for therapeutic intervention for AS”, the authors of a study concluded (61).
Blood lipids/Cholesterol
Also, many studies have shown that melatonin can reduce risk factors for cardiovascular diseases, including cholesterol. According to meta-analyses, supplementation reduces triglycerides, low density lipoprotein cholesterol and total cholesterol levels (if total cholesterol baseline levels are >200 mg/dl).
The effective dose was ≥8 mg/d and the lipid-lowering effects may start becoming visible after 2 months of continuous intake.
“Meta-analysis suggested a significant association between melatonin supplementation and a reduction in triglycerides (WMD: -31.54 mg/dL, 95% CI: -50.71, -12.38, p = 0.001), and total cholesterol levels (WMD: -18.48 mg/dL, 95% CI: -35.33, -1.63, p = 0.032)”, the authors of a meta-analysis explained (63).
The authors of another meta-analysis concluded:
“The results of our systematic review and Meta-analysis showed that supplementation of melatonin could be effective in improving lipid parameters and should be considered in the prevention of cardiovascular disease…” (64)
Hypertension
Another new meta-analysis shows that controlled-release melatonin (not an immediate-release preparation) can reduce the systolic blood pressure during sleep.
It also reduced asleep and awake diastolic blood pressure, without reaching statistical significance (65).
While more studies should be conducted, a clear trend is already visible: Melatonin participates in the regulation of blood pressure. But it is necessary to maintain a stable melatonin level which is possible by taking a controlled release product before sleep.
The fact that younger people produce more and have higher melatonin blood levels at night than older people, may, in part (besides several other factors) explain why they have a lower risk of developing cardiovascular diseases. Older people might overcome this reduced synthesis and reach a higher nocturnal blood level by taking a melatonin product, especially a controlled-release product.
Preeclampsia
Preeclampsia is a dangerous hypertensive disorder during pregnancy. 2 to 8% of all pregnant women are affected. Worldwide, it is responsible for more than 50.000 maternal and 500.000 fetal deaths per year (66).
Since melatonin has antihypertensive, antioxidant and anti-inflammatory effects, it makes sense to assume that it may be able to prevent preeclampsia or reduce its fatal consequences. In fact, a meta-analysis has shown that low melatonin levels are associated with the development and the severity of this disorder (67).
“Melatonin is a safe, endogenous hormone with impressive antioxidant and antihypertensive effects that may make it a useful adjuvant for the management of preeclampsia. These antioxidant effects have been elucidated in placenta cells, in mitochondria, and in vascular cells, all key contributors to the pathogenesis of preeclampsia (...) Perhaps most excitingly, melatonin may offer benefits that extend beyond maternal care to protect the fetal brain in hostile intrauterine environments, such as FGR. Melatonin has been investigated for a host of other disorders related to pregnancy. None of these studies raised safety concerns, even in high doses. Collectively, these findings highlight that melatonin is an exciting candidate for an adjuvant therapy for preeclampsia (...) An abundance of in vitro, animal-based and clinical evidence supports a role for melatonin in the management of preeclampsia, and indeed other disorders of pregnancy”, the authors of a review concluded (68).
Until now, the results of one RCT (a phase-1 trial) are available, showing significant benefits with melatonin, including an extended diagnosis to delivery interval and a lower need for pregnant women to increase antihypertensive medications. The researchers concluded:
“We have shown that melatonin has the potential to mitigate maternal endothelial pro-oxidant injury and could therefore provide effective adjuvant therapy to extend pregnancy duration to deliver improved clinical outcomes for women with severe preeclampsia.” (69)
More results will likely be available soon. Melatonin might be an effective treatment to prevent or treat preeclampsia.
In addition to that, never forget vitamin D during pregnancy. New meta-analyses of RCT´s have shown that vitamin D supplementation reduces the risk of preeclampsia by more than 60%. The higher the dose, the stronger the protective effect.
“Our findings are a call for action to definitively address vitamin D supplementation as a possible intervention strategy in preventing preeclampsia in pregnancy.” (70)
Strikingly, a meta-analysis from 2022 has shown that vitamin D supplementation during pregnancy reduces the risk of intrauterine or neonatal deaths by >30%. (72)
Another meta-analysis of RCT´s found that, in order to reduce the risk of unfavorable pregnancy outcomes, a daily dose >2000 I.U. is required.
In this way, gestational diabetes mellitus can also be reduced significantly (71).
Of note,a diagnosis of preeclampsia is independently associated with a strongly increased risk of developing heart failure or cardiovascular diseases in the future (73). Even for this reason, the fact that vitamin D (and probably also melatonin) can reduce the risk of preeclampsia, is highly valuable.
Myocardial infarction and injury
According to a prospective nested case-control study of participants from the Nurses' Health Study cohorts I and II, a lower nocturnal melatonin secretion was associated with a significantly higher risk of incident myocardial infarction, especially among women with an increased body mass index. The authors concluded that melatonin deficiency may be a novel and modifiable risk factor for myocardial infarction (74).
However, melatonin may not only help prevent heart diseases, it can also be used to treat acute myocardial infarctions or strokes to improve the clinical outcomes. Even though the survival rate of acute heart attacks has increased thanks to better treatments, many people who suffered a myocardial infarction still die within the following year.
“…myocardial infarction leads to chronic heart failure in many cases, exerting a huge global healthcare burden on a country’s economic resources. Despite timely reperfusion with primary percutaneous coronary intervention, mortality and morbidity following AMI (acute myocardial infarction) remain significant, with 7% death and 22% hospitalization for heart failure at one year.” (75)
The reperfusion (via implementing stents, balloons, bypasses etc.) strategies, such as the so called percutaneous coronary intervention or coronary artery bypass grafting that patients who suffered a heart attack often receive are a double-edged sword. On the one hand, they help reduce short- and medium-term mortality. On the other hand, they lead to so called myocardial ischemia/reperfusion (IR) injury. They harm the heart muscle. And this is one of the reasons why myocardial infarction patients have a high risk of developing heart failure within the following months. However, melatonin can help! A meta-analysis has shown that patients who received melatonin in association with reperfusion treatment (due to myocardial infarction, for example) had significantly lower troponin levels following the intervention, compared with those who received reperfusion treatment without melatonin. Lower troponin levels indicate that the damage done to the heart muscle is lower. And thus, the risk of negative long term outcomes (like developing heart failure) is lower as well. The authors concluded that melatonin is a cardioprotective agent (76).
Melatonin needs to be given before or during these interventions, because it has to be distributed in the myocardial areas to protect them from the damaging effects of the reperfusion. Since melatonin seems to be able to protect the heart from damage, one can assume that it also reduces the direct harm caused by a heart attack. Thus, if you have enough melatonin, you are not only at lower risk of suffering a heart attack, but an incident heart attack and the hospital-treatment of this heart attack would also cause less injury and have a less fatal impact.
In a recent study, 94 patients who underwent primary percutaneous coronary intervention due to an acute myocardial infarction, were randomized into two groups and received either intravenous melatonin or placebo during this reperfusion treatment. After two years of follow up, the primary endpoint (defined as: death or readmission to hospital due to heart failure) occured in 20.4% of the placebo patients and only in 6.7% of the patients who received melatonin after their heart attack. This translates into a 67% lower risk of suffering the primary endpoint within two years of follow up.
“The results of this pilot study indicate that treatment with intravenous melatonin in patients with AMI (acute myocardial infarction) undergoing primary percutaneous coronary intervention is associated with a reduced incidence of death or readmission due to heart failure.” (75)
Melatonin may thus not only reduce the risk of ever having a myocardial infarction, it also improves the long term prognosis of affected patients.
In a recent article, published by the orthomolecular news service, cardiologist Dr. Levy explained that Covid-infections and Covid-vaccinations may cause inflammation of the heart (leads to an elevated troponin level in the blood) which is likely responsible for many of the excess deaths that were seen during recent years. Especially since the vaccines were introduced, mortality increased in many countries. There was a strong increase in excess mortality following vaccination programs in highly vaccinated countries. And this was probably not only a “correlation” but actually causal, as analyses of data scientists like Prof. Neil and Prof. Fenton show:
“There is a clear signal that the vaccination programme is causing, at least, some of the excess death rate”, the professors concluded in their analysis, published in Dec 2022 (77).
Or according to the excess-mortality analysis from Professor Kuhbander and Professor Reitzner from Aug 2022:
“As can be seen (...) a visible positive effect of the vaccinations on excess mortality does not occur. Instead, the opposite is observed. Although at the beginning of September 2021, 82.7% of the population over 60 years and 65.2% of the population from 18–59 years were fully vaccinated, the number of excess deaths nevertheless started to increase strongly, reaching a level of almost 15, 000 excess deaths in December 2021 (...) The number of excess deaths closely follows the course of the number of vaccinations, showing an increase as soon as the number of vaccinations increases, and a decrease as soon as the number of vaccinations decreases. A similar safety signal in terms of a temporal relationship between an increase in vaccinations and deaths is also observed at the level of stillbirths. Exactly with the beginning of the vaccinations in the age group 18-59, the number of stillbirths suddenly increased after being stable for at least the two previous years.” (79)
Autopsy studies also confirmed that many of the (sudden) deaths that were seen in abundance in the populations following the mass vaccination programs can be causally linked to vaccination (vaccine-induced lethal inflammation of the heart) (78).
Dr. Levy argued that everyone should check troponin (and D-dimer) levels to find out whether there is a (subclinical) inflammation in the heart. If elevated, it should be treated with a protocol which includes various micronutrients and high dose vitamin C.
Since melatonin has shown to be cardioprotective, it may be considered to add it to this protocol. We do know that melatonin reduces the risk of developing thrombosis following a Covid-infection and we do know that melatonin prevents heart damage. As described in the section “Other infectious diseases”, there is also evidence that melatonin prevents or reduces myocarditis (inflammation of the heart).
It is thus reasonable to assume that not only many of the Covid-deaths but also many of the Covid-vaccine-induced deaths could have been prevented by early administration of melatonin.The anti-inflammatory, anticoagulant and cardioprotective effects of melatonin have been known before the pandemic started and before the vaccines were rolled out. The damages that Covid-vaccines can do to the circulatory system and to the heart have been known since early on. Thus, not only Covid-patients should have been treated with melatonin, but also vaccinated people should have received melatonin, at least for some days, to prevent or reduce the damages. Many of the Covid-deaths and vaccine-fatalities might have been preventable in this way.
Heart Failure
Heart failure is, unfortunately, a frequent disease. It is not only caused by myocardial infarction but has many different causes or risk factors. A deficiency of melatonin is likely an important cause. Worldwide, 23 million people are suffering from it (80). It mainly affects older people (who have very low melatonin) with a prevalence of 1 in 5 persons above 75 years (81).
Double-blind studies have also shown that melatonin is an effective (adjuvant) treatment for heart failure patients. It can significantly improve the heart functions (left ventricular ejection fraction) and reduce the severity of the disease (82)(83). The clinical outcomes, including the quality of life, improved as well. In other words, thanks to melatonin, the heart will have more energy again and will work more effectively, which leads to a reduction of the typical heart failure symptoms like shortness of breath, fatigue, irregular heartbeat, lowered ability to walk or do exercise (82)(83).
Since melatonin improves the heart functions, it most likely reduces the risk of death of these patients as well.
Importantly, to improve the prognosis even further, besides their usual care, heart failure patients should not only be treated with melatonin but also with other orthomolecular substances that improve the mitochondrial energy synthesis. Coenzyme Q10 is one of the most important agents for these people. In a double-blind trial, with 420 heart failure patients, long-term supplementation of daily Q10 (300 mg) has shown to strongly improve the heart function and reduce the symptoms and the risk of hospitalization and death. In fact, cardiovascular and all cause deaths were almost cut in half in the Q10 group during the 2 years of follow up: cardiovascular mortality (9% vs. 16%, p = 0.026), all-cause mortality (10% vs. 18%, p = 0.018), and incidence of hospital stays for HF (p = 0.033). (84)
Most likely, had the patients received Q10 + melatonin, the outcomes would have been even better. In order to profit from a synergistic effect, all cardiovascular-relevant micronutrients should be combined.
Stroke recovery
Melatonin has been used successfully in the treatment of stroke patients. It improves the recovery of both ischemic stroke and hemorrhagic stroke. In a double-blind RCT, published in 2022, patients with acute ischemic stroke received either placebo or 20 mg melatonin daily for five days. 30 and 90 days after treatment, the patients who received melatonin had significantly less neurological deficits and a lower stroke-related functional disability, compared with the placebo group.
“Although preliminary, our findings support the hypothesis that early treatment with melatonin may be helpful in improving functional and neurological recovery following stroke”, the authors concluded (85).
In another double-blind study with the title “Melatonin Supplementation May Improve the Outcome of Patients with Hemorrhagic Stroke in the Intensive Care Unit”, 40 adult hemorrhagic stroke patients in the ICU received either placebo or 30 mg of melatonin every night via nasogastric tube. Both the duration of mechanical ventilation (4 vs. 12 days) and ICU stay (8 vs. 12 days) were lower in the patients who were treated with melatonin, compared with placebo (significant for ICU stay and almost significant for mechanical ventilation). And even though it was not statistically significant, due to the relatively low number of patients in this study, mortality was 50% lower in the melatonin patients (15% vs. 30%) (86).
Melatonin prevents ventilator-associated lung injuries which may be one of the many mechanisms by which it reduces mortality in these patients. Also, melatonin can shorten the duration of mechanical ventilation by decreasing the amount of required sedative agents. Sedatives like morphine have respiratory depressant properties. Thus, if people receive melatonin, they do not need such a high amount of sedatives and so it is much easier to stop mechanical ventilation.
This was also confirmed in another double-blind study with traumatic intracranial hemorrhage patients (brain bleeding due to a head trauma). In those who received melatonin, the duration of ventilation was much lower than in the placebo group (7 vs. 12 days) and the requirement for sedatives like morphine was reduced. Also, according to the Glasgow Coma Scale, melatonin improved the neurological outcomes of the patients. They regained consciousness faster. (87)
Non-alcoholic fatty liver disease (NAFLD)
Melatonin also helps protect your liver.
“Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of about 25%. Incidence is increasing with rising levels of obesity, type 2 diabetes and the metabolic syndrome, and NAFLD is predicted to become the leading cause of cirrhosis requiring liver transplantation in the next decade”,
the authors of a 2018 review described (88).
In addition, NAFLD is also a leading cause of hepatocellular carcinoma. In the global overweight population, the prevalence of NAFLD is even 70%. (89)
Since melatonin is a regulator of lipid metabolism, it reduces liver fat accumulation. It also reduces oxidative stress and prevents lipid peroxidation inside the liver. In this way, melatonin may prevent/reduce the development or progression of NAFLD and thus protect the liver from severe complications such as steatohepatitis, cirrhosis, hepatocellular carcinoma and liver failure.
Besides other measures like weight loss, improving diet and physical activity, melatonin may aid in the treatment of this condition. Meta-analyses show that melatonin supplementation improves several liver parameters in patients with NAFLD (90)(91).
In the liver, melatonin scavenges free radicals to prevent lipid peroxidation and lipid membrane peroxidation, which has a main role in progression of steatosis to steatohepatitis, necrosis of liver cells, inflammation, stress oxidative, rising transaminases, and fibrosis.
The authors of a meta-analysis concluded:
“Melatonin could reduce the progress of NAFLD. It might also decrement hepatic function parameters. Thus, it could be used for managing NAFLD and possibly as part of the treatment plan for patients with NAFLD.” (90)
Bone loss
Even though this may be especially surprising for many people, new research shows that melatonin is similarly important for the maintenance of bone health as vitamin D, K2 etc. Double-blind studies with peri- and postmenopausal women have shown that supplementation of melatonin (3 mg daily before bedtime) helps prevent bone loss and can even increase bone mineral density (at femoral neck or in the spine) (92)(93). Thus, the reduced melatonin synthesis in older people may be one of the causes of “age-related” bone loss, osteopenia or osteoporosis and the subsequently increased risk of fractures. Especially in older people, fractures are extremely dangerous as the resulting inability to move and the long hospital stays may lead to a fast and severe physical degradation…
In order to maintain or improve bone health, it is important to provide all or many of the relevant micronutrients in a sufficient concentration.
In 2017, a very interesting double-blind study was published. Postmenopausal women with osteopenia (preliminary stage of osteoporosis) were treated with placebo or with MSDK, a daily combination of melatonin (5 mg), strontium citrate (450 mg) vitamin D (2000 I.U.) and vitamin K2 (60 mcg). The results were very promising, showing a meaningful increase in bone mineral density (BMD) and thus, a lower fracture risk probability in the future.
“In conclusion, combination melatonin, strontium (citrate), vitamin D3 and vitamin K2 significantly increased lumbar spine BMD by 4.3% and left femoral neck BMD by 2.2%, with a trend (p=0.069) towards an increase in hip BMD from baseline after one year in postmenopausal osteopenic women. The 10-year vertebral fracture risk probability decreased by 6.48% in response to MSDK therapy compared to 10.8% increase in placebo. MSDK reduced bone marker turnover primarily by increasing the bone formation marker P1NP and maintaining healthy bone turnover (↓CTx:P1NP ratios). MSDK demonstrated positive effects on inflammatory status and improved quality of life especially related to sleep.” (94)
While there are many additional nutrients and interventions (like exercise) that can or should be implemented to protect and restore bone health, one of the most promising measures is the intake of blackcurrant powder.
In 2022, a double-blind study was published, showing that the daily intake of 784 mg blackcurrant powder for 6 months significantly reduced the loss of whole-body bone mineral density in postmenopausal women.
“These findings suggest that daily consumption of 784 mg of blackcurrant powder for six months mitigates the risk of postmenopausal bone loss, potentially through enhancing bone formation.”
Of note, a lower dose (392 mg) was less effective (95).
Eye diseases
Melatonin, as one of the strongest antioxidants, protects the eyes from oxidative stress and in this way helps prevent certain eye diseases. For example, scientists describe that the age-related decline of melatonin status is one of the main underlying causes of “age-related” macular degeneration (AMD). (96)
According to authors of a review, published in 2020:
“The effect of melatonin on mitochondrial function results in the reduction of oxidative stress, inflammation and apoptosis in the retina; these findings demonstrate that melatonin has the potential to prevent and treat AMD.” (97)
AMD is (in a progressed form) the leading cause of vision loss or blindness in older people and affects 20 million people in the US. And:
“Melatonin has been shown to have the capacity to control eye pigmentation and thereby regulate the amount of light reaching the photoreceptors, to scavenge hydroxyl radicals and to protect retinal pigment epithelium (RPE) cells from oxidative damage. Therefore, it is reasonable to think that the physiological decrease of melatonin in aged people may be an important factor in RPE dysfunction, which is a well known cause for initiation of AMD,” the authors of a study explained.
In other words, melatonin deficiency may be one of the main causes of the (“age-related”) degeneration of macula which may finally lead to severe vision loss or even blindness. Melatonin protects your eyes.
In a case-series with 55 AMD patients (both wet and dry forms included), melatonin, 3 mg each day before bedtime, has shown to reduce pathologic macular changes in most participants.
“At 6 months of treatment, the visual acuity had been kept stable in general. Though the follow up time is not long, this result is already better than the otherwise estimated natural course (1,2). The change of the fundus picture was remarkable. Only 8 eyes showed more retinal bleeding and 6 eyes more retinal exudates. The majority had reduced pathologic macular changes. We conclude that the daily use of 3 mg melatonin seems to protect the retina and to delay macular degeneration. No significant side effects were observed.” (98)
Due to its strong antioxidative effects, melatonin is also likely effective in the prevention and treatment of other eye-conditions. For example, an RCT published in 2023 indicates that melatonin can reduce the risk of retinopathy of prematurity (ROP). This condition often affects preterm infants who have to undergo oxygen therapy. It can lead to many visual impairments and is the leading cause of blindness in infants. Preterm infants who received melatonin (3 mg/kg/day), administered from day 7 of birth to the end of week 37, had a 63% lower risk of developing an ROP. However, unfortunately, randomization was not ideal in this study, which may reduce the reliability of the result. Thus, this study should not be considered a proof but rather a strong hint that melatonin, in addition to standard treatment, might be able to reduce the risk of ROP (99).
Neonatal respiratory distress syndrome (RDS)
Neonatal respiratory distress syndrome is a frequent cause of mortality in neonates, annually affecting approximately 24.000 neonates in the US alone.
0.5 to 1% of all neonates develop this syndrome. Risk factors include low birth weight and prematurity (100). Melatonin has shown to be a highly effective treatment and its administration can be considered in addition to the standard therapy. For example, the authors of a placebo-controlled study published in 2004 summarized their findings like this:
“In the current study, we extend the original observations and report results in which 120 newborns diagnosed with RDS were either treated with melatonin (60 children) or given placebo (60 children). The cytokine measures were consistent with the previously reported findings and showed that melatonin reduced these values and also lowered nitrite/nitrate levels in serum of newborns with respiratory distress (...)Two of the non melatonin-treated newborns died while no children who received melatonin died. Melatonin was well tolerated by the newborns.” (101)
In another RCT with 80 neonates suffering from RDS that was published in 2022,
5 mg/kg/day of melatonin per gastric tube for 3 days in addition to standard treatment, which included administration of surfactant (a therapy that reduces mortality among RDS neonates), has shown to massively reduce risk of death.
In fact, the neonates in the group that received standard of care + melatonin recovered much faster and had a 50% lower risk of death.
Also, the risk of developing bronchopulmonary dysplasia, a chronic lung disease, was lower in the melatonin group (102).
Another RCT with 100 neonates with RDS has shown that early administration of melatonin reduces the risk of requiring mechanical ventilation by 75% (103).
Irritable bowel syndrome (IBS)
More than 10% of the worldwide population is suffering from IBS. Melatonin may be a very effective treatment for this condition. The enterochromaffin cells in the gastrointestinal tract are an important source of endogenous melatonin.
It regulates gastrointestinal smooth muscle motility, prevents inflammation and pain (104). It was shown that IBS patients have a dysregulated endogenous melatonin secretion (they do not produce enough melatonin).
The deficiency of melatonin in the gastrointestinal tract may be an important cause of the symptoms. A new meta-analysis found that, compared with placebo, supplementation of melatonin significantly reduced the severity of IBS. The effect was independent of additional medications. Melatonin was effective, no matter if it was administered as an adjuvant or as monotherapy. Pain also improved significantly, following the intake of melatonin, compared with placebo (105).
Even though more studies should be conducted, melatonin seems to be a very effective treatment for these patients. And although melatonin was regarded as safe and did not cause severe adverse events in IBS patients, clinicians who treat these patients with melatonin need to be aware that melatonin might be able to increase the colonic transit time in IBS patients. While this may be very beneficial for IBS-diarrhea-dominant patients, it could (maybe in rare cases) lead to problems for IBS-constipation-dominant patients. There are no reports about severe adverse effects (like ileus) of exogenous melatonin in IBS patients. However, it is important to be aware of potential problems, especially in the constipation-dominant patients. It is important to choose the right (individual) dose. Some data show that low dose melatonin may actually accelerate intestinal transit time. A high dose, on the other hand, slowed it. Thus, it might be reasonable to consider treating IBS-diarrhea-dominant patients with a higher dose, while IBS-constipation-dominant patients should be treated with lower doses (and of course, stopping treatment or reducing the dose even further if a prolonged transit time would be observed). Scientists suggested treating IBS-diarrhea-dominant with a higher dose (3 mg daily) and IBS-constipation-dominant with a lower dose (0.3 mg daily) may benefit these patients (106).
Note that typical symptoms of IBS may also occur in other bowel diseases, including autoimmune conditions like Crohn's Disease. Whether melatonin is also effective for all other bowel diseases, especially the ones with an autoimmune component, is not clear yet. In some cases, like Crohn´ Disease, even a potentially harmful effect of melatonin can not be excluded because higher quality research is still missing. Thus, if it is intended to use melatonin for IBS, it is recommended to make sure that the symptoms are actually caused by this or other conditions (like the next one) that have shown in higher quality research to respond favorably to melatonin.
Gastroesophageal reflux disease (GERD)
Strikingly, 1 in 5 people (20%) in the US are suffering from GERD, a very uncomfortable chronic digestive disorder. Symptoms include painful heartburn, regurgitation, dysphagia, chest pain and coughing etc. Logically, this condition can have a quite negative impact on life. It is, however, one of the most unnecessary disorders. We do know since 2006 how it can be cured.
Unfortunately, millions of people take proton pump inhibitors (PPI) like Omeprazol to treat symptoms like heartburn. These drugs reduce stomach acid levels and may improve the condition. However, they have dangerous side effects. Intake of PPIs may lead to deficiencies of magnesium, calcium iron, Vitamin C and B12. As omns-readers know, such deficiencies may contribute to the development of all existing diseases (107).
Dangerous infections (like Clostridium difficile) occur more frequently among patients taking PPIs (108).
The same is true for various cancer forms. People who are taking PPIs have a significantly increased risk of developing gastric cancer. And this does not only apply to very long term use. There was no duration-dependent effect (109). No matter if people take these drugs for <1 year or for >1 year, the risk of gastric cancer is increased. PPI use is also associated with an increased risk of pancreatic cancer, liver cancer and colorectal cancer (110).
Not to forget that PPI use is also associated with a significantly increased risk of depression. Researchers concluded that PPI´s may be a frequent cause of depression, especially in older people (111). So much unnecessary pain and suffering.
Melatonin (3 to 6 mg per day) has shown in clinical trials to be a very effective treatment for heartburn or GERD and the associated pain (112)(113).
However, In order to achieve the best possible clinical outcomes, melatonin should be combined with other orthomolecular substances. In 2006, an RCT with the title “Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole” was published. In this study 175 GERD patients received the PPI omeprazole (20 mg daily) and 176 other GERD patents received a daily combination of 6 mg melatonin, 200 mg l-tryptophan, 50 mcg vitamin B12, 100 mg methionine, 10 mg betaine and 25 mg folate. Strikingly, after only seven days, 90% of the patients taking the melatonin/micronutrient combination experienced relief, suggesting that it works extremely fast.
At the end of the study, after 40 days, ALL of the patients (100%) who received the melatonin/micronutrient combination reported a complete regression of GERD symptoms. In the omeprazole group, only 66% reported complete regression (114).
As in the case of many other melatonin studies that are described in this article, it is highly surprising that these results have not been shared widely. Millions of people are still taking dangerous PPIs to treat their GERD symptoms, just because no one told them that there is another way. A much more effective and much safer way.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
ME/CFS is a devastating chronic condition. It affects 17 million people worldwide and is not in any way comparable with normal fatigue.
It is characterized by severe fatigue which massively limits daily activities (1 in 4 affected can not leave the house and 6 of 10 are unable to work), autonomic symptoms like palpitations, dizziness and fluctuations in blood pressure. Thus, many sufferers can no longer stand or sit for long periods of time.
Affected people often suffer from immunological symptoms as well, such as a strong feeling of illness, swollen lymph nodes etc.
Another characteristic symptom is the Post-Exertional Malaise: A very low effort (like visiting a shop to buy something) may result in a severe exacerbation of fatigue, often making all other activities impossible for the following days.
Sometimes, the chronic ME/CFS is caused by an infection. It is also a frequent symptom following a Covid-infection. The subsequently described treatments are likely also a highly effective approach for long-covid overall.
Melatonin has shown in studies to be an effective treatment for this condition (115).
In a double-blind study, melatonin was administered in combination with zinc, which led to significant improvements:
“We found that oral melatonin plus zinc supplementation significantly improved the perception of physical fatigue and health-related quality of life in ME/CFS patients after 16 weeks of treatment (...) Based on these results, the administration of 1 mg of melatonin and 10 mg of zinc daily may be indicated as adjuvant treatment for ME/CFS patients to improve their fatigue…” (16)
Since another double-blind study shows that the combination of Coenzyme Q10 (200 mg) and NADH (20 mg) is also very effective for reducing fatigue in ME/CFS, it may be advisable to combine melatonin (and zinc) with Q10 and NADH. This will lead to dramatic improvements of mitochondrial energy synthesis (117).
Since an impaired intestinal barrier (leaky-gut) is one of the main sources of ME/CFS, it is highly important to repair the gut! The symptoms of chronic fatigue patients are largely caused by an activated immune system/increased inflammatory processes. The defect intestinal barrier (results from stress, infections, unhealthy diet, low intake of fiber and high intake of animal protein, intake of antibiotics etc.) is one of the main causes of these inflammatory processes.
A study shows that restoration of the intestinal barrier may lead to strong improvements or even full recovery of the chronic fatigue syndrome after several months of treatment (118). The treatment included zinc, n-acetylcysteine and l-glutamine. Many patients also received Q10, carnitine, curcumin or quercetin among others. Many of these substances have shown to repair the gut and the intestinal barrier.
In addition to that, the diet needs to be adjusted: More fiber, more plant based foods, less animal protein and no gluten. Intake of certain probiotics may also be considered and stress has to be reduced (by exercise or meditation).
Interestingly, decreased melatonin is also associated with an impaired intestinal barrier. Thus, one of the mechanisms by which melatonin helps in the treatment of ME/CFS may be that it improves intestinal health (119).
Schizophrenia
Schizophrenia is a devastating condition that affects approximately 0.5 to 1% of adults, presenting with both positive symptoms like hallucinations and negative symptoms like lack of motivation, communication etc. The symptoms may lead to severe impairments of life. 50% of all psychiatric hospital beds are occupied by schizophrenic patients. Research indicates that melatonin deficiency may contribute to its development.
“Altogether, our results show that melatonin signaling is crucial for functional differentiation of human ONPs, strongly suggesting that a deficit of this indoleamine may lead to an impaired neurodevelopment which has been associated with the etiology of schizophrenia.”
(201)
Of note, complete absence of or only a short duration of breastfeeding has shown to be a significant risk factor for schizophrenia (202) and as described above, breast milk contains melatonin. A low melatonin status (due to absence of breastfeeding, low exposure to NIR, low consumption of melatonin-containing foods etc. etc.) may impair neurodevelopment and increase the risk of developing schizophrenia.
At least two double-blind trials have shown that treatment with melatonin, 3 to 6 mg per day, significantly reduces symptoms of schizophrenia after 6 weeks (203)(204). Especially negative symptoms declined strongly. Positive symptoms also decreased, without statistical significance. However, the researchers noted that longer duration of treatment would likely also lead to a significant reduction of positive symptoms.
“…it can be concluded that melatonin medication can be effective in improving the negative symptoms of schizophrenic patients, without serious side effects, within six weeks. Also, considering the decreasing slope of symptoms in the melatonin group, it can be concluded that long- term use of melatonin may be effective in improving positive and general symptoms of schizophrenia.” (204)
Melatonin is thus an effective adjuvant treatment for schizophrenia. In addition, it has also shown to reduce or prevent adverse metabolic side effects (like weight gain) of antipsychotic medications (205).
Many studies indicate that vitamin D deficiency during neurodevelopment may be another important risk factor for this condition (206). Supplementation of vitamin D during the first year of life was associated in males with a >90% lower risk of developing schizophrenia later in life, compared with no supplementation (207).
And adjuvant treatment of schizophrenia patients with vitamin D + probiotics led to a significant reduction of symptoms (208). Both low melatonin and low vitamin D seem to impair adequate neurodevelopment and are likely responsible for many cases of schizophrenia. Of course, many other micronutrients are involved as well and the gut microbiota also seems to play an important role. For example, use of antibiotics (which massively disturb the bacterial composition in the gut) is associated with an increased risk of developing schizophrenia (209).
While that topic can not be discussed entirely in this single article, one of the most important factors that still needs to be highlighted is vitamin B3/niacin. Schizophrenia patients seem to suffer from a vitamin B3 dependence, meaning that (due to genetic variations) they require much higher doses of it than diet could ever provide. And since they do not receive as much as they need, severe mental symptoms may set in. For example, in a study with 30 acute schizophrenic patients, those who received 3 grams of niacin daily for one month had a much higher recovery rate (80% recovered) after one year than those who received a placebo (33% recovered) (210).
Of course, all this knowledge is widely ignored and millions of schizophrenic patients, especially those who do not respond adequately to standard treatment, keep suffering instead of being offered a protocol that consists of high dose micronutrients.
Alzheimer's Disease
Alzheimer's is a strongly increasing condition. It affects more than 10% of all people above 65 in the US. Melatonin deficiency may be one of the causes. Meta-analyses show that early treatment with melatonin is effective. In mild stage Alzheimer's patients, low dose melatonin significantly improved cognitive functions (measured with mini-mental state examination). In advanced stages, treatment did not help anymore (120)(121).
This indicates that, if you treat early, you may be able to reduce or stop the progression of Alzheimer's or even reverse it.
In order to increase the success, patients with mild cognitive impairment or early stage Alzheimer´s should be treated with a newly developed program that aims at eliminating all contributing factors. The program has shown to stop the progression and even reverse Alzheimer's. The improvements are breathtaking. Many patients who were no longer able to work due to severe memory loss, were subsequently able to return to work and had greatly improved memory. The success rate is very high. Treat Alzheimer's early with this program. For details, read the paper.
It includes, among other points:
-A plant-based high fiber diet, mildly ketogenic, with a fasting period of 12–16 hours each night. Blood ketone levels were monitored with fingerstick ketone meters, with a goal of 1.0–4.0 mM beta-hydroxybutyrate.
-(Almost daily) Aerobic exercise and frequent strength training.
-7 to 8 hours of sleep at night. Sleep apnea has to be treated.
-Stress reduction.
-For patients with low micronutrient values like vitamin D, Q10, minerals, omega-3, B-vitamins, supplementation was provided.
-Relevant hormones, including thyroid hormones, have to be restored, in part with bioidentical hormones. Note: The hormone melatonin was not mentioned. However, given the new results which show a significant treatment success with melatonin, it should be included.
-Gut restoration (leaky gut, dysbiosis etc. treated with diet, micronutrients and probiotics).
-Chronic infections like Herpes simplex or Epstein-Barr Virus have to be treated.
-Detoxification of metals like mercury and lead, organic pollutants like phthalates or organophosphate insecticides and biotoxins like trichothecenes (122).
Parkinson's Disease
1% of the population above 60 years is affected by Parkinson's. A double-blind randomized controlled trial showed that melatonin (10 mg daily one hour before bedtime) not only reduced inflammation (CRP) and serum insulin levels, improved glutathione levels, sleep, and anxiety symptoms, but also led to a significant reduction of the Unified Parkinson's Disease Rating Scale part 1 score (includes mentation, behavior, and mood)(123). Another study also indicates that melatonin treatments may lead to a higher quality of life and reduction of non-motor-symptoms in Parkinson's patients. These clinical improvements may in part be due to the higher sleep quality resulting from melatonin administration (124).
Thus, melatonin may be a valuable adjunct in the treatment of this condition.
Nocturia
Nocturia means: people wake up at night because they have to urinate. The older, the higher the prevalence. Approximately 75% of the elderly are affected. However, even in 20 to 40 year old men, up to 35% are affected (125).
Unfortunately, instead of seeking treatment, many accept it as a natural consequence of aging. However, it can and should be treated. Since it significantly impairs sleep and sleep quality, it can increase the risk of many diseases and problems including depression, falls, fractures, heart disease, increased risk of mortality etc.
Melatonin participates in the regulation of the bladder function. The age-related decline of melatonin synthesis is probably one of the most important causes. A double-blind trial with women >55 years who suffered from nocturia has shown that treatment with melatonin (2 mg before bedtime) is very effective. In the women who received melatonin, the frequency of voiding at night was almost cut in half (2.3 episodes at night pre-treatment reduced to 1.3 episodes at night following treatment) and sleep quality improved. In the placebo group, no changes occurred. Future studies have to evaluate whether a higher dose could be even more effective (126).
Anxiety
A Cochrane review published in 2020 found that melatonin has strong (and relatively direct) anxiolytic effects. Supplementation significantly reduced pre- and postoperative anxiety of surgical patients. And most strikingly, melatonin was right as effective as benzodiazepines, which are often used for treatment of anxiety disorders. Unfortunately, these drugs are not harmless at all. They have many (severe) side effects, can cause dependence after a very short time of intake and might even increase the risk of developing dementia (127).
“When compared with placebo, melatonin given as premedication (as tablets or sublingually) probably reduces preoperative anxiety in adults (measured 50 to 120 minutes after administration), which is potentially clinically relevant. The effect of melatonin on postoperative anxiety compared to placebo (measured in the recovery room and six hours after surgery) was also evident but was much smaller, and the clinical relevance of this finding is uncertain. There was little or no difference in anxiety when melatonin was compared with benzodiazepines. Thus, melatonin may have a similar effect to benzodiazepines in reducing preoperative and postoperative anxiety in adults”, the authors of the Cochrane review concluded.
Other RCT´s showed that melatonin administration, 3 to 10 mg in the evening, also reduced anxiety symptoms in other situations. For example, it lowered anxiety in Parkinson's patients and in Hemodialysis patients (128)(129).
Thus, melatonin is likely effective for anxiety and panic symptoms in general and may, if an adequate dose is used (could depend on the severity of symptoms) be similarly effective for anxiety and panic as the established benzodiazepines.
Pain
Melatonin, given in doses of 3 to 10 mg, has shown to reduce pain in many different situations. For example, compared with placebo, postoperative pain was significantly lower when patients received 5 mg melatonin one hour before surgery. Also, patients who received melatonin required less pain medications like opioids (130). Melatonin also strongly relieved pain in patients who were suffering from painful diabetic neuropathy (131).
In women suffering from endometriosis, melatonin, 10 mg daily, has shown in a double-blind trial to reduce daily pain scores by 40%. In addition, the odds of having to use an analgesic (due to strong pain) was reduced by 80%, which shows how effective melatonin can lower severe pain (132).
Besides being effective in acute situations, melatonin may also be an effective reliever for different chronic pain situations (like Fibromyalgia) and is also highly effective for migraine patients. A low melatonin status might be one of the causes of chronic pain.
Fibromyalgia
Fibromyalgia is a painful disorder that affects 2% to 5% of the adult population worldwide (several million people in the US alone). It is characterized by widespread musculoskeletal pain and is also associated with symptoms like fatigue or insomnia, among others.
In a phase II, randomized, double-dummy, controlled trial, treatment with Melatonin (10 mg before bedtime) reduced pain intensity in patients with fibromyalgia and improved sleep. Interestingly, melatonin monotherapy had a stronger pain-lowering effect than monotherapy with the drug amitriptyline which is widely used to treat this disorder. The combination of both melatonin + amitriptyline had the best pain-relieving effect (133).
Fibromyalgia patients should not forget coenzyme Q10. 300 mg of Q10 per day has shown to be an effective treatment for these patients, it resulted in strong reductions of pain, fatigue, morning tiredness and inflammation (134).
A combination of melatonin and Q10 might have synergistic effects and could thus be especially effective.
Migraine and severe headache
1 in 6 people overall and 20% of all women report that they suffer from migraine or a severe headache over a 3-month period, making this form of pain a huge public health problem (135).
However, melatonin is ready to help. It is not only an effective treatment for acute migraine (dose 8 mg or more) which leads to relief of pain in many patients within 2 hours (136).
More importantly, as shown in a meta-analysis published in 2022, melatonin (in daily doses of approximately 3 mg) significantly reduces the frequency, duration and severity of migraine attacks. Also, those who took melatonin required less analgesic drugs (137).
While melatonin is at least as effective as these drugs (it seems to be even more effective than amitriptyline, for example), the tolerance is much higher. These drugs cause more side effects (138).
Since magnesium, Q10 and riboflavin have also shown to be highly effective for migraine (reduced duration, frequency and severity of attacks), it is highly recommendable to consider combining them with melatonin (139)(140)(141).
New meta-analyses even confirmed that vitamin D is an effective treatment for migraine. So if you want to break free from migraine (or at least experience strong improvements) you do not want to miss vitamin D either (142).
Besides migraine, melatonin has also shown to be effective in other forms of headache, like (chronic) tension-type headache (143) or cluster headache (144).
Tinnitus
Tinnitus, an often stress- and painful perception of ringing or noise, affects 10 to 15% of adults, more than 50 million in the US alone. Especially the severe forms may lead to a very significant impairment of life, reduced performance, social withdrawal, depression, anger, helplessness, insomnia etc.
Older people are affected more often,maybe due to lower melatonin among other factors.
An RCT with 70 patients found that melatonin, 3 mg daily, is very effective for tinnitus, massively reducing the severity of the symptoms. In this study it has also shown to be more effective than sertraline, a drug that is often prescribed to treat this condition. After three months of treatment, the number of patients with severe tinnitus had almost halved in the melatonin group (reduced from 20 to 11.8%), while in the sertraline group, no improvement was seen in the severe category.
Also, before treatment, 45% of the patients in the melatonin group were suffering from moderately severe tinnitus and only 31.4% had slight or mild tinnitus. After 3 months of treatment, only 8.8% still had moderate tinnitus and the % number of patients with slight or mild tinnitus had more than doubled. It had increased to 76.5%. Also in this regard, melatonin was more effective than the drug (145).
In order to reach the best results, melatonin should be combined with other orthomolecular substances that have a role in tinnitus.
For example, in another trial, supplementation of Q10 improved tinnitus symptoms in patients with low Q10 plasma levels (146).
In a prospective interventional study, tinnitus patients were treated with a new supplement that contains 5-HTP, Ginkgo biloba, magnesium, melatonin, vitamin B5 and B6, and zinc. Within the following months, the severity and perceived loudness of tinnitus declined significantly. In accordance with this result, the negative emotional impact of tinnitus was reduced significantly as well (147).
Epilepsy
Epilepsy affects more than 60 million people. The global prevalence is estimated to be 0.5 to 1%, meaning that 1 in 200 to 1 in 100 people are suffering from it. While seizure control with antiepileptic drugs is often effective, approximately 33% of all epileptic patients are resistant to conventional treatment and keep suffering from epileptic attacks which can greatly impact life, depending on the form and severity (148)(149).
Several studies with treatment-resistant epileptic patients have shown that melatonin is a very effective (adjuvant) treatment. For example, in two recent double-blind trials with drug-resistant epileptic patients (idiopathic generalized tonic-clonic seizures and generalized epilepsy with generalized onset motor seizures), one control groups received only standard therapy + placebo and the intervention groups received standard therapy + 3mg melatonin 1 hour before bedtime.
According to the results, in the intervention groups, seizure frequency and seizure severity reduced substantially. Up to 70% lower severity of seizures/attacks which results in a much higher quality of life(150)(151).
Several previous studies and case reports also indicated that this condition responds to melatonin, sometimes even to the extent of complete or almost complete seizure control with ongoing high dose administration.
For example, in a case of severe infantile myoclonic epilepsy, resistant to various combinations of anti-epileptic drugs, melatonin was the only substance that finally led to (good) control (152)(153).
Strikingly, melatonin (0.3 mg/kg three times daily during a febrile illness) has also been used with very high success in patients with recurrent febrile seizures and was more effective than conventional treatment with the drug diazepam.
“Our data suggest that melatonin, administered at the onset of a febrile illness, may effectively reduce the likelihood of recurrent simple febrile seizures”,
the authors of an RCT published in 2019 concluded (154).
Many other substances including omega-3, magnesium, vitamin D, zinc etc. also have strong anticonvulsant effects.
RCT´s show that omega-3 supplementation often reduces seizure frequency in drug-resistant epilepsy patients by >30% (155).
A new meta-analysis, published in 2022, confirmed the high efficacy. Interestingly, a dose of 1500 mg or less of omega-3 fatty acids was more effective for the treatment of epilepsy than higher doses (156).
Andrew Saul´s page doctoryourself lists reports of people who had strong success with high dose magnesium as treatment for epilepsy (the dose drugs for epilepsy can often be reduced significantly).
Also, a study has shown that vitamin D supplementation (to correct a deficiency) resulted in a seizure reduction of 40% (157).
Some new studies even indicate that the combination of vitamin D + melatonin is more effective in reducing seizures than either vitamin D or melatonin alone (158).
Essential hormones/micronutrients all work together and have synergistic effects. It is reasonable to consider that a combination of adequate doses of all relevant hormones/nutrients may be extremely effective for drug-resistant epilepsy patients, potentially resulting in (almost) complete seizure control in many of these patients.
And if a proper diet is chosen, like a (mainly plant-based) ketogenic diet, seizure frequency will decline even further, as proven in meta-analyses (159).
Diabetes
Many RCT´s and meta-analyses have shown that supplementation of melatonin can improve diabetes type 2 parameters, including glucose levels and insulin sensitivity(160).
For example, a meta-analyses, published in 2021, has shown:
“Sixteen studies were included, of which 56% showed benefits from supplementation with melatonin in diabetes parameters compared with placebo. Our meta-analysis showed significant results for fasting blood glucose [mean difference: -4.65; 95% CI: -8.06, -1.23; p = < 0.01; I2 = 58%], glycated hemoglobin [mean difference: -0.38; 95% CI: -0.67, -0.10; p = 0.30; I2 = 18%], and insulin resistance [mean difference: -0.58; 95% CI: -1.00, -0.15; p = 0.17; I2 = 35%].” (161)
It also reduces oxidative stress and the diastolic blood pressure and increases HDL cholesterol in diabetes patients (162).
While the majority of studies show that melatonin has positive effects in the treatment of diabetes type 2, there are, however, also some contradictory results, suggesting a negative effect on insulin sensitivity with daily 10 mg of melatonin (163).
This is likely, at least in part, a dose issue. Taking a higher dose of melatonin, like 10 mg per day, for a longer duration, may have a negative effect on some diabetes patients. A significantly lower dose may be reasonable for these people.
In general, melatonin is definitely beneficial for glucose metabolism and has, as described above, been shown to be an effective adjuvant treatment for diabetes. But it is important to choose the right dose which may be individual. Choosing a physiological (up to 1 mg) rather than a pharmacological dose (defined as >1mg) may be a reasonable approach (to start with).
Of course, this should be discussed with a healthcare practitioner who has experience with the treatment of melatonin and who can help finding the correct individual dose.
Of course, vitamin D should never be forgotten. vitamin D supplementation improves glucose levels in diabetics (164). And so many other micronutrients, including Q10, vitamin C also highly effectively improve glycemic control and significantly reduce blood glucose levels in these patients (165).
In addition, please note that diabetes type 2 is reversible!
“Established Type 2 diabetes is now known to be a reversible condition in the early years, and the underlying mechanism is the removal of the excess fat from within the liver and pancreas in these susceptible individuals. The Diabetes Remission Clinical Trial has shown that around half of a primary care population of people with Type 2 diabetes of less than 6 years' duration can be returned to non-diabetic blood glucose control which lasts at least 12 months”, the authors of a 2019 review described (166).
Thanks to the Coimbra protocol, the autoimmune disease diabetes type 1 may also be stoppable or even reversible, but this is another topic.
Multiple Sclerosis (MS)
More than 400.000 in the US and more than 2.5 million people worldwide are suffering from the autoimmune disease MS.
A lot of research indicates that melatonin is likely of high benefit for MS patients.
“Recent evidence suggests that melatonin ameliorates multiple sclerosis by controlling the balance between effector and regulatory cells, suggesting that melatonin-triggered signaling pathways are potential targets for therapeutic intervention”,
the authors of a review explained (167).
Studies with MS patients have shown that melatonin, 5 to 10 mg daily, can improve the antioxidant status, reduce oxidative stress, inflammation and improve quality of life (168)(169)(170)(171).
A placebo-controlled trial has shown that melatonin, 6 mg before bedtime,reduces the risk of falling, and improves postural balance and mobility the following day (according to physical performance tests)(172). Also, in a small double-blind trial, there was a trend towards reduced severity of relapsing-remitting MS following daily melatonin supplementation (3 mg) for one year. Fatigue improved as well (173).
However, in order to be able to see a substantial impact on clinical outcomes and disease severity, a longer duration may be necessary, as highlighted in a very interesting case report, describing a woman with the symptoms of primary progressive multiple sclerosis. Treatment with glucocorticoids started immediately. However, unfortunately, her symptoms worsened.
“The disease and the demyelinating lesions progressed during the following 9 years reaching Expanded Disability Status Scale (EDSS) 8.0 (patient essentially restricted to bed, a chair or perambulated in a wheelchair).
At this point, the patient began taking melatonin at doses ranging from 50 to 300 mg per day. Melatonin was her only treatment for the next 4 years; during this interval, her EDSS progressively recovered to 6.0 (the person needs intermittent or unilateral constant assistance such as cane, crutch, or brace to walk 100 meters with or without resting). This long-lasting improvement is likely due to melatonin usage since it is related in time and because of its exceptionally long duration.” (174)
So, she could leave the wheelchair and walk again! What would have happened if she had started melatonin much earlier? Maybe, in this case she would have never progressed so far. The authors of another study also found that melatonin reduced disease progression of MS patients (175).
It is, however, very important for patients with autoimmune diseases of all forms, including MS, to be aware of the Coimbra protocol.
“For approximately 15 years, patients with autoimmune diseases, particularly MS, have been successfully treated using a high-dose vitamin D protocol. Because this method has been developed by Prof. Dr. Cicero Coimbra in São Paulo, Brazil, is frequently referred to as the “Coimbra protocol”, the authors of a 2021 review highlighted (176).
The main factor of this protocol is very high dose vitamin D and the success rates are huge, with many patients (including MS) experiencing a complete stop of disease progression, substantial improvements and often (partial) regression of symptoms. Early treatment is key! For this protocol, definitely consult with a therapist who learned how to administer this therapy. Self-treatment is (as in case of all other conditions) not indicated as the doses are very high and frequent lab tests are necessary. In order for this treatment to be effective, the dose must be adjusted to the specific lab parameters.
Other Autoimmune diseases
For some other autoimmune diseases, much more research is still required to evaluate the exact impact of melatonin. The role of melatonin might be complex, in part favorable and in part unfavorable. There are contradictory results, with some, mostly theoretical, preclinical or low quality data suggesting that melatonin might have a negative effect on a few autoimmune diseases like Crohn's Disease or Rheumatoid Arthritis (RA) (177), while much other data indicate that melatonin has a positive effect (or at least no negative effect), on Rheumatoid Arthritis or Hashimoto, for example (3).
Much of the data that has shown negative effects originates from preclinical research, not involving humans. Sometimes, very high doses were tested in such preclinical studies. For example, with regard to RA, 1 mg/kg body weight (which would translate into a very high dose of 70 mg of melatonin for a 70 kg person) had a negative effect on the disease course in a preclinical investigation) (177).
However, in a new double-blind trial with RA patients, melatonin, 6 mg daily, did not have a negative effect on the disease severity. To the contrary, the disease severity score declined significantly following daily melatonin treatment for many weeks. Noteworthy, the score declined in the control group as well and no significant difference was found in the end. So, while the study did not prove that melatonin is effective for RA, it indicated that melatonin, in a relatively low dose, at least seems not to be harmful for such patients (178). More studies are necessary to find out whether melatonin, in reasonable doses, might even be beneficial for people with this and several other autoimmune diseases.
Since more research is still required, before taking (higher dose) melatonin supplements, it may be reasonable for patients with certain autoimmune conditions to discuss their individual case with a healthcare practitioner (who has experience with melatonin treatment). And of course, starting with a low, physiological dose, is always important…
Sources
Aside from supplementation, in order to generally improve their melatonin status, people can:
-Reduce exposure to artificial lights and (computer/mobile) screens in the evening and at night. Note that even though many devices have so called blue-light filters, which are supposed to reduce the melatonin-suppression effect of screens, research indicates that you should not rely on them:
“The effect of blue light filters depends on the screen technology; however, the melatonin suppression index of mobile devices is not reduced sufficiently by the use of blue light-attenuating software”, the authors of a 2020 study concluded (181).
Artificial lights at night reduce the synthesis of melatonin in the pineal gland and thus increase health risks. Evolutionarily, humans are adapted to receiving no or only very low light from the night-sky after the sun had gone down.
Of course, many thousands of years ago, our ancestors started having fires in the evening or even at night. However, this probably had a positive impact on the melatonin-status. Fire (including candle light) emits infrared radiation which promotes the intracellular melatonin production. However, as people started moving further and further away from nature and natural laws, more and more (chronic) sickness has set in.
-Use an eye mask at night. Wearing an eye mask during sleep has shown to increase melatonin synthesis in the pineal gland and thus led to higher melatonin levels in the blood and also improved sleep (182).
-Increase exposure to bright light during the day, especially in the morning, either in the form of sun exposure or with a bright light lamp with >5000 lux. This will improve the melatonin synthesis of the pineal gland at night (5). For that reason, bright light therapy in the morning has also shown to be an effective treatment for insomnia.
-Stay more time outdoors in general and increase sun exposure to receive more near infrared radiation in order to increase the intracellular melatonin synthesis in various cells all over the body. If it is not possible to stay for more time outside, one can consider working with a red and near infrared lamp. Using such a lamp is called photobiomodulation (PBM) and many studies already confirmed that it has health benefits, including reduction of inflammation and pain (arthritis, head and neck pain etc.), improving health, wound healing, or mood/depression etc (179).
Interestingly, PBM has also shown to be effective for Covid in several studies (for example, faster recovery and lower risk of hospital admissions, ICU admissions and deaths compared with the control group)(214)(215) and even increased survival of cancer patients (216).
Many of the health benefits of these red and near infrared lamps may be due to increased intracellular synthesis of melatonin.
Such NIR lamps may, for example, be established on the writing table. A high enough dose (6.5 J·cm−2) needs to be chosen in order to receive the highest benefit.
Of note, depending on the latitude, on cloudy days or in winter months, exposure to NIR may not be as high as on cloud-free days or during summer months. That makes it more difficult to produce enough melatonin intracellularly. Thus, a near infrared lamp may not only be considered in situations when people spend most of their time indoors. Winter months (when it is more difficult to receive high enough doses of NIR from the sun to produce sufficient melatonin) may also be an indication for a red and near infrared lamp.
-Eat sufficient amounts of tryptophan. As described in the beginning of the article, tryptophan is the precursor of melatonin. Consumption of sufficient amounts of this amino acid is essential to being able to produce melatonin in the pineal gland and in the mitochondria of various or all cells in the body. After the intake of tryptophan, cells in the gastrointestinal tract even seem to release some melatonin into the blood (24). Thus, eating sufficient amounts of tryptophan helps build melatonin within the cells and also promotes an increased blood level of melatonin (from the gut, directly following consumption and from the pineal gland at night). In fact, tryptophan has also shown to improve sleep, probably due to improving melatonin production (194).
One of the additional benefits of eating a diet high in tryptophan is an improved mood and a lower risk of depression. For example, a double-blind study from 2015 has shown that eating a diet that contains >10 mg/kg body weight per day of tryptophan (this adds up to >700 mg per day for a 70 kg person) had a much better mood and a higher emotional well-being than those who ate <5 mg/kg body weight per day (less than 350 mg per day for a 70 kg person).
“The results of this double-blinded, within-subjects study indicate that participants consuming higher levels of tryptophan (>10 mg/kg body weight/d) had significantly less depression and irritability and decreased anxiety than when they consumed lower levels of tryptophan (<5 mg/kg body weight/d).” (183)
Please note that the low tryptophan diet with only 5 mg/kg body weight was based on the U.S. Recommended Daily Allowance (US RDA) of tryptophan. Thus, the higher tryptophan diet contained twice the US RDA! So this shows that the US RDA is too low. People need more tryptophan to stay (mentally) healthy.
Some of the healthy foods that are high in tryptophan include (per 100 g) spirulina (789 mg), pumpkin seeds (559 mg), soybeans (450 mg), edam cheese (400 mg), cashews (between 300 mg and 450 mg), peanuts (320 mg), lentils (250 mg), hazelnuts (210 mg), walnuts (205 mg) oatmeal (190 mg), amaranth (181 mg). To make sure tryptophan can cross the blood-brain barrier, it always needs to be consumed in combination with some carbohydrates.
-Practice meditation or yoga. Studies show that the practice of various forms of meditation or yoga in the evening/night leads to elevated melatonin plasma levels (184)(185), which may, in part, also help explain the many documented health benefits of such practices, including improved sleep (186)(187).
-Follow a healthy lifestyle and maintain a normal body weight. Smoking and a higher BMI seem to reduce the synthesis of melatonin in the pineal gland/and or deplete melatonin (due to increased oxidative stress that needs to be tackled by melatonin). The lower melatonin levels that were measured in these people may, according to scientists, partially explain the higher cancer risk of the affected individuals (188).
Interestingly, the so-called “age-related decline” of the nocturnal melatonin secretion in the pineal gland at night is not actually due to higher age. It is due to long-term unhealthy (eating) behaviors which lead to calcification of the pineal gland (3). Overeating seems to be a very important factor. It has been shown that calorie restriction drastically retards the aging process of the pineal gland and (in this way) helps keep nocturnal melatonin levels higher in advanced age (195).
Nowadays, many people in western countries eat too much and too often which may be one of the main causes of the age-related decline in melatonin secretion. Researchers argued that food restriction, which has shown to increase lifespan while reducing physiological deterioration and diseases, may mediate some of its effects through a sustained pineal activity in old age (195).
Since intermittent fasting (for example: not eating during a window of 14 or 16 hours per day), an approach which is easier for most people to follow and which has even shown to reduce depression in humans (196), has similarly positive effects on health and cellular metabolism as calorie restriction and has also shown to improve longevity (197)(198), it is likely that long-term intermittent fasting may help protect the pineal gland as well and thus keep melatonin secretion up, even in advanced ages.
-Do more exercise. 30 min of moderate to intense exercise, like running in the morning, has shown to increase (nocturnal) melatonin levels. This may be one of the mechanisms by which exercise improves sleep (189)(190).
Thus, exercise in the morning may help promote the synthesis of melatonin in the pineal gland at night. Besides that, and probably independent of daytime, exercise also seems to promote the extrapineal synthesis in various cells all over the body, as near infrared light does (22).
-Eat more foods that contain melatonin. As has been shown in many studies, a lot of foods contain melatonin, especially plant foods like certain forms of cherries, dark green vegetables, tomatoes, seeds, grapes, pineapples, mushrooms, berries, nuts like pistachios or walnuts etc. etc. Consumption of such foods has shown to increase melatonin blood levels (191)(192) and this increase of melatonin levels was associated with improved antioxidative defense of blood as shown following walnut consumption (192). A population-based cohort study from 2021 has shown that people in the highest quartile of melatonin intake from foods had a significantly lower risk of all-cause mortality compared with those in the lowest quartile (193).
Of note, even though melatonin from food may have positive health effects, the amounts in food are in general very low and it is very difficult or almost impossible to receive as much melatonin from food consumption during the day as from a low-dose melatonin supplement. Surely, for many situations food may be the best medicine, and the low amount of melatonin in food likely works in synergy with other antioxidative substances and micronutrients from the same sources. However, we do not have to decide between a healthy diet or a supplement. Depending on the individual circumstances, comorbidities, age etc. and in order to prevent or treat certain conditions or diseases, it may be reasonable to do both, eating healthy + taking a supplement to receive doses high enough (or even therapeutic) to achieve certain health benefits or reverse pathogenic processes. It should also be considered that foods are not a reliable source of melatonin. The content varies depending on the environment of the fields, growing conditions like temperature, sunlight exposure duration, agrochemical treatments etc (191).
-Whether a melatonin supplement should be taken to improve the melatonin status and/or prevent or treat conditions and diseases, needs to be decided on an individual basis.
So far, most of the available studies are treatment studies and even though, based on all available research, it is highly likely that long term intake of low or moderate doses of melatonin (especially by older people) reduces the incidence of diseases and mortality and increases longevity, long term prophylaxis RCTs with healthy (older) people that could prove whether years of taking melatonin reduces the risk of certain diseases, disease-specific mortality or all-cause mortality are not available yet.
Hopefully, we will soon have such studies. It would be incredible to see properly conducted long term prophylaxis studies with both vitamin D and melatonin, since they have synergistic effects and rates of deficiencies are extremely high for both, and even more in the older population.
Since the pineal gland produces -depending on the age- between 0.1 and 0.9 mg of melatonin per 24 hours (mainly at night), this dose range is considered physiological. Doses above this threshold are called pharmacological (3). This definition only seems to consider the amount of melatonin that is synthesized in the pineal gland although, as the most recent research indicates, most of the melatonin of the body is produced in other organs and cells.
However, supplementation of 0.3 mg of melatonin at night has shown to improve sleep (3), suggesting that a low dose like this may already provide health benefits, although in order to prevent or treat certain conditions, higher doses seem to be necessary, as described in this article. The optimal daily dose of melatonin that should or could be taken by healthy people to prevent diseases is still unknown, unfortunately. And of course, this dose would likely be highly individual, depending on the melatonin status of the body, differences in metabolic responses, genetic variations and millions of additional factors.
In most cases, melatonin should be taken in the evening or at night before bedtime.
Melatonin is extremely safe. The lethal dose of it is reported to be infinity, which means that melatonin did not lead to death, no matter how large the dose was (213).
Contraindications (against a higher dose of) melatonin may include the intake of certain drugs. Combination of some drugs with higher doses of melatonin might lead to sedation. Also, when taking blood thinners, caution is warranted due to the fact that melatonin has anticoagulant properties as well. Also, while melatonin reduces elevated blood pressure (especially at night) there is a possibility that taking melatonin in combination with some hypertensive medications may increase blood pressure. Drugs that may interact with melatonin include steroids, contraceptives, antidepressants or anticonvulsants etc. In high quality studies, melatonin has shown to be very effective for treatment resistant epilepsy, strongly reducing seizure duration and frequency. Interestingly, an old case series in the literature suggested- while confirming that melatonin effectively reduced seizures in some epileptic patients, in a few other patients melatonin was associated with a worsening (212) which may have to do with drug interactions or some genetic variations, dose issues or other confounding factors. In general, melatonin has proven in RCTs to be effective for epilepsy. While effective and helpful for the vast majority, it can not be excluded that a small number of patients may, depending on different circumstances like certain drugs, incorrect dosing or other individual factors have some negative effects.
Some other potential side effects, mainly harmless, are possible, including drowsiness or tiredness(for that reason, melatonin should not be taken before operating machines/driving a car etc).
In a review that investigated side effects that were reported after a daily intake of a pharmacological dose of 5 mg or more (which is probably more than most people need to prevent or treat health problems) the authors identified some potential side effects which may affect some people, including mood changes, a reduced physical performance, and a reduced insulin sensitivity. However, as already described above, melatonin is effective for diabetes, but a higher dose in combination with certain genetic variations may have an unfavorable effect. High doses might also have a negative effect on the ovarian function. Interestingly, headache has also been reported (211). However, this may also be a dose issue or due to certain genetic variations. As described above, headaches can be prevented and treated effectively with melatonin, 3 mg daily. Maybe a much higher dose may have a negative effect in some people, depending also on many other factors and genetic variations (211).
Such results suggest that, if it is intended to take melatonin for years to improve health, prevent diseases etc. a dose below 5 mg or a so-called physiological dose <1 mg may be best to profit from melatonin while keeping the risk of some side effects low.
Of course these are only general considerations. In reality, everyone is different and may respond differently. Thus, before taking any amount of melatonin or other supplements or drugs, consult a qualified therapist or physician who has experience with melatonin and who can provide individualized advice, based on the personal situation, medical history and current intake of medications etc.
Thank you for reading. I hope this article will benefit you in some way.
About the author: M. Langen is a new author, awaiting publication of his first book.
Medical disclaimer: The entire information and content in this article is for educational purposes only. It is not intended as medical advice. Always consult your health care professional on specific health problems. Before taking any supplements or medications, always consult your health care professional who can provide individualized advice and details of risks and benefits with regard to supplements and medications based on your personal situation and medical history.
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There are those who have SEVERE allergic reactions to melatonin, and CANNOT take such supplements safely. In such cases, this supplement can be life threatening.