Melatonin Beyond Sleep,Part I: An Overview

Abstract

The pineal hormone melatonin has many and various physiologic actions. While it plays key roles in sleep and chronobiologic functions, melatonin also possesses antioxidative and anti-inflammatory properties and helps modulate mitochondrial homeostasis. Because of these numerous actions beyond direct effects on sleep, melatonin has therapeutic potential in a large number of conditions. Trials demonstrate a multitude of actions of melatonin for people with liver disease, autoimmunity, cardiovascular disease, diabetes, cancer, and more. Part I, an overview, discusses melatonin's effects in general medicine, including a discussion of safety, while Part II specifically focuses on the use of melatonin in oncology.

Introduction

The ancient pineal hormone melatonin, a key pleiotropic molecule and circadian regulator, appears to be as old as life itself. The origins of melatonin began with photosynthetic cyanobacteria, which first appeared on Earth between 3.2 and 3.5 billion years ago. For these early microbes, melatonin likely served as an antioxidant, countering the generation of free radicals inherent in the process of photosynthesis.¹ As primitive eukaryotes phagocytosed these early proteobacteria and cyanobacteria, a symbiotic relationship evolved. The organelles that were the eventual result of this process (namely, mitochondria in animals and plants, and chloroplasts in plants) are thought to have retained their ability to synthesize melatonin. Thus, melatonin evolved along with life itself, gaining its additional functions in plants and animals over time.²

In modern animals, including humans, melatonin has retained its original ability to serve as an antioxidant, in addition to regulating circadian and sleep-wake rhythms, enhancing immunity, modulating mitochondrial homeostasis, and working as an oncostatic agent.² Its pleiotropic effects include binding to nuclear receptors, binding to intracellular proteins, binding to membrane receptors, and scavenging free radicals or non-radical toxic species in a receptor-independent fashion.^3,4 Melatonin receptors are ubiquitous in the body. Melatonin also readily crosses the body's physiologic barriers, such as the blood-brain barrier, the blood-testis barrier, and the placenta.⁴ Because of these wide-ranging effects, melatonin has a therapeutic versatility demonstrated by its efficacy in a variety of clinical conditions and scenarios.

In Part I of this review, the uses of melatonin in a variety of conditions, such as liver disease, cardiovascular (CV) disease, autoimmune disease, menstrual or menopausal concerns, and type 2 diabetes mellitus (T2DM), will be discussed. Part II will delve into the uses of melatonin as an oncostatic agent and in oncology. While this review is by no means exhaustive, it aims to touch on the wide variety of conditions for which melatonin may be useful, demonstrating its diverse clinical applications.

Note that in many of the studies referenced below, melatonin was listed by the author(s) as given “daily.” This is assumed to mean it was given at bedtime, even when the particular time was not specified. None of the studies reviewed below specifically assessed daytime administration of melatonin (although past studies have indeed examined the effects of daytime administration, and find it may induce a subjective sense of daytime sleepiness, a mild residual effect on psychomotor performance, or a mild decrease in core body temperature^5,6).

For those studies below that utilized a sustained-release melatonin formulation, this has been specified along with dosage. Trials comparing the therapeutic action of varying melatonin formulations are not abundant in the literature. Available data indicates that a sustained release formulation maintains a threshold value of melatonin for up to seven hours (compared to up to four hours for standard release).⁷ One study in the elderly found that dosing a 4 mg melatonin supplement (as 25% immediate release +75% controlled release) resulted in the maintenance of supraphysiologic concentrations of melatonin for an average of 10 hours, which could exceed a typical sleep period in some individuals.⁸ Additional trials comparing melatonin formulations or varying routes of administration (sublingual, immediate release, sustained release, etc.) would clearly be of interest to both clinicians and patients.

Liver Disease

While the primary site of nocturnal melatonin synthesis is the pineal gland, biosynthesis of melatonin has been demonstrated at a number of other tissue sites, such as the brain, skin, retina, and gastrointestinal tissues, including in enterochromaffin cells throughout the gut as well as in the liver.^9,10 In humans, the majority of melatonin is also metabolized by the liver, largely via glucuronidation and sulfuration.¹¹ Melatonin has been demonstrated to have a number of protective effects in the liver, including direct antioxidant effects, inhibition of hepatocyte necrosis or apoptosis, and a reduction in mitochondrial damage.¹⁰

In people with non-alcoholic fatty liver disease (NAFLD), melatonin may reduce transaminases or ameliorate other disease markers. In a randomized controlled trial (RCT) in 100 people with histopathologically confirmed NAFLD, melatonin supplementation for 3 months was compared to placebo. Melatonin supplementation led to significantly greater improvements in blood pressure (BP), aspartate aminotransferase (AST), and C-reactive protein (CRP) compared to placebo, and also resulted in a significant reduction in fatty liver grade (P = 0.001) (although strangely, the authors did not provide the dosage of melatonin utilized in this trial).¹²

In a meta-analysis of clinical trials, melatonin supplementation was found to lead to reductions in biomarkers in people with NAFLD. A total of 5 trials including 260 participants were included in the analysis. Melatonin was supplemented at doses ranging from 6 to 18 mg daily, with duration of trials being 4–56 weeks. Melatonin led to significant reductions in AST, alkaline phosphatase, and gamma-glutamyltransferase (GGT) (P < 0.001 for each).¹³

Melatonin may also benefit people whose NAFLD has progressed to nonalcoholic steatohepatitis (NASH). In a 12-week pilot-scale (N = 42) placebo-controlled trial, melatonin at 10 mg at bedtime (QHS) daily resulted in significant reductions in AST and GGT in people with NASH (P < 0.05 for both). Reductions in LFTs even persisted 12 weeks after melatonin was discontinued.¹⁴

Thrombocytopenia, a complication of chronic or advanced liver disease, has also been shown to be ameliorated with melatonin. In a double-blind, cross-over, placebo-controlled pilot study (N = 40), melatonin supplemented at 10 mg daily for 2 weeks resulted in a significant increase in the average platelet count compared to placebo (from 175.67 ± 92.84 to 191.10 ± 98.82, P < 0.001), while also leading to significant decreases in AST, ALT, total bilirubin, and the model for end-stage liver disease score (P = 0.03, P = 0.008, P = 0.01, and P = 0.004 respectively).¹⁵

Women's Medicine

Melatonin may be of special assistance to women with female health concerns, and also undergoes normal fluctuations in women with the phases of the menstrual cycle. Levels of urinary melatonin metabolites have been shown to peak prior to and during menstruation, gradually decreasing to their lowest point during ovulation.¹⁶ Progesterone secretion during the luteal phase may lead to a rise in melatonin levels during the late luteal phase. Melatonin levels also decrease from premenopause into menopause.¹⁷

Altered circadian melatonin rhythms may be present in women with menstrual concerns. Compared to unaffected controls, women with premenstrual dysphoric disorder (PMDD) have significantly decreased melatonin levels during both the follicular and luteal phases, and a reduced amplitude of melatonin circadian rhythm during the luteal phase. Women with PMDD also have a reduced area under the curve of melatonin in the luteal phase.¹⁸ Additionally, women with PMDD have been shown to have an increased sensitivity to light-induced suppression of melatonin, even at very low light levels (e.g., 200 lux).¹⁹

Supplemental melatonin may also be therapeutic in women with PMDD. In a small study of 5 women with PMDD, participants took 2 mg of sustained-release melatonin 1 hour before bedtime daily during the luteal phase only, for 3 consecutive menstrual cycles. After three menstrual cycles compared to baseline, the women had increased levels of urinary melatonin metabolites and increased stage 2 sleep (P < 0.001 for both). Objective sleep onset latency was also improved as was slow-wave sleep (P = 0.01 and P < 0.001). Urinary melatonin levels were directly correlated with improved slow-wave sleep. Ovarian hormone levels were unchanged pre and post intervention. Participants also experienced improvement in visual analog scale for mood (VAS-Mood) and Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM) scores from baseline.²⁰

In women with endometriosis, melatonin also improves menstrual symptoms. In a trial of 40 women ages 18–45 with endometriosis, participants were randomized to receive either placebo or melatonin, at 10 mg daily, for 8 weeks. Melatonin supplementation resulted in a reduction in daily pain score by 40% and a reduction in dysmenorrhea by 38%, compared to placebo. Melatonin also resulted in a reduction in use of analgesic by 80%, improved sleep quality, and a reduction of brain-derived neurotrophic factor (BDNF) levels (with BDNF thought to play an important role in modulation of chronic pain). The authors suggested that melatonin may work by affecting levels of pain signaling chemicals, or via a direct impact on pain pathways themselves.²¹

Melatonin may also have some special advantages for women who have undergone the menopausal transition. Supplementation of melatonin at 3 mg daily for 3 months has been shown to reduce climacteric complaints, such as irritability, fatigue, and hot flashes.²² At this same dose (3 mg), melatonin supplementation has also been found to result in increases in bone density in postmenopausal women with osteoporosis (with one year of treatment),²³ and to decrease fat mass while increasing lean mass (also in response to one year of treatment).²⁴

Diabetes

Diabetes is characterized by metabolic changes leading to either insufficient production of insulin by the pancreas, and/or a reduced action of or sensitivity to insulin, ultimately leading to elevated blood glucose. Diabetes is accompanied by a strong degree of oxidative stress, which may be related to increased lipid peroxidation, superoxide overproduction, an alteration in enzymatic systems, or a reduction in antioxidant levels (such as glutathione [GSH] or vitamin C).^25,26 Oxidative stress is also key in the progression of complications of diabetes, including microvascular and CV complications.²⁶ Nocturnal melatonin levels have been shown to be significantly reduced in diabetics compared to people without diabetes, and are also lower in those with retinopathic complications of diabetes than people without.²⁷ Melatonin supplementation has been shown to have a number of positive effects in people with diabetes.

In a 12-week randomized, double-blind, placebo-controlled trial, 60 people with T2DM and coronary heart disease received either 10 mg melatonin daily, or a placebo. Compared to placebo, use of melatonin was found to have a number of benefits. This included a significant increase in plasma GSH (P = 0.02), a significant increase in nitric oxide (NO) (P = 0.03), and a significant reduction in the oxidative stress biomarkers malondialdehyde (MDA) (P = 0.007) and protein carbonyl (P < 0.001). CRP levels also decreased significantly with melatonin (P = 0.001). Fasting blood sugar (FBS) was significantly reduced with melatonin (P = 0.03) as was serum insulin (P = 0.008). The homeostasis model of assessment-estimated insulin resistance (HOMA-IR) was significantly reduced (P = 0.04), as were systolic and diastolic BP (P = 0.01 and P = 0.04), and the ratio of total to high-density lipoprotein (HDL) cholesterol (P = 0.02). HDL levels were also significantly increased (P = 0.04), as was the quantitative insulin sensitivity check index (QUICKI, P = 0.01).²⁸

Similar effects have been demonstrated in diabetics undergoing dialysis. Compared to people that took placebo, those that took 10 mg melatonin daily for 12 weeks not only saw improvements in FBS, serum insulin, QUICKI, and HOMA-IR (P < 0.001, P = 0.01, P < 0.001, P < 0.001), but also had reduction in CRP and MDA, and increases in total antioxidant capacity (P = 0.001, P = 0.005, P < 0.001). Those who took melatonin also experienced improvements in scores related to sleep, depression, and anxiety, compared to those who took placebo (P = 0.007 for Pittsburgh Sleep Quality Index, P = 0.001 for Beck Depression Inventory index, and P = 0.01 for Beck Anxiety Inventory index).²⁹

A 2021 meta-analysis of melatonin for people with diabetes also confirmed beneficial effects. A total of 13 trials were included in the analysis, with 474 subjects in the intervention group and 453 in the control group. Included trials supplemented melatonin at doses ranging from 3 to 10 mg daily, for periods ranging from 4 to 24 weeks. Supplementation with melatonin showed beneficial effects in 56% of the included trials. Significant reduction of FBS (P < 0.01) was observed with supplementation of melatonin compared with placebo.³⁰

CV Disease

As mentioned above, melatonin receptors are widely distributed in the body, including throughout the CV system. Melatonin has a vasodilating and hypotensive effect. It also exerts favorable effects on the lipid profile, and as discussed in the section on Diabetes above, participates in glucose regulation. Melatonin may also have a protective effect on CV tissues mediated by its antioxidant function, rather than by direct receptor-mediated effects. Melatonin improves coronary blood flow and modulates the activity of NO synthase. Melatonin levels have also been shown to be decreased in patients with critical cardiovascular disease (CVD), such as those with congestive heart failure.³¹

Melatonin supplementation has been shown to attenuate age-dependent CV rhythms even at a modest dose given over short periods. At a dose of 1.5 mg daily given for 3 weeks, melatonin had a hypotensive effect, which was most pronounced between 3:00 and 8:00 in the morning (notably, the time associated with the highest risk of CV events), in people who had reduced nocturnal BP decline. The morning increase in heart rate was also modulated in people taking melatonin compared to placebo.³²

Melatonin also ameliorates endothelial function in people with advanced atherosclerosis. In people undergoing coronary artery bypass grafting (CABG) for three vessel coronary artery disease, one month of supplementation with melatonin 10 mg daily resulted in significant decreases in mean intercellular adhesion molecule, vascular cell adhesion molecule, and CRP levels (P < 0.05 for all). Serum NO also increased significantly (P < 0.05). There were no serious side effects reported.³³

In an additional trial in patients undergoing CABG, melatonin dosed acutely around the time of the procedure was also shown to have some benefits. Melatonin was dosed as a sublingual formulation, 12 mg, the night prior to the surgery, and again 1 hour prior to surgery. The duration of atrial fibrillation, a common complication following CABG, was significantly lower among patients receiving melatonin than those in a control group (P = 0.01). Levels of CRP and Creatine Kinase-Muscle-Brain subunit (CK-MB) were also significantly lower 24 hours postoperatively for people receiving melatonin (P = 0.001 and P = 0.004, respectively) compared to controls.³⁴

Melatonin may also benefit patients undergoing primary percutaneous coronary intervention. In subjects with ST-segment elevation myocardial infarction, melatonin was supplemented at 3 mg daily throughout the period of admission, given in addition to standard of care. Mean CK-MB levels were significantly decreased in people receiving melatonin compared to controls (198.24 ± 20.94 IU/L in the melatonin group; 118.2 ± 21.09 IU/L in the control group; P = 0.01). The authors concluded that melatonin may be useful for limiting the myocardial damage induced by ischemia-reperfusion.³⁵

Safety and Quality

In a 2022 study utilizing data from the National Health and Nutrition Examination Survey (NHANES), over the period of 1999 to 2018, use of melatonin supplements was reported to have increased from a rate of 0.4% between 1999 and 2000, to 2.1% in 2017–2018.³⁶ This is perhaps not surprising, since up to 50% of American adults are reported as experiencing insomnia.³⁷ With larger numbers of people potentially taking this supplement, questions arise about safety and quality of over-the-counter melatonin.

In one study of commercially available Canadian melatonin supplements, melatonin content did not meet the stated label claim within a 10% margin in greater than 71% of 30 assayed supplements. Actual melatonin content ranged from −83% to +478% of the stated label claim. Additionally, 26% of sampled supplements were found to contain serotonin, at amounts ranging from 1 to 75 μg.³⁸ Clearly, patients should be cautioned that quality of an over-the-counter melatonin supplement may vary widely, and clinicians should only recommend melatonin supplements that are subject to rigorous manufacturing quality controls as well as voluntary raw ingredient and finished product testing to assure product and ingredient quality.

Moving from quality to safety, what does the evidence show? Studies of short term use of melatonin for sleep onset insomnia in adults consistently demonstrate safety. These include the following:

A sustained-release melatonin formulation at a dose of 2 mg nightly for 6 months was safe in adults, including elderly individuals, with sleep onset insomnia (555 participants completed the trial). There were no signs of tolerance, and no withdrawal symptoms or rebound insomnia following discontinuation of melatonin. Adverse events were mild, and there were no significant differences in safety outcomes between melatonin and placebo groups.³⁹

In a trial of 157 people with Alzheimer's disease, a 2.5 mg sustained-release melatonin formulation was well tolerated for 2 months, with no significant difference in the number or grade of adverse events between placebo and melatonin groups. As an aside, melatonin did not result in changes in objective measures of sleep function, but improved subjective caregiver ratings of sleep quality.⁴⁰

In a trial of 354 adults ages 55–80 with insomnia, treatment with a sustained-release melatonin 2 mg daily for 3 weeks had a good safety profile, with no difference in safety measures comparing melatonin to placebo.⁴¹

Occasional questions may also come from patients regarding the safety of melatonin in specific conditions, such as hypertension, sleep apnea, or epilepsy. These questions seem to arise from conflicting information regarding safety found in consumer health resources. Additionally, patients may ask about the safety of melatonin in children.

Melatonin has been shown to be safe (and not only safe, but therapeutic) in people with hypertension. The natural circadian (nocturnal) decline in BP is noted to coincide closely with the rise of melatonin.⁴² It is suggested that melatonin deficiency may be a contributor to nocturnal hypertension. Melatonin may function as a peripheral artery dilator (reducing peripheral resistance), promote nocturnal sympathetic nervous system suppression, and serve as a vasoprotectant.⁴³ Melatonin has been shown to be safe (and efficacious) in men with arterial hypertension, men with essential hypertension, and in women with a blunted nocturnal BP decline.^42,44,45 Meta-analyses have confirmed a therapeutic antihypertensive effect of melatonin in various populations, including in people taking atypical antipsychotics, people with bipolar disorder or schizophrenia, people with NAFLD or T2DM, and people with metabolic syndrome.^46,47

Regarding sleep apnea, one concern cited in popular media is that melatonin, as a hypnagogic, may increase sleep-disordered breathing. On the contrary, melatonin has been shown through clinical study to be safe (and again, not just safe, but therapeutic) for these individuals. People with obstructive sleep apnea (OSA) have been shown to have abnormal melatonin secretion, with an absent nocturnal serum melatonin peak.⁴⁸ In a case series in people with not only untreated OSA but also rapid eye movement sleep behavior disorder, melatonin supplementation was found to lead to clinical symptom improvement.⁴⁹ In a small trial in children with epilepsy, melatonin supplementation led to an improvement in sleep apnea (as well as overall sleep function).⁵⁰ In a one month trial of adult patients with CAD, two thirds of whom were identified as having sleep apnea, melatonin at a dose of 5 mg nightly did not aggravate sleep-disordered breathing, an important consideration in patients at increased cardiac risk.⁵¹

An additional question regarding melatonin safety is a perceived risk for the heightening of seizure activity in those with epilepsy or other seizure disorders. Trials in both adults and children are reassuring in terms of the safety profile for people with seizure disorders. In adults, 3 mg of melatonin nightly is a useful adjunct to valproate, improving the responder rate, seizure-free rate, seizure frequency, and antioxidant status compared to a placebo.⁵² A brief trial in young adults and children found that a higher dose of melatonin (10 mg) supplemented for 3 weeks led to no significant change in maximal number of seizures, seizure duration, sleep efficiency or latency, while diurnal seizures specifically decreased significantly in comparison to placebo.⁵³ Additionally, in children with epilepsy who are seizure-free on valproate, adjunctive melatonin (dosed at 6 mg for children <9 years old/weighing <30 kg, or 9 mg for children <9 years old/weighing >30 kg) improves quality of life (QOL) measures without the occurrence of adverse events.⁵⁴

One concern voiced specific to the use of melatonin in children is a potential effect on puberty. This concern appears to have been driven by the observations that exogenous melatonin has the ability to suppress gonadotropin-releasing hormone in animals, and that the normal decline in nocturnal melatonin levels seen during adolescence aligns with both sexual development and the progression of Tanner stages in children.⁵⁵ In a small study (N = 80) in children with autism spectrum disorder (ASD) supplemented with 2, 5, or 10 mg melatonin for up to 2 years, there were no adverse effects on children's growth or pubertal development (with changes in mean weight, height, body mass index, and Tanner staging all within normal ranges for age, and with no evidence of delay), and no safety concerns related to either the use or discontinuation of melatonin.⁵⁶

Additional studies assessing for the safety of melatonin in children include the following:

In a 2020 meta-analysis of RCTs in children and adolescents, side effects with short-term use of melatonin were mild to moderate, and included fatigue, headache, gastrointestinal upset, or mood change. The analysis included 387 children or adolescents from 7 clinical trials. One serious adverse event, migraine, occurred in the analysis. Melatonin was given at doses of 1–6 mg for periods of 1–4 weeks.⁵⁷

In a 26-week trial conducted in children with both sleep problems and neurodevelopmental disorders, melatonin was administered at 1 mg nightly, with the dose being increased up to 2–4 mg as needed based on the child's clinical condition. Melatonin was found to be well-tolerated, with 94 of 99 children completing the trial, and with only one child discontinuing melatonin due to a treatment-emergent adverse event (somnolence).⁵⁸

In an evaluation of melatonin for migraine prophylaxis, 60 children were treated with melatonin at a dose of 0.3 mg/kg body weight for 3 months. Side effects occurred in 14 children (23%): sleepiness in 7, vomiting in 4, mild hypotension in 2, and constipation in 1 participant. Three children stopped melatonin due to excessive daytime sleepiness.⁵⁹

Melatonin was both safe and efficacious in children and adolescents with ASD, with or without attention-deficit hyperactivity disorder or neurogenetic disorders. Melatonin was dosed as a sustained-release formula, starting at 2 mg escalated to 5 mg, for 13 weeks.⁶⁰

Autoimmunity

Lastly, a separate discussion of the evidence for use of melatonin in autoimmune conditions seems warranted. Melatonin is well-demonstrated as an immune modifier. In people with autoimmune conditions, might this lead to an enhancement of immune function that worsens the disease state?⁶¹ Consumer health resources online specifically direct patients not to take melatonin if they have autoimmune conditions.^62,63 What is the rationale for this recommendation, and what does the evidence show?

In rheumatoid arthritis (RA), preclinical studies are conflicting,⁶¹ and limited clinical trials show mixed effects. Melatonin dosed at 10 mg daily for 6 months in people with RA (N = 75) results in an increase in some inflammatory markers (erythrocyte sedimentation rate, neopterin, and plasma kynurenine), but paradoxically, this increase was not associated with any alterations in the concentrations of proinflammatory cytokines or clinical symptomatology.⁶⁴ In an additional small trial in people with RA (N = 64), melatonin at 6 mg daily for 12 weeks actually decreased disease activity and markers of oxidative stress compared to baseline status.⁶⁵ This is an area in which additional clinical studies would clearly be useful.

A small 2021 trial (N = 25) in people with systemic lupus erythematosus found that melatonin reduced oxidative stress and had no effects on disease activity. Melatonin was supplemented at 10 mg daily for 12 weeks. Melatonin resulted in a significant reduction in serum MDA compared with baseline as well as with the placebo group (P = 0.003 and P = 0.004, respectively). Melatonin did not cause a significant change in disease activity, either compared to baseline or to placebo (P > 0.05).⁶⁶ Again, this was a small trial, so additional trials are much needed.

In multiple sclerosis (MS), melatonin appears to contribute to the seasonality of disease relapses. In a cohort of 139 patients with relapsing remitting MS, there was a 32% reduction in relapses during the fall and winter (P = 0.02). Subjects were found to have increased melatonin secretion in fall and winter, and lower levels during spring and summer. There was a significant negative association between 6-sulfatoxymelatonin (6-SMT; the primary metabolite of melatonin in the urine, and a surrogate biomarker for blood melatonin concentration) and the MS exacerbation rate (P < 0.01), which was confirmed in an age and gender-adjusted regression model: for each 6-SMT unit increase, there was a 3% reduction in the number of relapses (P = 0.007).⁶⁷ People with MS with lower overnight 6-SMT have also been shown to have greater disability and severity of fatigue, and overnight 6-SMT levels are inversely related to fatigue severity, number of relapses in the preceding 12 months, and Expanded Disability Status Scale (EDSS) scores in these patients (P = 0.016, P = 0.01, and P = 0.049, respectively).⁶⁸

In a 12-month pilot-scale (N = 26) double-blind, randomized, placebo-controlled trial among people with relapsing remitting MS receiving weekly interferon beta therapy, there was no difference in primary or secondary outcomes (including number of relapses, change in EDSS, number and volume of new T2 and gadolinium-enhancing brain lesions, performance on the Multiple Sclerosis Functional Composite, and measures of fatigue and depression) with supplementation of melatonin at a dose of 3 mg daily. Notably, while these measures were not improved, they were also not worse, and no participant reported a serious adverse event with one year of melatonin supplementation.⁶⁹ Lower dose melatonin is also efficacious for sleep difficulties in people with MS. In a study utilizing a starting dose of 0.5 mg, escalating up to 3 mg as needed, melatonin taken for 2 weeks improved mean total sleep time significantly (P = 0.03).⁷⁰

A trial utilizing a higher dose of melatonin (25 mg daily) also demonstrated safety for people with MS. Thirty-six people with relapsing remitting MS being treated with interferon beta received either melatonin or placebo for six months. There was a significant decrease in markers of oxidative stress and pro-inflammatory cytokines with administration of melatonin, compared to placebo. Melatonin was well tolerated, with no significant difference in the rates of side effects between the melatonin and placebo groups.⁷¹

Considering the evidence above, it has been the author's practice to weigh the use of melatonin supplements in people with autoimmune conditions on an individual basis. Careful observation for worsening of clinical signs or symptoms may be warranted in some patients. Individual cases of symptom flare with melatonin supplementation are documented in the literature (such as those in myasthenia gravis, or autoimmune hepatitis associated with primary sclerosing cholangitis).^72,73 Additionally, elevation of melatonin may be seen in some autoimmune disease states (such as ankylosing spondylitis, where it correlates with spinal ossification⁷⁴), but it also seems possible that some of the increases seen in these conditions may not be causative, but rather compensatory, in response to increased inflammation.⁶¹

At the same time, discounting an important, non-toxic, low-cost, and often effective natural sleep aide in these patients as a whole may not be the most reasonable strategy. Sleep disturbance is a common concern in people with autoimmune conditions, and may strongly impact QOL for some sufferers. Balancing these factors can be accomplished by thoroughly reviewing the potential risks and benefits of melatonin with an individual patient based on their specific situation. At least in some situations (perhaps most particularly in MS, where more data is available), it seems possible that melatonin may even have additional benefits for these patients beyond the support of sleep function. More clinical trials in this area are eagerly awaited.

Conclusions

The ancient pleiotropic molecule melatonin has a great variety of clinical uses, in many cases extending beyond its benefits for sleep. This review touches on just a few of melatonin's clinical applications. These include NAFLD, menstrual and menopausal conditions, CVD, and T2DM, among others. Melatonin generally has a good safety record and has been shown in numerous trials to be well tolerated in both adults and children. Part II of this review will go on to discuss the rationale for, and clinical use of, melatonin in oncology.▪

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