Endogenous melatonin is produced from tryptophan by 5-HTP and serotonin. The bi-directional neural processes from the gut and the brain rely on specific metabolic reactions, such as the conversion of tryptophan into serotonin. In many ways, serotonin provides the foundation for the connection between the gut-brain axis, as it directly affects and influences neurological response and central nervous system transmission. Tryptophan metabolism is directly influenced by inflammatory and immune responses, which trigger kynurenine pathway.

Melatonin is both water- and lipid-soluble (‘amphiphilic’); thereby, it can freely flow among all bodily tissues, especially across the selective blood–brain barrier, making it likely one of the most formidable antioxidants within the central nervous system ^[1][60]. Preliminary research also indicates that it may be an active component in the glymphatic fluid, assisting in removing metabolic waste such as amyloid buildup ^[2][61]. Theoretically, based on this finding, it may be worthwhile from a therapeutic perspective to dose melatonin so that older adults with neurodegenerative conditions could increase cerebrospinal and glymphatic fluid levels. However, this concept is still in its infancy.

Neurodegenerative conditions share mitochondrial dysfunction in their pathogenesis. Mitochondria, the cellular energy source, are also the target of oxidative damage. The sensitive nature of mitochondrial membranes, which can be damaged by many factors, may find protection with the oral administration of melatonin ^[3][62]. Mitochondrial membranes selectively take up melatonin, a function not shared by other antioxidants ^[4][63].

Human circadian rhythms are entrained to the environmental day primarily by light exposure, particularly at dawn and dusk ^[5][64]. Melatonin supplementation can also modulate the circadian rhythm by causing an advance or delay, depending on the administration time. In this manner, melatonin acts as a chronobiotic. The melatonin phase response curve specifies how exogenous melatonin will shift the individuals’ body clock when given at various times in relation to their sleep midpoint ^[6][65]. For instance, 0.5 mg and 3.0 mg of melatonin taken eleven hours before the sleep midpoint will cause a phase advance, so the individual feels sleepy earlier and awakens earlier. Both doses of melatonin taken in the morning, approximately 6 h after the sleep midpoint, will cause a phase delay. Of note, when melatonin is taken 4 h before the sleep midpoint, i.e., at bedtime, the low dose of 0.5 mg does not shift the circadian rhythm, while the 3.0 mg dose will cause a phase delay. This dosing regimen may contribute to the occasional complaints of a paradoxical effect of melatonin supplements on sleep.

Circadian rhythm sleep-wake disorders are either intrinsic or extrinsic. Intrinsic circadian rhythm disorders appear when the individual’s body clock is either off-set from the norm, as in delayed or advanced sleep-wake phase disorder, or irregular, as in non-24 sleep-wake rhythm disorder. Lifestyle factors can result in extrinsic circadian rhythm disorders such as shift work disorder or jet lag disorder ^[7][66]. Melatonin supplements can be used therapeutically for both conditions ^[8][67].

Studies using melatonin have explored how shift work, particularly night work with its exposure to light at night, may increase the risk of cancer, aggravate both gastrointestinal and cardiovascular disease, complicate pregnancy, and interfere with drug therapy ^[9][68]. Multiple studies, opinions, and guidelines have suggested melatonin as primary therapy for improved health and sleep of shift workers ^[10][11][12][69,70,71]. Thus, at a larger, more macroscopic level, as mentioned previously, imbalances in melatonin may be associated with what might be referred to as a “darkness deficiency,” or a lack of adequate evening darkness to initiate the secretion of melatonin by the pineal gland.

Delayed sleep-wake phase disorder is a persistent shift in sleep-wake times later than social norms, causing insomnia-like symptoms, difficulty waking in the morning, and excessive daytime sleepiness. This condition is best treated with precisely-timed melatonin, considering the desired bedtime and wake time. A randomized study of people with delayed sleep-wake phase disorder found that a low dose of melatonin (0.5 mg) an hour before the desired bedtime, along with behavioral strategies for four weeks, resulted in earlier sleep onset, improved sleep efficiency during the first third of the night, and reduced subjective complaints ^[13][72].

With increasing travel and global connectivity, more individuals need to recover from jet lag sooner and faster. Many studies support melatonin’s use in reducing the ill effects of jet lag and speeding up the normalization of circadian rhythms ^[14][73]. In a Cochrane review, nine out of ten trials found that melatonin effectively reduced jet lag symptoms in travelers, especially if traveling eastward or over five time zones ^[15][74]. Specific phase-shifting protocols support the sleep phase during travel across time zones. Therapeutics include precisely-timed melatonin, light, and dark. These protocols are best known by sleep specialists ^[16][75].

Although melatonin has, in some ways, become synonymous with sleep, other clinical approaches would serve as first-line interventions before using melatonin. Dysfunctional sleep does not have one mechanism, such as reduced melatonin, but potentially several causes, some or all, may be impacting melatonin levels. With over eighty sleep disorders ^[17][76], full assessment and diagnosis are important for effective treatment. Underlying inflammation-related diseases may need to be addressed, such as metabolic syndrome, sleep apnea, and any type of joint or muscle pain ^[18][19][77,78]. Even hormonal fluxes related to estrogen, cortisol, and insulin are essential to assess for imbalance and correct accordingly ^[20][21][22][79,80,81]. Moreover, there may be an association between environmental toxins such as heavy metals (e.g., arsenic) and sleep disturbance ^[23][24][82,83]. Sleep hygiene, such as room temperature, adequate darkness, noise, and comfort of bed and pillows, would be simple actions to ensure a healthy environment ^[25][26][84,85]. Further to the sleeping room, engaging in healthy lifestyle practices such as refraining from stimulants, eating or being on devices too close to bedtime, and unwinding from the day’s stresses with relaxation practices such as a warm bath or physical activity, need consideration ^[27][28][86,87]. From a nutritional standpoint, assessing dietary intake of macronutrients, especially tryptophan-containing sources of protein ^[28][87], along with micronutrients such as magnesium ^[29][88], vitamin D, and calcium, would be essential for ensuring a biochemical foundation that would foster healthy sleep ^[30][89]. Thus, melatonin would be utilized preferentially when the other changes have been implemented if there was an indication.

Melatonin has a hypothermic action. A decrease in core body temperature is soporific ^[31][90]. In this way, exogenous melatonin can have a direct effect on sleep. A meta-analysis of melatonin for the treatment of primary sleep disorders analyzed nineteen studies involving 1683 individuals. Melatonin had a statistically significant effect on reducing sleep latency and increasing total sleep time. Trials that used higher doses of melatonin and conducted over a longer duration demonstrated even greater effects on these two sleep issues, and overall sleep quality was also significantly improved in melatonin users ^[32][33][1,91].

With the retina as the target tissue perceiving light and signaling to the pineal gland, it is of interest to determine the role of melatonin in the retinal-pineal gland axis and related dysfunctions. In fact, individuals who are blind tend to have increased abnormalities in circadian rhythm compared with those who have sight ^[34][96]. Relatively smaller amounts of melatonin are produced in the retina compared with the pineal gland ^[35][97]. Despite the logical interrelationship between the retina photoreceptors and light sensitivity, there has not yet been a deep exploration into the utilization of melatonin for eye disorders. However, interest has been expressed for inflammatory conditions such as ocular neuritis and uveitis ^[36][98]. Some researchers suggest that glaucoma may be a therapeutic target for melatonin ^[37][38][99,100]. Age-related macular degeneration is another serious ophthalmic condition that theoretically could benefit from melatonin administration, although significant clinical research is currently lacking ^[39][40][101,102].

Overall, clinical data suggest that melatonin supplementation improves sleep and neurotransmission and reduces sundowning in those with Alzheimer’s disease. At a mechanistic level, it may decrease the progression of the disease through its protection of neuronal cells from amyloid-beta, possibly due to the facilitation of its degradation and transport from the brain matter through the glymphatic fluid ^[41][42][43][103,104,105]. In a small pilot study of elderly patients with a mild cognitive deficit, the ability to remember previously learned items improved, and depression decreased with melatonin ^[44][106]. A more extensive, longer-term study found that patients with mild cognitive impairment scored better on the Mini-Mental Status Exam and the Sleep Disorders Index when taking melatonin ^[45][107]. Oxidative stress is one of the leading causes of age-related brain dysfunction by impairing neurogenesis. Thus, researchers are exploring influences on monoamine synthesis, a common target for diseases of the aging brain ^[46][47][108,109], as well as the potential of melatonin as a therapeutic in dementia.

Migraines have a solid correlation to altered gut microbiota involving amines and indoles. Depleted gut melatonin may be involved in migraine occurrence because of the relative increase in N-acetylserotonin to melatonin ratios, resulting in hyperactive glutamatergic excitatory transmission in migraines. Migraines can also be correlated with many autoimmune disorders tied to melatonin regulation failure. These conditions include Hashimoto’s thyroiditis with associated hypothyroidism, rheumatic diseases, and antiphospholipid syndrome ^[48][110]. Ultimately, the gut microbiota may influence CNS function and, over time, could cause neurological diseases, including Alzheimer’s disease, mood and anxiety disorders, multiple sclerosis (MS), Parkinson’s disease, and migraines.

Migraine headaches are comorbid with several health conditions, including neurological, psychiatric, cardiovascular, cerebrovascular, gastrointestinal (GI), metaboloendocrine, and immunological disorders. It is suspected that the gut-brain axis is a network of complex interactions between the nervous and GI systems with significant contributions from intestinal microbiota. Many neurological disorders feature elements of the kynurenine

pathway of tryptophan, specifically the dysregulation of tryptophan metabolism and subsequent melatonin production ^[48][110].

A randomized, multi-center, parallel-group design was conducted in which melatonin was compared with amitriptyline and placebo for twelve weeks. A 3 mg dose of melatonin reduced migraine frequency, demonstrating the same effectiveness as amitriptyline in the primary endpoint of the frequency of migraine headaches per month ^[48][110]. Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency, and melatonin was better tolerated than amitriptyline. It has also been reported as an effective treatment for primary headache disorders ^[48][110].

An additional surveillance study observed sixty-one patients diagnosed with chronic tension headaches ^[49][50][111,112]. Patients were given 3 mg of melatonin for thirty days following a baseline period and followed up after sixty days. Quality scores were obtained using VAS pain intensity, Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D) at the study’s inception, post-thirty days of treatment, and post-sixty days of treatments. Overall, significant decreases in pain and tension headache-associated symptoms were observed after melatonin use. Sleep quality was also significantly improved during and after the study ^[49][50][111,112].

Melatonin has been used to treat chronic tinnitus in adults. One study observed a significantly greater decrease in tinnitus scores on an audiometric test and self-rated tinnitus after treatment with melatonin compared to placebo ^[51][113]. Hormonal influences such as puberty, the menstrual cycle, pregnancy, hormonal birth control, hormone replacement therapy, and menopause are possible explanations for why women may experience tinnitus. Other changes that could influence and worsen tinnitus during these times could be lack of sleep, fatigue, and stress.

When it comes to attentional disorders and the autistic spectrum, the profound effects of melatonin may be far-reaching. Research groups have evaluated the genes that encode melatonin metabolism in patients with attention deficit hyperactivity disorder (ADHD) compared to controls. Genetic results suggest a melatonin-signaling deficiency in ADHD ^[52][114]. Sleep disorders are comorbid in those with ADHD, affecting cognitive, behavioral, and physical development. In most individuals with ADHD, there is a delayed circadian phase (evening preference) and subsequent issues with daytime function. In these individuals, endogenous pineal melatonin is significantly dampened during the evening hours (triggered by dim light).

Evidence suggests somewhat variable responses to supplemental melatonin in clinical ADHD. This variability could be due to differing or overlapping etiologies of ADHD, whether it is a manifestation of genetic SNPs related to sleep disturbance and circadian rhythm dysfunction or attributed to the melatonin-signaling deficiency. More research is needed to determine appropriate dosage protocols specific to the pathophysiology of ADHD under the supervision of a qualified healthcare professional ^[53][54][115,116].

Sleep disturbances in autism have led researchers to investigate melatonin’s role in this spectrum of disorders. It was found that autistic patients have low melatonin levels caused by a primary deficit in ASMT gene activity ^[55][117]. In a double-blind, placebo-controlled study, investigators tested children diagnosed with autism spectrum disorder (ASD) (n = 103) and healthy children (n = 73) for serum melatonin, the oxidants of nitric oxide, and malondialdehyde levels. Overall, children diagnosed with ASD and positive family history had higher serum melatonin and nitric oxide levels, with significantly lower malondialdehyde/melatonin ratios, suggesting greater impaired oxidant-antioxidant metabolism and balance in children with ASD ^[56][118].

Improvements in LDL cholesterol and blood pressure have been shown in as few as two months of melatonin use (5 mg/day, two hours before bedtime) in thirty patients with documented metabolic syndrome who had not responded to a three-month intervention of therapeutic lifestyle modifications ^[57][120]. Further, melatonin has been shown to decrease nocturnal hypertension, improve systolic and diastolic blood pressure, reduce the pulsatility index in the internal carotid artery, decrease platelet aggregation, and reduce serum catecholamine levels ^{[58][59][60][61]}[121,122,123,124]. A recent meta-analysis and systematic review by researchers at The Chinese University in Hong Kong concluded that a controlled-release oral melatonin supplement reduced asleep systolic blood pressure by 3.57 mm Hg ^[58][121].

Cai et al. ^[62][125] correlated low levels of endogenous melatonin to decreased long-term survival in patients with pulmonary hypertension. As illustrated, multiple mechanisms are involved with the pleiotropic abilities of melatonin that not only have been shown to have antioxidant, inhibition of oxidative stress, and anti-inflammatory effects but also in inducing vasodilation, cardio-protective, cancer-protective, and benefits in respiratory diseases. Melatonin levels were attributed to hyper-activation of the sympathetic system and/or the renin-angiotensin system in patients with pulmonary hypertension ^[62][125].

Other studies have shown that melatonin improves outcomes in patients with heart failure and is considered a preventive and adjunctive curative measure in these patients ^[61][124]. A randomized double-blinded placebo-controlled clinical trial with two parallel arms using either placebo or oral 10 mg melatonin supplementation per day for twenty-four weeks in patients with heart failure and reduced ejection fraction observed improvements in endothelial function in those who did not also have diabetes ^[63][126].

There has been some discussion as to whether melatonin may be helpful in conditions involving glycemic control, such as in non-insulin-dependent type 2 diabetes. A recent, relatively small, placebo-controlled study in male diabetics showed reduced insulin sensitivity by 12% after 10 mg of melatonin for three months ^[64][127]. The difference in effects of melatonin on oral glucose tolerance in the diabetic population may involve polymorphisms in the type 2 diabetes-associated G allele in the melatonin receptor-1B gene (MTNR1B) ^[65][66][67][3,128,129]. In one clinical trial with Spanish type 2 diabetics ^[68][130], the relationship between endogenous melatonin, dietary carbohydrate, and the effects of late-night eating were investigated. It was found that glucose tolerance was impaired in the late versus the early eating condition, especially in MTNR1B G-risk allele carriers, known to have insulin secretion defects. While this type of genotype is not easily assessed through current clinical laboratory assessment, it is best to monitor melatonin supplementation and any changes in blood sugar response in patients with glycemic control issues.

The hypothalamic-pituitary-gonadal axis is controlled through hormones. Although the data need further delineation, there is a bidirectional relationship between melatonin and sex steroids, especially estrogen, that is determined by many factors ^[69][131]. For example, the role of melatonin becomes increasingly important in the menopausal transition with sleep disturbances and changes in metabolism. Therefore, its effects on female health aspects such as pregnancy, fertility, and ovarian and uterine dysfunctions are worth noting in the sections below, highlighting relevant research in these areas.

Pregnancy is a critical time for fetal programming of hypertension. As an antioxidant therapy, melatonin may help prevent hypertension in the offspring of patients with a family history of hypertension ^[70][135]. It has been hypothesized that oxidative stress negatively impacts fertility. Since melatonin is a strong scavenger of oxidative factors, it could improve both male and female fertility and sperm and oocyte quality, resulting in increased fertilization ^{[71][72][73][74]}[136,137,138,139]. Melatonin shows promise for advanced age infertility and improving IVF outcomes ^{[75][76][77][78][79]}[140,141,142,143,144].

Delivery by cesarean may also be associated with higher levels of pro-inflammatory cytokines compared to vaginal birth ^[80][145], thereby shunting the production of pineal gland melatonin synthesis and upregulating the tryptophan conversion into the kynurenic pathway, offsetting the serotonin-melatonin pathway ^[81][146]. Women who delivered vaginally versus by cesarean had higher colostrum melatonin levels ^[80][82][145,147]. Finally, administering 10 mg of melatonin, compared with 5 mg or placebo, to women before the cesarean section with spinal anesthesia was shown to reduce the severity of their pain, duration of analgesic use postoperatively, and facilitated their ability to be more physically active in less time after surgery ^[83][148].

The results of supplemental melatonin in women with endometriosis are mixed. In a randomized, double-blind placebo-controlled trial, Schwertner et al. found that melatonin at 10 mg nightly reduced endometriosis pain by about 40% and reduced the use of pain-relieving medications by 80% over two months ^[84][149]. However, more recently, a small clinical trial ^[85][150] with women taking either a placebo or 10 mg melatonin during the menstrual week did not find any difference in pain reduction between the two groups. Based on the difference in findings between the two studies, a longer supplementation duration might be worth exploring in women with endometriosis.

This nutrient alone is not enough to manage the pain from endometriosis ^[86][87][151,152], but when it comes to pain relief, it may be a safer clinical starting point than pharmaceutical analgesics, which may have significant side effects.

Polycystic Ovarian Syndrome (PCOS) is a gynecological, endocrine disorder affecting 5–10% of women. It is a multifactorial disease with increased androgens, hirsutism, acne, insulin resistance, central obesity, amenorrhea or oligomenorrhea, poor sleep, anovulation, and decreased fertility ^[88][153]. Melatonin is relevant for PCOS given that not only are there melatonin receptors on the cells as in other tissues, but melatonin is synthesized in the oocytes, ovarian follicular cells, and cytotrophoblasts of the placenta ^[89][154]. As discussed above, melatonin and its metabolites are powerful antioxidants that can preserve oocyte quality.

Both the circadian pattern and levels of melatonin are altered in PCOS. In adolescents with PCOS compared to control participants, melatonin offset is later in terms of both clock time and their wake time, while melatonin duration is longer. In adolescents with and without PCOS, later melatonin offset is associated with increased serum-free testosterone levels and worse insulin sensitivity. This finding suggests that morning circadian misalignment may be part of the pathophysiology of PCOS ^[90][155]. Other studies have found that melatonin patterns are altered in PCOS with higher serum levels but decreased follicular fluid levels, typically higher than serum levels ^[91][156]. A meta-analysis including 2553 women with PCOS and 3152 control women found that two nucleotide polymorphisms in the melatonin receptor 1A and 1B genes are significantly associated with PCOS ^[92][157].

Six months of melatonin treatment in forty normal-weight women with PCOS causes meaningful hormone changes. Androgens, free testosterone, hydroxyprogesterone, anti-Mullerian hormone, and low-density lipoprotein all significantly decreased, while there was no change in other lipid parameters or glucoinsulinemic measures. Menstrual irregularities decreased in 95% of the women ^[93][158]. This result is due to a direct effect of melatonin on the ovaries that is independent of insulin. In an eight-week trial, eighty-four participants with PCOS received either melatonin, magnesium, melatonin plus magnesium, or a placebo. Melatonin alone significantly improved subjective sleep as measured by the Pittsburgh Sleep Quality Index (PSQI) and serum high-density lipoprotein cholesterol. When melatonin and magnesium were taken together, it resulted in a significant decrease in insulin, cholesterol, low-density lipoprotein cholesterol, and testosterone levels ^[94][159]. In a randomized, double-blind, placebo-controlled study of fifty-eight women (ages 18–40 years old) they took either 10 mg of melatonin or a placebo an hour before bed for twelve weeks. Results at the end of the intervention found improvements in the melatonin group compared to placebo for mental health on the Beck Depression and Beck Anxiety Inventories. Subjective sleep quality improved on the PSQI. Lab analysis showed improvements for the melatonin group, including decreased homeostasis model of assessment-insulin resistance (HOMA-IR), serum insulin, total and LDL-cholesterol, and increased quantitative insulin sensitivity check index. Additionally, those who took melatonin had upregulation of genes for the low-density lipoprotein receptor and peroxisome proliferator-activated receptor gamma ^[91][156].

Broad therapeutic benefits include melatonin’s role in oral care and digestive function, periodontal inflammation, post-dental surgery, and antioxidant protection against dental materials ^[95][96][160,161]. Studies have investigated its use in Helicobacter pylori (H. pylori) infections, gastric and duodenal ulcers, gastroesophageal reflux disease (GERD), and inflammatory bowel disease ^[97][98][99][162,163,164]. Melatonin and its precursor tryptophan have protective effects on mucosal tissue. A study in which H. pylori-infected individuals were given melatonin, placebo, or tryptophan with omeprazole is of interest. Each of the three groups had seven subjects with gastric ulcers and seven with duodenal ulcers. At the twenty-one-day mark, those treated with either tryptophan (250 mg twice daily) or melatonin (5 mg twice daily) had no ulcers, whereas the placebo group had three gastric ulcers and three duodenal ulcers. Additionally, of note is that in one study on GERD, melatonin given at 3 mg daily over eight weeks showed similar improvement in symptoms as omeprazole ^[99][164].

A study indicated that gut bacteria have a circadian clock and respond to melatonin, allowing the bacteria to synchronize with the human circadian rhythm ^[99][164]. The melatonin produced in the GI tract can, in turn, assist with gut motility and mucosal integrity via its antioxidant activity and support of the microbiome. Finally, smaller-sized studies show that melatonin can improve symptoms of pain, bloating, and constipation in individuals with Irritable Bowel Syndrome-Constipation (IBS-C) and Irritable Bowel Syndrome-Diarrhea (IBS-D) presentations. Dosing melatonin at 0.3 mg daily for IBS-C and 3.0 mg for IBS-D may benefit patients with IBS ^[100][165].

Promising, emerging research indicates that melatonin supplementation may have therapeutic benefits for autoimmune conditions, such as multiple sclerosis (MS) and perhaps Hashimoto’s thyroiditis, most likely due to its involvement in anti-inflammatory mechanisms, oxidative stress reduction, and modulation of the gut microbiota ^[101][166]. Melatonin is linked to the seasonal relapse rate in patients with MS ^[102][167]. Clinical data investigating melatonin supplementation in individuals with MS have reported better quality of life with lower doses ^[103][168] and reduced oxidative stress and inflammatory markers ^[104][105][169,170] in this patient population. Anderson, Rodriguez, and Reiter ^[106][171] conducted a systematic review of the correlation between the gut microbiome, gut permeability, and the possible pathophysiology of MS. An overall gut dysbiosis in patients with MS was identified as a result of increased ceramide production. The suppression of melatonin is suspected to cause this metabolic shift directly or indirectly, further complicating the circadian dysregulation that is evident in MS patients.

While not extensively studied in clinical trials, vitamin D and melatonin have been suggested to be part of a nutritional protocol for individuals with Hashimoto’s thyroiditis due to their molecular actions ^[107][172].

Currently, there is an ongoing scientific discussion regarding the use of melatonin for COVID-19. With its ability to impact mechanisms that modify immune regulation, melatonin has been included as one of the top recommendations as a preventive and therapeutic option for COVID-19, along with zinc, selenium, vitamin C, and vitamin D ^[108][109][173,174]. Although scientific evidence is not definitive, there are some initial indications that melatonin could be beneficial and is also considered to be safe ^[109][110][174,175].

In a systematic review and meta-analysis of thirteen clinical trials, melatonin supplementation was found to decrease inflammatory compounds (TNF-alpha, IL-6, C-reactive protein), although with a more significant lowering effect on TNF-alpha and IL-6, especially with studies ≥ twelve weeks and at a dosage ≥ 10 mg/day ^[111][176]. Athletes may be a population that experiences bouts of inflammation for which melatonin could help reduce proinflammatory mediators. In a study of oxidative stress markers in those who ran a 50 km (31 m) course, those who took melatonin had reduced levels of stress markers ^[112][177], underscoring not only the mechanism of antioxidant protection but also a practical use in athletes who are exposed to oxidative stress and inflammation that may increase their risk for vascular incidents.

Another clinical application of melatonin may be environmental toxicity. Melatonin may be one of the many antioxidants to help mitigate oxidative stress from human exposure to toxicants such as bisphenol A ^[113][178]. However, much more research is needed to understand how melatonin provides benefit relative to other antioxidants.

The scientific research lineage of utilizing melatonin supplementation in those with cancer dates back at least three decades. Most notable is early research conducted on patients with solid metastatic tumors, in which it was demonstrated that high doses of melatonin were effective in arresting tumor growth and improving quality of life markers ^[114][179]. Lissoni’s group, well-recognized pioneers in the field of psycho-immune-neuroendocrinology ^[115][180], provided several reports on this dose throughout the 1990s ^[116][181] with subsequent studies confirming his findings ^{[117][118][119][120]}[182,183,184,185]. Of particular mention, one of Lissoni’s studies indicated that melatonin supplementation (20 mg daily, starting seven days before chemotherapy) was helpful in chemotherapy response rate in fifty metastatic non-small cell lung cancer patients ^[121][186]. Interestingly, there was an interaction between melatonin’s efficacy and the spirituality of the patient, with greater effects noted in those with spiritual faith ^[121][186]. This intriguing finding relates to the dynamic nature of how various therapies like melatonin supplementation can be enhanced through mindset or a belief system, which is a relevant topic for immune system functioning; hence, the field of psycho-immune-neuroendocrinology.

Melatonin may help to re-establish altered circadian rhythm in cancer. Patients with breast and colorectal cancers were observed to have altered circadian rhythms associated with flattened cortisol levels throughout the day ^[122][187]. Mortality was positively associated with erratic circadian rhythm and poor sleep. Normally, cortisol levels are lowest in the evening hours and start to rise in the morning. Cortisol and melatonin work inversely, so as cortisol rises, melatonin decreases and vice versa ^[123][188]. These two endocrine messengers provide some clinical information, albeit somewhat indirectly, about the function of both the hypothalamic-pituitary-adrenal axis and the pineal gland, which is pivotal for disease outcomes like cancer where there is neuroimmune involvement ^[116][181]. Lissoni et al. also suggested that the pineal gland produces other indole hormones that could be therapeutic in cancer ^[124][189].

Under states of stress and high cortisol, tryptophan’s conversion to serotonin and melatonin is shunted to kynurenine. Often, patients with cancer experience chronic fatigue, anemia, depression, and overall decreased quality of life. Researchers recognized that individuals with solid tumors have an initial immune response involving pro-inflammatory cytokines as the body recognizes self from non-self ^[125][190]. During this process, the kynurenic pathway is accelerated, causing inflammation-mediated tryptophan catabolism, fatigue, anemia, and depression ^[126][191]. In such cases, supplementation with melatonin may be an effective way to augment the standard of care and mitigate the inflammatory cascade that ultimately leads to decreased quality of life.

In night-shift workers, circadian disruption is prevalent due to light exposure at night ^[127][192]. Upon review of human clinical trials specific to breast cancer risk in night-shift workers, researchers reported melatonin’s ability to suppress the aerobic metabolism of tumors (known as the Warburg effect) while suppressing the tumor cells’ proliferation, tumor cells’ survival, metastasis, and potential drug resistance. In human models, circadian rhythm disruption due to artificial light exposure at night significantly increased breast cancer risk ^[128][129][193,194]. A meta-analysis examined the role of melatonin in forty-six different microRNAs found in breast, oral, gastric, colorectal, prostate, and glioblastoma cancers. The microRNAs associated with breast, gastric and oral cancers were most responsive to melatonin treatments. Researchers identified the actions of melatonin to upregulate genes correlated to immune and apoptotic responses, where melatonin downregulated tumor cell survival involved in metastasis and angiogenesis ^[130][195].

Based on cell and preclinical data, it has been suggested that melatonin acts on both anabolic and catabolic aspects of bone metabolism ^[131][196]. Over the years, limited published clinical trials using a relatively small number of study subjects have demonstrated melatonin’s role in rebalancing bone remodeling in perimenopausal women ^[132][197] and increasing bone density in postmenopausal women with osteopenia ^[133][198]. In these studies, up to 3 mg of supplemental melatonin was used. According to findings from the year-long clinical trial referred to as Melatonin-micronutrients Osteopenia Treatment Study (MOTS), a combination of melatonin (5 mg), strontium (citrate) (450 mg), vitamin D3 (2000 IU/50 mcg) and vitamin K2 (MK7) (60 mcg) may be able to favorably impact bone markers such as bone mineral density in postmenopausal, osteopenic women, compared with placebo ^[131][196]. In addition to beneficially modifying bone markers, the intervention improved quality of life measures such as mood and sleep quality ^[131][196]. Of course, it cannot be inferred that melatonin was responsible for these effects since it was given as a combination supplement.

Investigators reviewed melatonin as a pivotal compound in age-related skeletal muscle disorders because of its involvement in mitochondrial function through its antioxidant potential ^[134][199]. Any research findings in this direction may be helpful for those with cachexia or sarcopenia. Furthermore, these authors suggested that it would be interesting to explore melatonin’s effect on the gut microbiome as it relates to skeletal muscle (the ‘gut-muscle axis’) ^[134][199].