Melatonin

Scientific Name(s): Melatonin , circadin , melatol

Common Name(s): MEL

Uses

Melatonin is used for numerous conditions but has shown the most promise in short-term regulation of sleep patterns, including jet lag. Results from clinical trials are inconsistent.

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Dosing

Jet lag : Eastbound travel : A preflight, early evening treatment of melatonin should be followed by treatment at bedtime for 4 days after arrival. Westbound travel : Melatonin for 4 days at bedtime when in the new time zone. Sleep disorders : Difficulty falling asleep : Melatonin 5 mg 3 to 4 hours before an imposed sleep period over 4 weeks. Difficulty maintaining sleep : A high dose, repeated low doses, or a controlled-release formulation. Children 6 months to 14 years of age with sleep disorders : Melatonin 2 to 5 mg has been used. Thermal injury : Up to 20 mg orally/IV for 28 to 30 days then 10 mg orally daily for 1 year.

Contraindications

Melatonin should not be used by patients who have autoimmune diseases.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Caffeine and fluvoxamine may increase the effects of melatonin, while melatonin may decrease the antihypertensive effect of nifedipine. Melatonin may possibly potentiate the effects of warfarin.

Adverse Reactions

Possible adverse reactions include depression, dizziness, enuresis, excessive daytime somnolence, headache, and nausea. Drowsiness may be experienced within 30 minutes after taking melatonin and may persist for approximately 1 hour and, thus, may affect driving ability. There may be an increased risk for seizures in children with severe neurological disorders.

Toxicology

There is little or no evidence of any major toxicities with melatonin, even at high doses.

History

Melatonin is one of the hormones produced by the pineal gland in all vertebrates. It is also produced in extrapineal organs, such as the eye, GI tract, bone, skin, lymphocytes, platelets, and thymus. Early animal studies in the mid-1960s revealed its ability to affect sexual function, skin color, and other mammalian functions. It is a mediator of photo-induced antigonadotrophic activity in photoperiodic mammals, and it affects thermoregulation and locomotor activity rhythms in birds. It also has been implicated in time-keeping mechanisms in the pineal gland. Early studies showed that diurnal variations in estrogen secretion in rats could be regulated by changes in melatonin synthesis and release, induced by the daily cycle of light and dark via the efferent limb of the reflex in the sympathetic innervation of the pineal gland. Continual darkness depresses the estrous cycle. , In addition to being produced in vertebrates, melatonin is also found in plants, bacteria, unicellular eukaryotes, and invertebrates.

Melatonin secretion is inhibited by environmental light and stimulated by darkness, with secretion starting at 9 PM and peaking between 2 and 4 AM at approximately 200 pg/mL. The duration of melatonin production varies throughout the year with shorter periods occurring during the summer months and longer periods occurring during the winter months. Nocturnal secretion of melatonin is highest in children and decreases with age. , Studies in the 1990s have led to widely expanded uses of melatonin including easing insomnia, combating jet lag, preventing pregnancy (in large doses), protecting cells from free-radical damage, boosting the immune system, preventing cancer, and extending life.

Although melatonin is not approved for marketing as a drug product, it has been classified as an orphan drug since November 1993 for the treatment of circadian rhythm sleep disorders in blind people with no light perception. It is commercially available as a nutritional supplement, either as a synthetic product or derived from animal pineal tissue. Use of the tissue-derived product is discouraged because of a risk of contamination or viral transmission. Most commercial brands are available as 300 mcg or 1.5 or 3 mg tablets under various names. Patients should seek medical advice before undertaking therapy.

Chemistry

Chemically, melatonin is defined as N-acetyl-5-methoxytryptamine and is an indoleamine. It can be isolated from the pineal glands of beef cattle or synthesized from 5-methoxyindole as a starting material via 2 different routes. It is a relatively low molecular weight hormone of 232 Da and is a pale yellow crystalline material.

Uses and Pharmacology

Pharmacological disruption of melatonin production can occur via beta-1 and alpha-1 receptors because of sympathetic innervation of the pineal gland. Its biosynthesis involves several steps. First, tryptophan is converted to serotonin. , , Then, acetylation by arylalkyamine N-acetyltransferase (AA-NAT), the rate limiting step in melatonin synthesis, is followed by conversion by the enzyme hydroxyindole-O-transferase (also known as acetylserotonin methyltransferase), into melatonin. The suprachiasmatic nucleus of the anterior hypothalamus is responsible for the regulation of melatonin production. Its synthesis is inhibited by light and stimulated by periods of darkness independent of sleep. Elevation in melatonin production at night is due to increased AA-NAT activity. To date, 3 G-protein-coupled melatonin receptors have been cloned as well as 1 nuclear receptor. They are present in the periphery and CNS. Once in circulation, melatonin is metabolized in the liver where it is hydroxylated in the C6 position and then conjugated and excreted as 6-sulphatoxyMEL, a reliable marker for melatonin production.

The plasma half-life is short, 20 to 50 minutes, , , and plasma levels return to baseline within 24 hours after discontinuation of chronic dosing of less than 10 mg/day. , Doses of melatonin 5 mg produce estimated peak blood levels 25 times above physiological levels, but do not alter endogenous melatonin production. ,

Dozens of articles have appeared in medical literature on the various purported activities of melatonin. A selected overview of studies includes those regarding melatonin's role in the following: as an antioxidant and free radical scavenger, , , general health and disease treatment, hypothermic properties, control of seasonality and winter depression, , oncostatic actions on estrogen-responsive MCF-7 human breast cancer cells, treatment of neoplastic cachexia, effect on primary headaches and prophylaxis of cluster headaches, direct effect on the immune system , including activation of human monocytes, GI physiology, thermoregulatory processes, the cardiopulmonary system, potentially beneficial cardiovascular effects , including reduction in hypercholesterolemia, treatment of myoclonus in children, effects on puberty, improvement in tinnitus, human and animal reproduction, studies in human sleep, premedication for gynecological procedures, modulation of sympathetic neurotransmission, infant colic (possible), a proconvulsive hormone, purported chronobiotic and anti-aging properties, , and potentially glucose homeostasis for patients with diabetes. Melatonin administration has been studied to reduce the toxicity and/or increase the efficacy of various drugs, such as aspirin, bleomycin, carbamazepine, cisplatin, cyclophospamide, cyclosporine, cytarabine, doxorubicin, epirubicin, erythropoietin, gentamicin, haloperidol, indomethacin, iron, isoniazid, morphine, omeprazole, phenobarbital, and ranitidine.

A number of melatonin trials have attempted to resolve some unanswered questions and have shown a lack of effect on tardive dyskinesia, rapid-cycling bipolar disorder, and the rate of improvement of major depressive disorder.

Among the most common positive medical claims are entraining the blind, overcoming jet lag, immunotherapeutic potential, hastening the onset of sleep, and dampening the release of estrogen. Melatonin may diminish breast cancer rates and be useful at higher doses (ie, 75 mg) for oral contraception.

The effects of melatonin for insomnia in children with attention deficit hyperactivity disorder, autism spectrum disorders, and Smith Magenis syndrome have been evaluated. , , , , ,

Melatonin is not Food and Drug Administration (FDA) approved. The FDA warns users that there is no assurance that it is safe or that it will have any beneficial effect. Many health food manufacturers and some pharmacies and clinics have made this inexpensive hormone available for various medical purposes.

Blind entrainment

The sleep-wake cycle in humans without light-dark cues approximates 25 hours, causing the sleep cycle to shift by 1 hour each day. After several weeks, such individuals are awake at night and asleep during the day. Blind people with little or no perception of light often develop free-running circadian rhythms of more than 24 hours and subsequently develop sleep disturbances characterized by chronic fatigue and involuntary napping during the day. In case reports and small controlled studies, a daily dosage of oral melatonin 0.5 to 10 mg has been used to entrain free-running activity rhythms in blind people by advancing and stabilizing the phase of endogenous melatonin secretion. , , Although success has varied in these reports, the importance of melatonin administration time has been recognized. For example, the administration of melatonin (5 or 10 mg for 2 to 4 weeks at bedtime) to an 18-year-old blind man with chronic sleep disturbances produced slightly improved sleep onset, but did not reduce daytime fatigue or hypersomnolence. ,

However, the administration of melatonin 5 mg for 3 weeks 2 to 3 hours prior to habitual bedtime decreased sleep onset (approximately 1.4 hours), slightly increased sleep duration (34 minutes), and improved sleep quality and daytime alertness. The authors suggest that there is a Phase Response Curve for the exogenous administration of melatonin; the maximum phase advancing effects occur when melatonin is administered approximately 6 hours prior to the onset of endogenous melatonin secretion. , The average cumulative phase advancement of melatonin rhythms after 3 weeks of treatment with 5 and 0.5 mg daily was 8.4 and 7 hours, respectively. ,

Jet lag

Melatonin's ability to modulate circadian rhythms has prompted several studies investigating the use of this agent in the prevention of jet lag. , , , Although the effects have been variable, most patients have reported general improvement in daytime fatigue, disturbed sleep cycles, mood, and recovery times. These studies are limited by the small number of participants and a focus on subjective ratings of effects with little or no evidence of actual changes in circadian shift (ie, changes in oral temperature or cortisol levels).

Several melatonin regimens have been examined 5 to 10 mg daily for various durations. In one study, 52 aircraft personnel were randomized to placebo, or early or late melatonin groups. The early group started melatonin 5 mg daily 3 days before departure until 5 days after arrival. , The late group received melatonin upon arrival and for 4 additional days. When compared with placebo, the late melatonin group reported less jet lag, fewer overall sleep disturbances, and a faster recovery of energy and alertness. However, the early group that received melatonin for 8 days reported jet lag symptoms similar to the placebo group and a worsened overall recovery.

Additional data suggest that benefits were also experienced by international travelers. However, there is little information on the optimal dose or formulation. As a guide, the most appropriate timing for melatonin administration appears to be preflight early evening treatment followed by treatment at bedtime for 4 days after arrival when traveling eastbound; whereas, on a westbound flight it is better to take melatonin for 4 days at bedtime when in the new time zone. Note that individuals may experience drowsiness within 30 minutes after taking melatonin that may persist for about 1 hour and may affect driving ability.

Insomnia

Although the administration of melatonin has been shown to shift melatonin secretion and circadian rhythm patterns, its direct hypnotic effect, if any, has not been clearly established. Decreased circulating melatonin serum levels have been demonstrated in people of all ages with insomnia and in healthy elderly individuals. ,

In small studies of healthy volunteers or people with chronic insomnia, very large doses of melatonin 75 to 100 mg administered at night (9 to 10 PM) produced serum melatonin levels exceeding normal nocturnal ranges and hypnotic effects. These include decreases in sleep onset, fewer nighttime awakenings, and increases in stage 2 sleep and sleep efficiency (percentage of time asleep/time in bed). , , Midday administration of large doses also increased serum melatonin levels beyond normal nocturnal ranges, increased subjective fatigue, and decreased cognitive function and vigor. ,

The administration of smaller doses (0.3 to 6 mg) produced inconsistent hypnotic results. This may be because of the inclusion of patients with a variety of sleep disorders, different drug formulations, and different administration times (midday to 15 minutes before bedtime). , , , , , , The time to reach peak hypnotic effect was longer when melatonin 5 mg was administered at 12 PM versus 9 PM (3.66 hours vs 1 hour). , Delayed latency with daytime administration may be related to the already low circulating melatonin levels during the day. Low doses (0.3 or 1 mg) administered to healthy volunteers at 6 PM, 8 PM, or 9 PM decreased onset latency and latency to stage 2 sleep, but did not suppress rapid eye movement (REM) sleep or induce hangover effects.

In patients with difficulty falling asleep, low doses of melatonin should be sufficient in promoting sleep onset. Administration of melatonin 5 mg 3 to 4 hours before an imposed sleep period over a 4-week period decreased the time to sleep onset without affecting other sleep parameters, such as total duration or sleep architecture. However, in patients with difficulty maintaining sleep, low doses of melatonin may not produce sufficient blood concentrations to maintain slumber. A dose of oral melatonin 2 mg produced peak levels approximately 10 times higher than physiological levels, but levels remained elevated for only 3 to 4 hours. , To maintain effective serum concentrations of melatonin throughout the night, a high dose, repeated low doses, or a controlled-release formulation may be needed. When compared with placebo in a trial of 12 elderly people with chronic insomnia, melatonin increased sleep efficiency (75% vs 83%) and decreased wake time after sleep onset (from 73 to 49 minutes). , However, there were no differences between the groups for total sleep time (365 vs 360 minutes) or sleep onset (33 vs 19 minutes).

Sleep onset and sleep maintenance were improved in elderly people with insomnia after 1 week of immediate (1 mg) and sustained-release (2 mg) melatonin preparations. Sleep onset improved further when the sustained-release form was continued for 2 months. , Physically ill patients with insomnia in a hospital setting who were given a low dose (averaging 6 mg) also fell asleep faster and slept longer than their placebo-matched counterparts. Melatonin may be particularly useful when traditional hypnotics are contraindicated.

In a large meta-analysis, melatonin was not found to be beneficial for patients with secondary sleep disorders or sleep disorders accompanying sleep restriction.

Children with sleep disorders

Several case reports have described the use of melatonin 2 to 5 mg in children 6 months to 14 years of age. , Outcomes of studies in children have been similar to those in adults. Melatonin given to healthy or developmentally impaired children was most effective in treating delayed sleep onset. A controlled-release formulation was required for sleep maintenance. It has been proposed that children with multiple complex neurodevelopmental problems may require higher doses (2 to 12 mg) than initially proposed. Sleep disturbances are very common in patients suffering from autism spectrum disorders (ASD). One study found results suggesting that patients with ASD have low melatonin levels owing to a deficit in the acetylserotonin methyltransferase enzyme. In an open-label study, 25 children with autism suffering from sleep difficulties were assessed. Melatonin, prepared as a special formulation of 1 mg fast-release and 2 mg controlled-release given over a 6-hour period, was given for up to 24 months. Part of the study designed involved 1 month of discontinuation occurring at month 7. Only 20 children completed the study. During treatment, sleep patterns for all of the children improved. After discontinuation with melatonin, 16 patients returned to pre-treatment sleep scores while the remaining 4 patients continued to have improved sleep scores. The 16 patients who returned to baseline were given longer periods of treatment with melatonin. At 1- and 2- year follow-up visits, those who continued melatonin showed a significant improvement in sleep pattern in comparison to their discontinuation scores ( P < 0.001). No adverse reactions were noted by the investigators.

Melatonin may play a role in the treatment of sleep difficulties for patients with autism, pervasive developmental disorder, and Asperger syndrome. In an investigation of children between 2 and 18 years of age with autism (71%), pervasive developmental disorder (19%), or Asperger syndrome (5%), the effects of melatonin 0.75 to 6 mg were assessed. Response to melatonin was measured according to parental report. Parents reported that sleep was no longer a concern after treatment in 25% of the patients. Sixty percent reported that sleep had improved but continued to be a concern, and 13% reported that sleep continued to be a major concern. Additionally, 1% of patients reported worsening of sleep and 1% had an undetermined response. Though findings are limited by the study design (retrospective and lack of placebo), it contains a larger population of participants than most studies to date.

The use of melatonin for sleep in children with attention deficit hyperactivity disorder (ADHD) has also been evaluated. In a 4-week, randomized, double-blind, placebo-controlled study, 105 medication-free children 6 to 12 years years of age with ADHD suffering from chronic sleep-onset insomnia (SOI) were randomized to receive melatonin or placebo. Melatonin was dosed in a weight-based fashion. Sleep was assessed using sleep logs and actigraphy (movements were recorded with a device worn on the wrist). Additionally, because children with ADHD and SOI who are not receiving treatment have a delayed increase in endogenous melatonin levels at night, the dim light melatonin onset (DMLO) was also assessed. DMLO is considered to be the time in which endogenous melatonin levels increase and is considered to be a marker of the biological clock rhythm. Patients treated with melatonin experienced an advance in sleep onset by 26.9 ± 47.8 minutes compared with a delay of 10.5 ± 37.4 minutes with placebo ( P < 0.0001). Additionally, sleep latency ( P = 0.001), total time asleep ( P = 0.01), sleep efficiency ( P = 0.011), and difficulty falling asleep ( P < 0.0001) were improved with melatonin therapy compared with placebo. Patients treated with melatonin also had an advance in DMLO of 44.4 ± 67.9 minutes compared with a delay of 12.8 ± 60 minutes with placebo ( P < 0.0001). Melatonin did not affect behavior, cognition, or quality of life. It was concluded that melatonin may be useful in patients with ADHD when complaints of insomnia are persistent and become a burden on the child.

Stimulant therapy for ADHD can increase the sleep-onset latency (SOL) of children by as long as 30 minutes. In a 2-phase study, children 6 to 14 years of age with ADHD and treated with stimulants were allowed to continue in a double-blind, randomized, crossover trial of melatonin versus placebo if they continued to experience initial insomnia lasting longer than 60 minutes. Nineteen participants entered into the double-blind phase of the trial and were randomized to receive placebo or melatonin 5 mg in a crossover fashion for 30 days (10 days with melatonin/placebo, 5-day washout period, 10 days of melatonin or placebo, and 5-day washout period). The baseline SOL was 91.7 minutes assessed via somnologs. After the crossover design, the mean SOL on placebo was 62.1 ± 26.6 minutes versus 46.4 ± 26.4 minutes on melatonin. The effect size of the difference between melatonin and placebo treatment was 0.6. Seventeen continued into an open label follow up for an additional 3 months of therapy with melatonin. At the end, the SOL was 31 minutes, which was not statistically significant in comparison with the SOL measured during randomized treatment.

Smith-Magenis syndrome (SMS) is associated with sleep attacks, daytime napping, and interruption of nocturnal sleep believed to be due to an inversion of melatonin's circadian rhythm. Data taken from a study of one 3-year-old boy with SMS supplemented with melatonin 6 mg or placebo over 12 consecutive nights suggest that melatonin supplementation is associated with a shorter time to sleep induction (3.36 ± 2.23 hours with melatonin vs 7.32 ± 3.71 hours with placebo, P < 0.05). However, supplementation was not associated with an increase in diary recordings of sleep duration or improvement in quality scores. Data from this study should be interpreted cautiously because only one study subject was assessed.

Tinnitus

The effect of melatonin on tinnitus and sleep was assessed in a prospective, open-label study. Patients between 18 and 70 years of age with a history of tinnitus for 6 months were given melatonin 3 mg 1 to 2 hours before bedtime for 4 weeks. They were then observed with no melatonin for an additional 4 weeks. The mean Tinnitus Handicap Inventory score decreased by 6.6 (95% confidence interval [CI], 1.4 to 8.8, P = 0.02) between weeks 0 and 4. A decrease of 7.8 in the mean Tinnitus Handicap Inventory score was observed between weeks 0 and 8 (95% CI, 3.7 to 12.9, P = 0.006). However, neither score decreased by the predetermined value of 10 points for clinical significance. The mean Pittsburgh Sleep Quality Index (PSQI) score decreased by 2.9 points between weeks 0 and 4 (95% CI 1.6 to 4.2, P < 0.0001) and decreased by 2.5 points between weeks 0 and 8 (95% CI 1.3 to 3.7, P = 0.0003). These were clinically important based on the authors' predetermined value of 2.5. Additionally, there was an association between the change in PSQI and the change in Tinnitus Handicap Inventory scores between weeks 0 and 4 (correlation coefficient = 0.46, P = 0.04). The effects of melatonin on improving sleep and tinnitus continued through week 8, though no melatonin was administered. This may be explained by a lack of a washout period.

Fibromyalgia syndrome

Melatonin has been reported to improve sleep, severity of pain, tender point count, and global physician assessment in patients suffering from fibromyalgia. One commentary describes how melatonin 6 mg was given to 4 patients with fibromyalgia. After 15 days of treatment, patients reported normal sleep and a reduction in pain. At this time, hypnotics were withdrawn. Other medications such as analgesics and antidepressants were withdrawn after 30 days. They continued to report normal sleep patterns, lack of pain and fatigue and improvements in behavioral symptoms, such as depression. Melatonin is potentially beneficial in this population of patients due to the following: modulating sleep/wake cycles; providing benzodiazepine-like effects to decrease anxiety; synchronizing the circadian rhythms of neurotransmitters, such as gamma-aminobutyric acid, dopamine, and glutamate; exerting antistress properties; providing anti-inflammatory effects; and inhibiting macrophage and monocyte activation.

Systemic sclerosis

Systemic sclerosis is a systemic disease that is associated with fibrosis of the skin and internal organs due to endothelial damage. The effects of melatonin 8 to 16 mg/day in divided doses in combination with vitamin E and adrenocorticotropic hormone, were assessed in 5 patients suffering from systemic sclerosis. All patients experienced a partial response with regard to disease activity after 1 month of treatment. All 5 patients continued treatment for 7 to 44 months (average, 16.6 months) and had no disease progression. The response may be due to melatonin's antiaggregating effects on platelets as well as reparative effects on the endothelium. Vitamin E and adrenocorticotropic hormone were given in combination to increase the effects of melatonin. Melatonin given with Vitamin E and adrenocorticotropic hormone may be a safe and effective treatment for patients with systemic sclerosis.

Immunotherapeutic potential

Activation of melatonin receptors has been shown to enhance the release of a number of cytokines, including gamma-interferon, IL-1, IL-2, IL-6, and IL-12 in human monocytes. Melatonin may be used to stimulate the immune system during viral and bacterial infections. A potential role has been postulated in the treatment of viral encephalitis, septic shock, and secondary immunodeficiencies (eg, acute stress). However, through this proinflammatory action, melatonin may play an adverse role in autoimmune diseases.

Cancer protection

Several studies suggest that partial responses and stabilization of disease occur, to varying degrees, with the use of melatonin as adjunctive therapy in patients with malignant solid tumors. However, the majority of these studies are open-labeled trials in patients in poor clinical condition with advanced disease who did not responded to conventional therapy. Melatonin has demonstrated some inhibitory effects on tumor growth in animal models and in in vitro cancerous breast cell lines. Proposed oncoprotective mechanisms of melatonin include stimulatory effects on circulating natural killer cells and potent antioxidant activity. Preliminary studies have examined the use of melatonin in patients with solid tumors (eg, melanoma, pineal tumors) and as adjunctive amplifier therapy with interleukin in various metastatic tumors (eg, endocrine, colorectal). , , , , , European studies on B-Oval (containing melatonin) show that it can slow the growth rate of human tumor cells. A nightly supplement (melatonin 10 mg) improved 1-year survival rates in patients with metastatic lung cancer. Additionally, melatonin may play a protective role against various chemotoxicities from administration of chemotherapeutic agents. For example, melatonin may protect against doxorubicin-induced cardiomyopathy by modulating zinc distribution. Of note, melatonin does not interfere with doxorubicin's mechanism of action but possibly exerts anticancer effects by inhibition of P-glycoprotein-mediated efflux from cancer cells. Melatonin potentially has a role in the management of retinoblastoma via inhibition of angiogenesis to suppress growth of retinoblastoma cells.

Well-controlled trials are needed before the utility of melatonin as an oncostatic agent can be assessed.

Ocular diseases

Melatonin is endogenously produced in the retina and ciliary body of the eye. It is responsible for modulating light sensitivity and the photoreceptor outer segment shedding rate. Evidence from animal models suggests that melatonin may provide a protective effect for conditions such as photokeratitis, cataracts, retinal ischemia/reperfusion injury, glaucoma, and retinopathy of prematurity. Melatonin protects against free radical damage in these conditions due to its ability to decrease oxidation of lipids, proteins, and DNA. Oxidative damage is reduced as a result of melatonin's ability to maintain glutathione levels in cells and mitochondria. Not only does melatonin exert antioxidant effects by acting as a free radical scavenger, but it is also responsible for maintaining and/or increasing the activities of antioxidative enzymes and enhancing mitochondrial electron transfer to avoid free radical generation. Topical administration of melatonin could offer a specialized delivery of melatonin to the eye for the treatment of ocular diseases.

The effects of melatonin on anxiety, analgesia, and intraocular pressure (IOP) during cataract surgery were evaluated. Forty patients who underwent cataract surgery under topical anesthesia were randomized to receive either oral melatonin 10 mg or placebo 90 minutes before surgery. Anxiety scores were reduced after premedication ( P = 0.04) and during surgery ( P = 0.005) compared with placebo. Verbal pain scores and fentanyl requirements were lower in those treated with melatonin compared with placebo. For those treated with melatonin, IOP decreased from 17.9 ± 0.9 mm Hg to 14.2 ± 1 mm Hg after premedication and 13.8 ± 1.1 mm Hg during surgery ( P < 0.001). Oral melatonin potentially has a role for patients undergoing cataract surgery by providing anxiolysis, analgesia, and decreasing IOP.

Gastrointestinal disorders

Melatonin is beneficial for treating disorders of the GI tract by exerting antioxidant effects, inhibiting hydrochloric acid and pepsin secretion, and acting as an immunostimulant. , Ultimately, these effects lead to regeneration of the GI epithelium lumen. The effects of melatonin for the treatment of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and functional dyspepsia have been reported. Enterochromaffin cells found in the GI tract secrete 400 times as much melatonin as the pineal gland.

In a case report, a 64-year-old white woman reported symptoms consistent with GERD for which she was treated with a proton pump inhibitor. Because of concerns regarding the worsening of her osteoporosis with proton pump inhibitor therapy, she switched to a natural therapy containing D-limonene. After 3 trials with this, symptoms returned upon discontinuation of her proton pump inhibitor. She then received a trial of a natural product that contained melatonin 6 mg with other natural ingredients (5-hydroxytryptophan, D,L-methonine, calcium, L-taurine, betaine, riboflavin, vitamin B6, and folic acid). After 40 days of treatment, the proton pump inhibitor was discontinuation with no return of GI symptoms. When trying to reduce the dose of melatonin, GERD symptoms reappeared. Based on these findings, melatonin may offer a more natural approach for the management of GERD symptoms, though larger clinical trials are warranted.

In patients with IBS, a "bad bowels cause bad dreams" hypothesis was postulated suggesting that patients with IBS have more frequent REM sleep. In a randomized, double-blind, placebo-controlled study, 40 patients with IBS 20 to 64 years of age with sleep difficulties were randomized to receive either melatonin 3 mg or placebo for 2 weeks. After treatment, melatonin therapy was associated with a statistically significant improvement in abdominal pain scores compared with placebo ( P < 0.001). However, other measures, such as abdominal distension, stool frequency, total bowel symptoms, posttreatment changes in stool type, abnormal sensation of defecation, or quality of life, did not differ statistically between the 2 groups. There were no statistically significant differences between melatonin and placebo groups in various sleep parameters, such as time in bed, total sleep time, SOL, non-REM sleep, REM sleep, sleep efficiency, and arousal index. Melatonin may be beneficial in relieving IBS-associated abdominal pain. Th