Jet Lag

Melatonin for the treatment of jet lag has been extensively studied in controlled studies and proven to be remarkably successful in reducing jet lag symptoms.¹⁰ In one early double-blind, placebo-controlled study, 20 healthy volunteers (8 women, 12 men; 28 to 68 years) engaging in long-haul air flights across five time zones were invited to participate to explore the effects of melatonin on their jet lag symptoms. Subjects were randomly assigned to 5 mg of melatonin or placebo for three days before their outward flight (London to New Zealand) and during the flight between 10:00 am and 12:00 pm local time, as well as for three days after their arrival between 10:00 pm and 12:00 am. According to the results of visual analogue scale (VAS) testing, those using the melatonin had less overall jet lag symptoms at day 10 (mean score 2.15) versus placebo (3.40; P <0.01). Moreover, the melatonin group experienced a better adaptation pattern in terms of sleep pattern, daytime tiredness, and normal energy levels than the placebo group (P <0.05).¹¹ Although this latter study suggested an optimal time pattern for melatonin use in an eastbound flight, another author noted that bedtime may not be an ideal time to employ melatonin on a westbound flight that crosses less than six to eight time zones. He suggested employing a lower dose of melatonin (0.5 mg) on the westbound flight later in the evening as “melatonin has the least phase shifting effects when it overlaps with endogenous secretion.”¹²

Acute Sleep

It is estimated that 50 to 70 million American adults have difficulty sleeping.¹³ This issue of poor sleep quality can have profound consequences for the individual and society at large, including an increased risk of accidents and mood and behavioral changes, as well as a reduction in work productivity.¹⁴ One of the numerous options available to help improve overall sleep is melatonin, both in healthy adults as an acute remedy for insomnia and in the elderly dealing with issues of chronic insomnia.

The acute use of melatonin in healthy adults without insomnia at doses of 0.3 to 1 mg at 8:00 or 9:00 pm significantly reduces sleep-onset latency and latency to stage 2 sleep compared with the placebo (P <0.001). Moreover, melatonin does not produce any “sleep hangover” symptoms (according to the Profile of Mood States and Four Choice Reaction Time Test) commonly associated with benzodiazepine-type drug use.¹⁵

Insomnia in the Elderly

Most elderly individuals report sleeping an average of 7 hours a night. Although the total amount of sleep time does not change as we age, alterations in sleep architecture are common.¹⁶ This includes a decrease in both deep sleep (stages 3 and 4 slow wave sleep) and rapid eye movement (REM) sleep, as well as an increase in stage 1 (light) sleep.¹⁷ Older individuals also have a reduction in endogenous melatonin production (likely due to a deterioration in the neuronal functioning of the SCN), which in turn disrupts the normal wake/sleep cycle.¹⁸

In a controlled clinical trial, 30 men and women over 50 years of age with both chronic insomnia and normal sleep patterns were randomized to receive capsules with either 0.1, 0.3, or 3 mg of melatonin or placebo 30 minutes before bedtime for 7 days. Treatments were separated by a 1 week washout period. Using polysomnography, the researchers concluded that although melatonin did not improve sleep efficiency in normal subjects, those with chronic insomnia had significant improvements in sleep efficiency at all three melatonin doses used, with the 0.3 mg dose triggering the strongest effect (P <0.0001). The physiologic dose acted primarily in the middle portion of the night and raised plasma melatonin levels to normal. The authors noted that 3 mg of melatonin significantly raised plasma levels throughout a portion of the day and triggered reductions in core body temperature after ingestion of the hormone.⁶

Prolonged Release Melatonin in the Elderly

After a 2-week single blind run-in period, 354 elderly men and women (55 to 80 years of age) with primary insomnia were randomized to receive 2 mg of a prolonged release (PR) melatonin or placebo 2 hours before bedtime, for 3 weeks. Subjects enrolled in the study were asked to complete a sleep diary measuring quality of day and night, plus a battery of sleep questionnaires including the Pittsburg Sleep Quality Index (PSQI), Leeds Sleep Evaluation Questionnaire (LSEQ), as well as quality of life (World Health Organization-5 [WHO-5] Well Being Index) and clinician Clinical Global Impression (CGI) scores. At the conclusion of the trial, those who took the melatonin had improved (26%) quality of sleep and morning alertness as recorded by the LSEQ in contrast to placebo (15%) (P = 0.014). Sleep latency, as noted by the PSQI results, improved in subjects employing the PR melatonin by 24.3 minutes compared with 12.9 minutes for the placebo group (P = 0.028). Quality of life as recorded by the WHO-5 Index was also improved in the active group (P = 0.034).¹⁹ A similar study supported the latter conclusion with a positive effect found on the restorative value of sleep in elderly patients using 2 mg of PR melatonin. Moreover, melatonin users did not experience any rebound insomnia or withdrawal symptoms at the conclusion of the controlled study. The authors noted that plasma cortisol increased in middle-aged adults, and this phenomenon might impair sleep. Administration of PR melatonin in older adults with primary insomnia may delay the production of nighttime cortisol, with subsequent improvements in both sleep quality and morning alertness.²⁰

Magnesium, Melatonin, and Zinc on Primary Insomnia and the Elderly

Magnesium, along with zinc, is crucial for the endogenous synthesis of melatonin according to the results of one study. Elderly men and women (n = 43; average age 78.3 years) living in a long-term care facility were invited to participate in a double-blind, placebo-controlled study of 60 days’ duration on melatonin, zinc, and magnesium on primary insomnia. Each volunteer was randomized to receive a 100 g pear pulp food supplement with 5 mg melatonin, 225 mg of magnesium, and 11.25 mg of zinc, or placebo 1 hour before bedtime for 2 months. At the conclusion of the trial, those employing the active supplement experienced an improvement in their overall PSQI scores compared with placebo (P < 0.001). Moreover, the LSEQ results confirmed that those employing the food mixture not only had better quality of sleep but had greater ease getting to sleep (P <0.001). Quality of life was measured by the Medical Outcomes Study Short-Form 36 scale, which noted that the active group had better physical and mental functioning after 8 weeks of treatment (P = 0.006). Adverse effects were minimal, with only two participants in the treatment group complaining of headache, whereas one volunteer in the placebo group complained of epigastric pain.²¹

Insomnia in Perimenopausal Women

In a case series of reports, 11 perimenopausal women (45 to 52 years) with insomnia were treated with 7.5 to 15 mg of mirtazapine for 2 to 4 weeks. Two milligrams of melatonin were then added to the treatment regimen, along with a concomitant reduction and discontinuation of mirtazapine for 30 to 90 days. Global PSQI scores decreased from 17.45 at baseline to 8.55 at the second visit (mirtazapine and PR melatonin) to 6 by the third visit (PR melatonin) (P <0.01). These latter changes were paralleled by a similar drop in PSQI sleep latency scores, with 52.73, 21.36, and 18.64 minutes at baseline, visit 2, and visit 3, respectively (P <0.01). Volunteers also noted that their quality of life as measured by the WHO-5 score improved significantly by 89% from baseline (P <0.01).²²

Chronic Sleep Onset Insomnia in Children

Pediatric insomnia is estimated to affect 1% to 6% of children, but can be significantly elevated to 50% to 75% if there are other associated psychiatric or neurodevelopmental issues such as attention deficit hyperactivity disorder (ADHD), autistic spectrum disorders (ASDs), and epilepsy.²³

A group of children (49 boys, 13 girls; aged 6 to 12 years) with chronic sleep-onset insomnia of more than 12 months’ duration were randomized to receive 5 mg melatonin or placebo at 7 pm for 30 days. Using several questionnaires measuring overall health status (RAND General Health Rating Index and Functional Status II), children who used the melatonin had better outcomes in terms of eating, sleeping, response to attention, fatigue, illness, and overall health than those who received the placebo (P <0.05). In addition, melatonin users had an advancement in their sleep onset by 57 minutes (P = 0.003), a reduction in sleep latency by 17 minutes (P = 0.048), and a decrease in their dim light melatonin onset (DLMO) by 82 minutes (P <0.001).²⁴

Fibromyalgia

Fibromyalgia (FM) is a challenging condition with characteristic symptoms that include widespread and variable chronic pain, as well as fatigue, stiffness, cognitive disturbances, depression, and insomnia.²⁵ Although alterations in the secretion of melatonin have been observed in FM patients, whether or not this latter phenomenon contributes to the pathophysiology of this disease remains controversial.²⁶ Several studies suggested, however, that melatonin is of value in treating this chronic musculoskeletal condition.

Twenty-one female patients (average age 51 years) who met the American College of Rheumatology (ACR) criteria for primary FM for at least 6 months before their participation in a uncontrolled pilot study were invited to help evaluate the effects of a 3 mg capsule of melatonin 30 minutes before bedtime for 1 month. Of the 21 patients who completed the study, 19 were found to have a significant reduction from baseline in musculoskeletal tender point count (−28.6%), severity of pain (−33.4%), and sleep disturbances (−67.2%) as measured by VAS (P <0.05). Although fatigue, depression, and anxiety did not show statistical improvement on VAS, the overall physician and patient VAS global treatment assessment scores of FM disease status (with 10 representing the worst score) improved from 7.6 to 5.7 and 7 to 4.7, respectively. Four patients experienced mild and transient side effects during the trial, including tremor, heartburn, anxiety, and somnolence.²⁷

In another randomized, double-blind placebo-controlled trial, 101 patients (6 men, 95 women; 18 to 65 years) with ACR confirmed primary FM were randomized to one of four treatment groups: (A) 20 mg/day fluoxetine and placebo; (B) 5 mg/day melatonin and placebo; (C) 20 mg/day fluoxetine with 3 mg/day melatonin; and (D) 20 mg/day fluoxetine and 5 mg/day melatonin for 2 months. Using the Fibromyalgia Impact Questionnaire (FIQ) to evaluate the clinical outcomes, the researchers determined that compared with baseline, both fluoxetine and melatonin as single therapies significantly reduced within-group symptom scores by 21.5% and 18.9%, respectively (P <0.05). However, those volunteers combining fluoxetine and melatonin at both 3 and 5 mg doses experienced nearly comparable (28.8% vs 28.9%) and highly significant reductions in their FIQ scores (P <0.001). Although all treatments reduced FIQ pain scores, it was interesting to note that the reduction in fatigue scores in groups B, C, and D by 23.7%, 20.3%, and 34.7%, respectively, compared with only 9.9% in the fluoxetine only treatment group. Fluoxetine as a single agent did not alter the rest/sleep score compared with the significant improvements seen in groups B, C, and D.²⁸

Chronic Fatigue Syndrome

Much like FM, chronic fatigue syndrome (CFS) is associated with a number of symptoms, including intense and disabling fatigue that does not improve with rest.²⁹ One of the factors contributing to fatigue and sleep disturbances in CFS is disruption in the hypothalamic-pituitary-adrenal axis.³⁰ However, under research scrutiny, both adults and adolescents with CFS have increased levels of melatonin, suggesting the hormone has no role to play in this disorder.³⁰ Research on DLMO concluded that a certain subset of CFS patients may respond to the therapeutic use of melatonin. DLMO is a naturally occurring event that may account for delayed sleep phase syndrome in 10% of chronic insomniacs.³¹

Twenty-nine patients (24 women, 5 men; average age 33.2 years) with CFS were asked to take 5 mg of melatonin at bedtime for 3 months. Using the checklist individual strength (CIS) questionnaire to measure several variables, the authors determined that the total score (P = 0.006), as well as the sub-scores of fatigue (P = 0.017), concentration (P = 0.031), motivation (P = 0.010), and activity (P = 0.008), improved significantly after 90 days of melatonin use. Moreover, those patients with late DLMO (>21.30 hours) overall CIS and its subscores were better than in those CFS patients with early DLMO.³²

Children with Epilepsy

Seizure-free epileptic children (n = 31; 3 to 12 years of age) with a history of either partial or generalized seizures and utilizing 10 mg/kg per day of sodium valproate participated in a double-blind, placebo-controlled study of 8 weeks’ duration. The children were randomized to receive either melatonin tablets (6 mg for those less than 9 years of age and less than 30 kg body weight or 9 mg for those more than 9 years of age and more than 30 kg body weight, to be taken in the evening) or comparable placebo 1 hour before bedtime. The primary end point of the study was evaluated using the parental Sleep Behavior Questionnaire. By the conclusion of the controlled trial, those children using the additional melatonin had a significantly greater average percentage reduction in their total sleep scores (24.4%) compared with placebo (14.4%) (P <0.05). Moreover, the median reduction in the parasomnia scores significantly favored those who took melatonin (60%) relative to the placebo (36.4%) (P <0.05). No adverse effects were noted during the trial.³³

Autism/Fragile X Syndrome

In a recent review and meta-analysis, the authors noted that children with ASDs not only have a higher incidence of sleep-associated problems, but that melatonin use led to significant improvements in sleep duration and sleep-onset latency compared with placebo (P <0.01). This poor sleep pattern in turn can lead to a worsening of overall autistic behavior symptoms.²³

In one double-blind, placebo-controlled, crossover trial, 18 subjects (16 boys, 2 girls; mean age 6 years) with ASD or fragile X syndrome, or both, and insomnia were randomized to receive 3 mg melatonin or placebo 30 minutes before bedtime for 14 days. After 2 weeks, subjects were crossed over, such that the active group received placebo and vice versa. Children were evaluated using actigraphy and parentally recorded sleep diaries. After 4 weeks and in 12 of 18 children who had complete data sets, the authors noted that those using the melatonin had an improvement in the total night’s average sleep duration (+21 minutes longer than placebo; P = 0.02), a reduction in sleep latency time (28 minutes vs placebo; P = 0.0001), and a 42-minute earlier sleep-onset time in contrast to the placebo group (P = 0.02).^24a

Children with Migraine/Tension-Type Headaches

Headaches and migraines are two of the more likely reasons that will cause children to complain of pain. Annual prevalence for migraine and tension-type headaches can vary with between a 3% to 11% and a 10% to 24% occurrence, respectively.³⁷

In an uncontrolled pilot study, 22 children (10 boys and 12 girls; age range 6 to 16 years) with various types of long-standing (average 40.05 ± 30.2 months) headache-type discomfort (13 recurrent migraines/no aura; 8 chronic tension-type headaches; 1 migraine with aura) participated in a 12-week study on the effects of oral melatonin. After a 1 one-month washout period in which all preventive therapy was discontinued, the children were asked to take 3 mg of melatonin at bedtime for 90 days. At the conclusion of the study and according to the results of a structured daily headache diary, the frequency (i.e., the number of attacks per month) and the duration of attacks (hours) decreased from 12.3 to 5.7 and 13.5 to 9.7, respectively (P <0.001). Pragmatically, and as the authors noted, 14 of the 21 subjects (one child stopped the melatonin due to excessive somnolence) had a greater than 50% reduction in headache attacks. Notably, four of the children had complete resolution of their headaches.³⁸

Functional Dyspepsia

Postprandial fullness and early satiation, along with epigastric pain and burning without evidence of upper gastrointestinal structural pathology on endoscopy are the hallmark of Rome III diagnostic criteria for functional dyspepsia.³⁹ One group of researchers suggested that melatonin use stimulates enterocytes to produce bicarbonate, which in turn may help neutralize gastric hydrogen chloride and, therefore, reduce symptoms as evidenced by the following study.⁴⁰ Sixty patients (18 men, 42 women; ages 19 to 39 years) with a 3 to 12-year history of nonulcer dyspeptic symptoms (i.e., chronic or recurrent epigastric pain) were randomized to receive 5 mg of melatonin or placebo in the evening for 3 months. After 12 weeks of treatment and using a 10-point scale (0 = no symptoms; 10 = maximum symptoms) for therapeutic evaluation, 17 of 30 (56.6%) patients using the melatonin had their condition resolve completely, such that they did not require further treatment, whereas an additional 9 of 30 (30%) patients experienced a partial improvement in symptoms (i.e., reduction in nighttime gastric pain) (P <0.01). Although four patients in the active treatment group noted no change in symptoms, a larger percentage of subjects (93.3%) using placebo noted no change in their condition. The authors noted that those who had a previous infection with Helicobacter pylori were less likely to respond to melatonin treatment.⁴⁰