Melatonin

[misty]

Thread Started on Nov 14, 2005, 5:21pm

I give my DD melatonin to help her sleep. She'd be up until all hours without it. I like to read everything I come across about the supplements I give my daughter. Heres some info in case any of you are considering melatonin for your children or yourselves.

Melatonin, Sleep Enhancement, and ADHD
Written by: Anthony Kane, MD
Overview
Melatonin is a natural hormone, which is produced and secreted by the pineal gland. Melatonin plays an important role in the regulation of many hormones in the body. Among its key roles, melatonin controls the body's circadian rhythm, an internal 24-hour time-keeping system that controls when we fall asleep and when we wake up.

Melatonin is also a very powerful antioxidant. In one study, melatonin was 60 times more effective than Vitamin C or water-soluble Vitamin E in protecting DNA from damage. Preliminary evidence suggests that it may help strengthen the immune system.

Uses

The most accepted function of Melatonin is it role in sleep regulation. Melatonin supplements help induce sleep in people with disrupted circadian rhythms. Melatonin is significantly more effective in decreasing the amount of time required to fall asleep, increasing the number of sleeping hours, and boosting daytime alertness.

Melatonin is purported to be one of those miracle substances that has a hand in everything. This may be due to the fact that during the height of the antioxidant craze, Melatonin was found to be a more powerful and more universal antioxidant than both vitamin C and vitamin E. Whatever the reason, Melatonin ostensibly plays a role in numerous health conditions.

Here is a partial list:

Insomnia
Osteoporosis
Menopause
Depression
Eating Disorders
Breast Cancer
Prostate Cancer
Cancer-related Weight Loss
Sarcoidosis
Rheumatoid Arthritis
Epilepsy
Sunburn
Viral Encephalitis
Heart Disease

Insomnia

As many parents realize, drugs like Ritalin are not without side effects. One of the major complaints that parents have is that their children who take Ritalin can't fall asleep at night. Many parents report that their children, who may be only five or six years old, are wide awake until 11 pm or later.

Melatonin may be able to help these children. Since it is the primary chemical in the body that helps to induce sleep, children who suffer from insomnia often find that Melatonin restores their normal sleep cycle and helps them to be more awake and alert during the day.

How to Take It

There are currently no guidelines as to how to take Melatonin. Sensitivity to Melatonin is an individual thing and doses that are ineffective in one person may be too much for someone else. The best approach for any condition is to begin with very low doses and slowly add more until you get the effect that you are seeking.

In children, it is best to start with a dose of about 0.3 mg/day or less. Although current research suggests that even doses as high as 10 mg are perfectly safe, it is best to proceed with caution.

In adults, 3 mg is usually a safe starting dose and you can increase it or decrease it as you see fit.
Adverse Effects

Melatonin is one of the least toxic substances known. In one extensive clinical trial, a high dose of 75 milligrams of melatonin per day was given to 1400 women in the Netherlands for up to four years with no ill effects.

The only consistent side effect of high doses has been drowsiness and a slower reaction time



Possible Drug Interactions

Melatonin may interact or interfere with other drugs. These include:
Antidepressant Medications
Antipsychotic Medications: many of these medications are now being used in treating children with ADHD and Bipolar disorder
Benzodiazepines
Blood Pressure Medications
Blood-thinning Medications, Anticoagulants
Interleukin-2
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Steroids and Immunosuppressant Medications
Tamoxifen
If your child is taking any of these things, you should consult with his doctor before giving Melatonin.

Also, caffeine, tobacco, and alcohol can all diminish levels of melatonin in the body while cocaine and amphetamines may increase melatonin production.

Conclusion

Often children with ADHD have a great deal of difficulty falling asleep. This can be due to the medications that they are taking or just be one component in the spectrum of their problems. When used properly, melatonin may be a safe and effective way to handle sleep problems in ADHD children.

Anthony Kane, MD

[misty]

The Use of Melatonin in Children With Sleep Disturbances
Marcia L. Buck, Pharm.D., FCCP

The administration of exogenous melatonin has been used in a variety of clinical settings, most frequently in the management of sleep disturbances, including insomnia and jet lag. Although considered a dietary supplement and not regulated by the Food and Drug Administration (FDA), melatonin was classified as an orphan drug by the FDA in November 1993 for the entrainment of circadian rhythm in blind people. In children, melatonin has been used for chronic insomnia, as well as in the management of sleep disturbances associated with vision disturbances, attention deficit/hyperactivity disorder (ADHD), and neurologic injury.[1- 3]

Pharmacology
Melatonin (N-acetyl-5-methoxytryptamine) is a chronobiotic, a neurohormone involved in the regulation of the sleep-wake cycle. It is produced in the pineal gland through the conversion of tryptophan, first to serotonin, then N-acetylserotonin, and finally to melatonin. Melatonin is normally secreted during darkness, in response to the release of norepinephrine from retinal photoreceptors and the resulting activation of the retino-hypothalamic-pineal system. Levels begin to rise at nightfall, with peak serum concentrations typically occurring between 2 and 4 AM in adults. Secretion during daylight is minimal.[3]

Melatonin promotes sleep through regulation of the activity of the suprachiasmatic nucleus (SCN), located within the anterior hypothalamus above the optic chiasm. Impairment of melatonin production, secretion, or binding within the SCN may lead to chronic disturbances in both sleep onset and duration. In these patients, exogenous melatonin may be beneficial to regulate the sleep-wake cycle. Exogenous melatonin was first synthesized over two decades ago. It produces the same effects and is metabolized in the same manner as the endogenous neurohormone.[1- 3]

Pharmacokinetics
After oral administration of exogenous melatonin, peak concentrations are achieved within 60 minutes. Melatonin is hepatically metabolized, with 80 to 90% converted to sulphatoxymelatonin (aMT6), an inactive compound which is excreted in the urine. The average elimination half-life of melatonin in adults is 20 to 50 minutes. The administration of exogenous melatonin does not appear to affect endogenous production or secretion.[2]

Use in Children
Since the first case report by Palm and colleagues in 1991,[4]there have been over two dozen papers describing the use of melatonin in children with sleep disturbances. Several studies have been published by Jan and colleagues of the Children's Hospital Visually Impaired Program at British Columbia's Children's Hospital. In 1994, they published a study of 15 children (ages 6 months to 14 years) given melatonin for sleep disturbances.[5]All of the subjects had failed to respond to traditional therapy, including nonpharmacologic measures to improve sleep hygiene. Nine of the patients had mental retardation, and two had ADHD. Nine children had either ocular or cortical vision impairment. The study was a double-blind crossover randomized design, with each child receiving melatonin at a dose of 2.5 to 5 mg or placebo at bedtime for a period of 7 to 10 days, then switching to the alternative arm after a 4 to 5 day wash-out period. Sleep diaries were maintained by the subjects' careproviders. Patients responding to therapy remained on melatonin after completion of the study and were followed at three and six months.

Thirteen of the 15 children had a favorable response to melatonin, with improvement in sleep duration. All of the subjects experienced clinical benefit, with improved daytime mood and behavior. Children with delayed sleep onset experienced the greatest response. The effective dose ranged from 2.5 to 10 mg; higher doses or the administration of a second dose during the night produced no additional benefit. Ten of the patients continued on therapy after conclusion of the study, for periods up to a year. No adverse effects related to melatonin were reported.

Building on their initial case report, Palm and colleagues published the results of an open study of melatonin in eight blind children and young adults in 1997.[6]The patients ranged in age from 3 to 23 years of age, and all had significant sleep disturbances. Serum and urine concentrations of melatonin were evaluated in five patients prior to treatment, revealing delays in the time of peak concentrations (range 03:00 to 12:00). Administration of melatonin in doses of 0.5 to 4 mg produced improvement in all patients. Benefit was maintained long-term, up to six years in some patients. No adverse effects were reported.

Further support for the use of melatonin was added by Pillar and colleagues in their 1998 case report.[7]The patient was a 13 year old girl with psychomotor retardation and a one year history of an irregular sleep-wake cycle. Serial measurements of urine aMT6 were abnormally low, with no time-related differences indicating nocturnal release of melatonin. Actigraph recordings revealed no discernible night/day differentiation in sleep patterns. Administration of 3 mg melatonin nightly produced an immediate improvement in her sleep-wake cycle with an increase in total nocturnal sleep from an average of 5.5 to 7.7 hours and a reduction in daytime sleep from 4.4 to 2.8 hours. Urine nocturnal aMT6 levels measured one month after starting therapy showed a distinct increase at night, with a peak at 22:00.

During 2001, two studies of melatonin were published in the Journal of Child Neurology.[8,9]In February, Smits and coworkers reported their randomized, placebo-controlled trial of melatonin in 40 children (6 to 12 years of age) with chronic insomnia.[8]The children were randomized to receive either 5 mg melatonin or placebo, given nightly at 6 PM over a 4 week treatment period. At the conclusion of the study, patients could be continued on therapy if desired by the parents. Both sleep diaries and actigraph recordings were used to assess efficacy. Sleep onset and duration were significantly improved in the melatonin group, but showed no difference in the placebo group. Sleep latency, wake-up times, and sustained attention reaction times were not affected. Two children had headaches for the first two days of melatonin treatment. After 18 months, 13 of the 38 children evaluated had discontinued therapy without the return of insomnia. In one child, melatonin was stopped due to lack of effect. One child developed generalized epilepsy 4 months into the study, but causality with melatonin was not suggested.

Later that year, Dodge and Wilson published an additional randomized, double-blind, placebo-controlled, cross-over trial of melatonin in 20 children with developmental disabilities.[9]The melatonin dose was 5 mg in all children. In 18 of the subjects, time to sleep onset was significantly shorter with melatonin than placebo. The duration of sleep was greater than baseline values during melatonin treatment, but the difference between the melatonin treatment period and placebo was not statistically significant. The authors also failed to find a difference in the number of nighttime awakenings. They reported no adverse effects.

In 2002, Ross and colleagues published an observational study of melatonin administration in 49 children with neurodevelopmental disorders.[10]The patients ranged in age from 1 to 13 years, and the most frequent underlying illness was epilepsy. Patients less than 5 years of age were started on a dose of 2.5 mg nightly, while older children were started on 5 mg. Doses were increased by 2.5 mg increments at 3 day intervals until the desired effect on sleep patterns was achieved or the patients reached the maximum dose (7.5 mg in patients less than 2 years or 10 mg in older children). Of the 46 patients with evaluable sleep diaries or case notes, 34 (69%) showed improvement after receiving melatonin. In the 28 children with complete diaries, total sleep, nighttime sleep, duration and number of interruptions, and time of sleep onset improved with melatonin. The median sleep time increased from 54 to 65.5 hours/week after treatment. The median number of interruptions in sleep decreased from 7 to 3.5.

Melatonin appears to be beneficial in the management of the delayed sleep onset and frequent awakenings observed with other neurologic illnesses as well. Additional papers have noted the efficacy of melatonin in sleep disturbances associated with Rett syndrome and tuberous sclerosis, as well as in a child with a pineal tumor.[11- 13]In a double-blind, placebo-controlled cross-over study of nine girls with Rett syndrome, melatonin in doses of 2.5 to 7.5 mg nightly produced significant benefits in sleep characteristics.[11]Sleep latency decreased from 42.1±12.0 (mean+SE) to 19.1±5.3 minutes during the first three weeks. Total sleep duration also improved, but the difference from baseline was not statistically significant.

In the January/February 2003 issue of Clinical Pediatrics, Ivanenko and colleagues from Kosair Children's Hospital Research Institute at the University of Louisville published a retrospective review of 32 children treated with melatonin in their program.[1]All had been referred to their sleep program after failure to benefit from conventional treatments. The children ranged in age from 2 to 18 years (mean 9.6±4.5 years). Several children had comorbidities, including ADHD (in 44% of subjects), anxiety (25%), affective disorders (9%), and mild developmental delay (9%).

Twenty-nine (90.6%) of the children experienced benefit from melatonin, with improvement in sleep onset and/or sleep maintenance. Average time to sleep onset, based on caregiver journals, declined from 90±52.5 to 25.4±11 minutes, and nocturnal awakenings declined from 18.7±15 to 1.2±2 times per week. The patients were treated with an average melatonin dose of 2.0±1.2 mg (range 0.3 to 6 mg), given one hour before bedtime. There was a positive relationship between patient age and dose, with the 2 to 6 year old group requiring an average dose of 1.4±0.6 mg and the 12 to 18 year olds requiring 2.8±1.4 mg. Although many caregivers reported clinical improvement within days of the initiation of therapy, normal sleep patterns were usually achieved within 1 to 2 weeks. The average duration of follow-up was 2 months, with the longest follow-up at 10 months. Melatonin was stopped in three patients due to lack of sustained response. No adverse effects were noted.

Earlier this month, Smits and colleagues published another study of melatonin for pediatric insomnia.[14]Building on the positive response in behavior reported by parents in their earlier study, the authors conducted a similar randomized, double-blind placebo-controlled trial in 62 children (6 to 12 years in age). Patients received either 5 mg melatonin or placebo at 7 PM for 4 weeks. In addition to standard measurements of sleep characteristics, health status was evaluated with the RAND General Health Rating Index (RAND-GHRI) and Functional Status II (FS-II) questionnaires. Total scores for both measures improved significantly more in the melatonin group than with placebo. The standardized response means for the RAND-GHRI were 0.69 in the melatonin group versus 0.07 in the controls, with FS-II scores of 1.61 versus 0.64. Melatonin advanced sleep onset by an average of 57 minutes, and salivary measurement of melatonin production showed an onset occurring an average of 82 minutes earlier during melatonin administration.

Drug Interactions
Melatonin has been reported to interfere with the antihypertensive effect of extended-release nifedipine.[2]The mechanism of this interaction has not been determined.

Adverse Effects
Exogenous melatonin appears to be well tolerated. In most clinical trials and case series, no adverse effects have been noted. Headache, excessive sedation, and transient depression have been reported, most often with doses greater than 8 mg/day. Isolated cases of rash, a psychotic episode, gynecomastia, and autoimmune hepatitis have also been reported after melatonin use, but in none of these cases has melatonin been identified as the cause.[1- 3]

In a 1998 study published in Lancet, melatonin administration to six children with underlying seizure disorders produced a worsening of seizures in three.[15]Although this finding has not been reported in other papers, the benefit to risk ratio of melatonin in patients with seizures should be carefully weighed before initiation of therapy. Because melatonin may also play a role in immune function, it is not recommended for patients with autoimmune disorders.[2]

Dosing
Based on the case series and clinical trials published to date, melatonin should be initiated at a dose of 2.5 to 5 mg in children with sleep disturbances. The dose should be administered in the evening, approximately 30 to 60 minutes before bedtime. Dose titration should be based on response.[1- 14]Some authors have noted that children with neurologic injury may require higher doses. In patients with nighttime awakenings, a controlled release dosage form may be more effective than standard immediate release products.[16]

Availability and Cost
Melatonin is available at most pharmacies and health food stores. It is manufactured as both immediate release and controlled release tablets and capsules. The most commonly available dosage strengths are 300 mcg, 1, 3, and 5 mg. In the Charlottesville area, the cost of a 60-tablet bottle (3 mg tablets) ranges from $3 to $8.

Melatonin is not considered a drug product, and is not regulated by the FDA. Patients and their families should be instructed to purchase only synthetic melatonin, rather than the bovine-derived product, in order to avoid potential exposure to infectious agents. In addition, careproviders should be aware of the potential for variation in content among brands, as well as the presence of contaminants. A voluntary verification program has been developed by the United States Pharmacopeia (USP) to provide consumers with information on the quality of dietary supplements such as melatonin. The "USP verified" symbol on these products, while not a guarantee of efficacy or safety, indicates compliance with accepted manufacturing practices and standardization of contents.

Summary
Endogenous melatonin plays an important role in the regulation of the sleep-wake cycle. In children with sleep disturbances, the administration of exogenous melatonin appears to reduce the time to sleep onset and minimize nighttime awakenings. Melatonin is generally well tolerated, with few reports of adverse effects. In patients for whom traditional pharmacologic and nonpharmacologic therapies to improve sleep have failed, melatonin may be a useful adjunctive therapy.

If you have comments or suggestions for future issues, please contact us at Box 800674, UVA Health System, Charlottesville, VA 22908 or by e-mail to [e-mail]. This newsletter is also available at www.healthsystem.virginia.edu/internet/pediatrics/pharma-news/home.cfm

[jerbear]

just wanted to say that i use melatonin myself, 3mgs a half an hour before i go to sleep and it works great!! i use it when i have to wake up at 1am to go to work and it does a good job of putting me in that sleep cycle of going to bed early and waking up early. i find that if i don't get at least four hours sleep the medication isn't nearly as effective. im on adderall 20mgs three times a day. the melatonin i buy is a dissolving mint-flavored strip like a listerine breath freshening strip, its tasty and effective!!

[misty]

What brand is that, Jerbear? I'd love to try that brand with my daughter. She takes the pills as needed....not every night.

[charliegirl]

Where do you get it? My son would love that and maybe I could get him to take it when he is bouncing off the walls at bed time and beyond.

[jerbear]

the name brand is SHORT CUTS, if i remember correctly i bought it at either jewel/osco or walgreens. i just googled melatonin pm and found it on EBAY and it's being sold in 6packs each package containing 48 strips each (288 strips-aint i a math wiz!)for 20$/w shipping. any pharmacy should have it though.

[misty]

Thanks Jerbear! I'm going to look and see if they have it at Walmart or Eckerds around here!

[unicorn]

I may have to get those for Tiff. She takes 5mg pills, but those sound good too. Misty if you get those soon, let us know how they work.

[alan]

Hey you guys i was wondering if yall could clear something up for me about melatonin.
I was told that if you were an asthma sufferer you should not take it as it is not recommended.
Any body know for sure??

[misty]

I wasn't sure, Alan, but I looked it up & heres what I found:

People with asthma should consider limiting the use of melatonin as a sleep aid, according to researchers at National Jewish Medical and Research Center. Pulmonologist Rand Sutherland, M.D., M.P.H., and his colleagues report in the September 2003 issue of the Journal of Allergy and Clinical Immunology that higher levels of melatonin were associated with an overnight loss of lung function in asthma patients. Previous studies by the same group have shown that melatonin induces the release of chemicals that promote inflammation, a hallmark symptom of asthma...........

www.sciencedaily.com/releases/2003/09/030908070842.htm

This article is from the WebMD
Medical News Archive

Melatonin, a popular sleep aid often used to treat jag lag, may worsen asthma, according to a new study. And, it doesn't seem to take much to cause an effect - even small amounts of the supplement could cause problems.

Melatonin is a naturally-occurring hormone produced by our bodies. Its popularity as a supplement is based on its ability to regulate sleep patterns, but scientists also have found that it can have an effect on inflammatory diseases such as asthma. Melatonin can cause the release of body chemicals that provoke inflammation............

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