Melatonin Supplementation Improves Sleep in Children with Autism Spectrum Disorder

Study evaluates dose effectiveness of melatonin with sleep difficulties due to ASD

By Jessica Mitchell, ND

Reference

Malow B, Adkins KW, McGrew SG, et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. J Autism Dev Disor. 2012 Aug; 42(8):1729-37.
 

Design

Open-label dose-escalation study. The first week consisted of structured sleep education, including establishment of regular bedtime and wake time. Parents were educated on use of actigraphy and began using the machine. The actigraphy readings were used to confirm the inclusion criteria of >30 min sleep onset.
 
After the first week, participants began a 2-week acclimation phase in which parents were asked to give the children inert liquid 30 min before bed that was flavored the same as the melatonin.
 
Children then began the dose escalation phase starting at 1 mg melatonin given 30 minutes before bedtime. Each dose was given for three weeks. When a satisfactory dose was established, that dose was maintained until the end of the 14-week trial. The doses were escalated from 1 mg to 3 mg, 6 mg, and finally 9 mg.
 

Participants

Twenty-four children age 3–10 with a clinical diagnosis of autism spectrum disorder (ASD) who were free of psychotropic medications.
 

Study Parameters Assessed

Parental report of sleep onset delay of 30 min or more, 3 or more nights a week. Children at Tanner II or higher stage, or those with hormonal values (ACTH, cortisol, estrogen, testosterone, FSH, LH and prolactin) that were not consistent with prepubertal status were excluded.
 

Other Exclusion Criteria

Comorbidities that affect sleep, including gastroesophageal reflux, psychiatric disorders, and sleep apnea
 

Outcome Measures

Dose effectiveness, response time to doses, safety, tolerability, feasibility of actigraphy data, and accuracy of questionnaire-acquired data were assessed.
 

Key Findings

All 24 children responded to doses between 1 mg and 6 mg (7 at 1 mg, 14 at 3 mg and 3 at 6 mg).  Participants’ age and weight were not associated with melatonin dose response. Parents reported improvement in sleep difficulties, sleep onset delay, sleep duration, and sleep total. Parents also reported improvement of affect, attention deficit/hyperactivitiy disorder (ADHD) behaviors, repetitive behaviors, and compulsive behaviors. Parenting Stress Index improved. There were no changes in laboratory findings and only 1 adverse effect (loose stool). Improvement in sleep was seen within 1 week of dosing at the effective dose.
 

Practice Implications

This study confirmed what many people who treat autistic patients already know: that melatonin is a very useful sleep aid. Sleep dysfunction is a common concern of parents with autistic children, and many have already tried melatonin on their own. In fact, the Autism Research Institute reported in March 2009 that of the 1,687 parents using melatonin, 66% reported a benefit, 8% reported a worsening and 26% reported no effect.1 According to this survey, melatonin is one of the most useful treatments for autism, rating better than all drugs. Only other non-drug therapies including chelation, food allergy treatment, subcutaneous vitamin B12,  and 2 specialized diets (gluten-free diet and the specific carbohydrate diet) were perceived as more beneficial than melatonin by parents. One reason so many parents have already tried melatonin is because of how common sleep difficulty is in autistic children. Autistic children have been shown to secrete less melatonin over a full 24 hours than their age-matched controls, and this decrease in production correlates with the degree of autism.2
 
This is not the first study to show benefit of the use of melatonin. Rossignol and Frye conducted a systemic review and meta-analysis of 35 melatonin and autism spectrum disorder studies and published their findings in 2011.3  They found significant improvements in sleep duration and sleep onset latency, but not in night-time awakenings. They also found the reported side effects were minimal to none.
 
This study confirmed what that melatonin is a very useful sleep aid in children with autism.
 
The current study was to limit the participants to under 10 years of age due to the unknown effect of melatonin on puberty. This is a concern because melatonin is considered a “master hormone” that can influence the entire endocrine system through circadian changes. However, 1 small study has suggested this may be of minimal concern. It was a Dutch study published in 2011 that followed 57 children who had previously been enrolled in a melatonin treatment study for sleep disturbance. They only included participants who had been using melatonin for >6 months. The age of these participants was 8.6–15.7 years; mean duration of use was 3.1 years and mean dose was 2.7 mg. The researchers found that treatment with melatonin was effective for sleep improvement with minimal side effects. They then compared Tanner Stage to normal and the age of menarche compared to their mother for the participants who were over 13 years of age. While the sample size was small, there was no significant difference found, suggesting that long-term use of melatonin did not affect puberty development and was well tolerated.4 Knowing that melatonin is safe to use during puberty and adolescence is important because even adolescents with high-functioning autism spectrum disorder are 3 times more likely than their neurotypical peers to report sleep disturbances and have an increase in reported problems with fatigue.5
 
Melatonin may not be the only supplement that helps sleep disturbance in children on the autism spectrum. Dosman et al found that of the 33 autistic spectrum disorder children who completed their study, 77% had restless sleep that improved significantly with iron therapy. Of these children, 69% had insufficient dietary iron intake, which led to low ferritin levels.6
 
It is also important to recognize the combination of treatments in an effort to help children sleep. A study published in the Journal of Sleep Research in 2012 showed that autistic children who received both melatonin and cognitive behavioral therapy had a better treatment effect than those receiving either treatment alone.7
 
This study contributes to the growing body of research suggesting that melatonin supplementation for children on the autistic spectrum is both safe and effective for treatment of sleep onset delay. This appears to lead to improvement in symptoms of ASD. Of course, good sleep is foundational to the health and wellbeing of our patients. To date, studies suggest we should feel comfortable using melatonin in children on the autism spectrum. It is certainly an easy, inexpensive, and nontoxic therapy to try in this population, with good reason to expect benefit.

About the Author

Jessica Mitchell, ND, graduated from Southwest College of Naturopathic Medicine in 2005. During her general practice residency she discovered her passion for pediatric medicine. In 2007, she became the first naturopathic pediatric resident. During her residencies, she participated in 2 double-blind, placebo-controlled studies on biomedical treatments of autism. Articles from this research have been published in the Journal of Toxicology and BioMed Central Clinical Pharmacology. She has worked in conjunction with the Arizona branch of the American Academy of Pediatrics on its obesity committee and is a founding member and treasurer of the Pediatric Association of Naturopathic Physicians. Mitchell is currently an assistant professor and residency director at Southwest College of Naturopathic Medicine. She oversees student medical rotations at the medical center and at 2 free clinics in Phoenix and maintains a private practice at Southwest Naturopathic Medical Center.

References

  1. Parent Rating of Behavioral Effects of Biomedical Interventions. Autism Research Institute. www.autism.com. ARI Publ.34/March 2009.
  2. Tordjman s, Anderson GM, Bellissant E, et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. 2012; 37(12):1990-1997.
  3. Rosignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol. 2011;53(9):783-792.
  4. van Geijlswijk IM, Mol RH, Egberts TC, Smits MG. Evaluation of sleep, puberty and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia. Psychopharmacology. 2011; 216(1):111-120.
  5. Baker E, Richdale, A, Short M, Gradisar M. An investigation of sleep patterns in adolescents with high-functioning autism spectrum disorder compared with typically developing adolescents. Dev Neurorehabil. 2013;16(3):155-165.
  6. Dosman CF, Brian JA, Drmic IE , et al. Children with autism: effect of iron supplementation on sleep and ferritin. Pediatr Neurol. 2007;36(3):152-158.
  7. Flavio C, Flavia G, Sebastiani T, Panunzi, Valente D. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. J Sleep Res. 2012; 21(6): 700-709.