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Melatonin and Autism Ranking: Strong positive evidence

Melatonin Melatonin is a hormone and neurotransmitter produced by the pineal gland.  Very small amounts of it are found in foods such as meats, grains, fruits and vegetables. You can also buy it as a supplement.

Melatonin is normally released soon after it starts to get dark. The amount produced then increases until about two to four in the morning, and then drops off again. Melatonin is involved in many functional processes including regulating the sleep-wake cycle. 

Some people believe that melatonin regulation may be abnormal in some people on the autism spectrum, causing them severe sleep problems. Those sleep problems may include difficulties falling asleep and difficulties staying asleep. 

Some people believe that some of those sleep problems can be overcome or reduced by taking melatonin supplements, sometimes as part of a comprehensive, multi-component treatment plan. 

Our Opinion

There is some research which suggests that melatonin regulation may be impaired in some individuals on the autism spectrum. However the relationship between sleep problems and melatonin processing in people on the autism spectrum is complex and poorly understood.

There is a small amount of high quality research (seven controlled trials) and a small amount of low quality research (seven single case designs with three or more participants) into the use of melatonin as an intervention for people on the autism spectrum.

This research suggests that melatonin may be helpful in improving some sleep problems in some children and young people on the autism spectrum.

There isn’t enough high quality research to determine if melatonin is helpful in improving sleep problems in adults on the autism spectrum. 

There isn’t enough high quality research to determine if melatonin provides any other benefits to people on the autism spectrum.

There is a need for more research into the relationship between sleep problems and melatonin processing in people on the autism spectrum.

There is also a need for more research into the use of melatonin as an intervention for people on the autism spectrum. This research should use more scientifically robust, experimental methodologies with a wider range of participants. It should investigate if there are different subsets of individuals on the autism spectrum (such as those with circadian rhythm problems) who might benefit most. It should also investigate how melatonin could be used as part of comprehensive, multi-component treatment plans.

If you are going to use melatonin supplements on a regular basis, we recommend that you should seek advice from a responsible health professional such as a GP or pharmacist. That health care professional should undertake a full evaluation of your sleep problems before prescribing melatonin. If they do prescribe melatonin, they should check the effectiveness and any side effects and stop treatment if there is no indication of a clinically important response at 4 weeks.  They should start with a low dose, use the minimum effective dose needed and regularly review the benefits of any adverse events.

Disclaimer

Please read our Disclaimer on Autism Interventions


Audience

Melatonin is normally prescribed for adults aged over 55 years old who have difficulty falling or staying asleep. According to the Net Doctor website, accessed on 22 August 2017, this is because older adults produce less melatonin in their bodies.

 “The release of natural melatonin starts to decrease as we get older and can cause difficulties with sleeping. Taking this medicine before bed may therefore be particularly helpful for people aged over 55 years who are suffering from … insomnia.”

However, some researchers have suggested that melatonin regulation in people on the autism spectrum of all ages may also be impaired. Because of this they may also have more problems falling or staying asleep. Those researchers have suggested that those individuals may benefit from taking melatonin supplements.

 

Aims and Claims

Aims

Melatonin is normally prescribed to help people who experience significant sleep problems which have lasted more than a month and which have not responded to other forms of treatment. It is also sometimes prescribed for other people (such as shift workers) or for other conditions (such as jet lag).

Common sleep problems include 

  • Late sleep onset time: falling asleep late at night
  • Long sleep onset latency: taking a long time to fall asleep
  • Short sleep duration:  sleeping for a  reduced amount of time
  • Night awakenings: waking up in the middle of the night

The exact mechanism by which melatonin helps to reduce sleep problems is unclear.  Most researchers (such as Tordjman et al, 2013) have suggested that melatonin works by regulating basic regular physiological rhythms such as circadian rhythms (which govern the body clock).  However, some researchers (such as Doyen et al, 2011) have suggested that melatonin may work in other ways. For example, they suggest that “… melatonin may act non-specifically as a hypnotic agent [tranquilliser] to promote sleep… or … may promote sleep by decreasing core body temperature”. 

Some researchers (such as Guenole et al, 2011) suggest that reducing sleep problems may help reduce other problems. 

“Sleep problems in children with ASD also dramatically alter the sleep of their parents and are associated with family stress, possibly amplifying ASD symptoms and interfering with treatment. Conversely, it is reported that successful management of sleep may improve daytime global functioning in children with ASD.”

Claims 

There have been various claims made for the use of melatonin as an intervention for people on the autism spectrum. For example, 

  • Galli-Carminati et al (2009) claimed that “Melatonin administered in the evening dramatically improved the sleep-wake pattern in all patients. Melatonin appears to be effective in reducing sleep onset latency [the time taken to fall asleep] and is probably effective in improving nocturnal awakenings and total sleep time in adults with autism.”
  • Malow et al (2012) claimed that the use of melatonin “showed improvement in sleep, behavior, and parenting stress”.
  • Wronjan et al (2009) claimed that “…night sleep duration was longer on melatonin … by 21 minutes, mean sleep-onset latency (the time taken to fall asleep) was shorter by 28 minutes, and sleep-onset time was earlier by 42 minutes.

Key Features

Melatonin is a hormone and neurotransmitter produced by the pineal gland.  Very small amounts of it are found in foods such as meats, grains, fruits and vegetables. You can also buy it as a supplement.

According to the Net Doctor website, accessed on 22 August 2017, 

“Melatonin… is normally released soon after it starts to get dark. The amount produced then increases until about two to four am, and then drops off again. Melatonin is linked with the control of circadian rhythms and promoting sleep.”

According to Doyen et al (2011), melatonin may be involved in the regulation of a wider range of functions “…including body temperature, water balance, blood volume, sleep and activity. “   

Administration

In the UK, melatonin is licensed for the short term treatment of insomnia in adults aged 55 years or over. 

It is not licensed for any other group or for the treatment of any other conditions.  It is normally taken after meals, 30 to 60 minutes before bedtime. 

Types

Natural melatonin supplements are made from the pineal gland of animals but can be contaminated with a virus so these are not usually recommended. Synthetic, manmade supplements of melatonin do not carry this risk. 

Fast release melatonin supplements are designed to help you get to sleep quickly, while slow release or modified release melatonin supplements are designed to help you stay asleep.

Melatonin supplements are available in the form of tablets, capsules or liquid.

Brands and Dosages

Melatonin is sold under a variety of brand names, each of which may come in different strengths. For example, in the UK melatonin is available as

  • Circadin 2mg modified-release tablets (Flynn Pharma Ltd)
  • Melatonin 3mg modified-release tablets (Imported from the United States))

However the exact dosage will depend on the nature of the condition being treated, your body weight, the brand of melatonin being used etc.

Cost and Time

Cost

The cost of using melatonin will depend on a number of factors including the supplier, the brand, the dosage, and the length and frequency of treatment.

According to the BNF website accessed on 22 August 2017, the NHS indicative price for 30 circadin 2mg modified-release tablets was £15.39.

We found a wide range of suppliers providing melatonin supplements for a wide range of prices when we did an online search on 23 August 2017. Prices varied from £5.11 to £11.50 for 60 3 mg tablets.

Time

Melatonin is usually taken once a day, after the evening meal and 30-60 minutes before bedtime.  However, Doyen et al (2011) noted that, if melatonin is used to treat delayed sleep phase syndrome, it may need to be taken several hours before bedtime.

There is no consensus on what the correct length of melatonin treatment should be, although Doyen et al (2011) noted that a limited number of children may need treatment throughout their lives.

We have identified a number of NHS organisations which have made recommendations on the length of treatment. For example, the Swale Clinical Commissioning Group (2013) recommended the following regime for the treatment of sleep disorders in children and adolescents with neurodevelopmental disorders 

  • “Upon initiation, if improvement in symptoms is not observed after one month, melatonin should be discontinued.
  • If melatonin has successfully established a good sleep pattern, a trial withdrawal of melatonin should be undertaken at the first, subsequent specialist review which will occur 3 to 6 months following initiation. 
  • The continuing need for melatonin should be assessed periodically by the specialist including by stopping the medicine for up to two weeks each year.”

Risks and Safety

Hazards

According to the BNF website, accessed on 22 August 2017, melatonin has few side effects but these may include the following: 

- Uncommon

Abdominal pain; abnormal dreams; anxiety; chest pain; dizziness; dry mouth; dry skin; dyspepsia; glycosuria; headache; hypertension; irritability; malaise; mouth ulceration; nausea; nervousness; proteinuria; pruritus; rash; restlessness; weight gain.

- Rare

Aggression; angina; arthritis; electrolyte disturbances; flatulence; gastritis; haematuria; halitosis; hot flushes; hypertriglyceridaemia; impaired memory; increased libido; lacrimation; leucopenia; mood changes; muscle spasm; nail disorder; palpitation; paraesthesia; polyuria; priapism; prostatitis; restless legs syndrome; salivation; syncope; thirst; thrombocytopenia; visual disturbances; vomiting

Contraindications

There are some contraindications (something which makes a particular treatment or procedure potentially inadvisable) for melatonin. 

For example, according to the BNF website, accessed on 22 August 2017, melatonin may be contraindicated for individuals with autoimmune disease.  The website also recommends that melatonin should be avoided in pregnancy and during breast feeding or in people with hepatic impairment. It also advises caution in people with renal impairment.

Melatonin may interact with a number of other medications, particularly cimetidine, fluvoxamine and oestrogens.

If you have concerns about melatonin you should seek advice from a responsible professional such as a GP. 

Notes

Angina (chest pain); autoimmune disease (condition in which the body’s immune system attacks itself); cimetidine (medicine used to treat ulcers and other conditions); dyspepsia (indigestion); electrolyte (nutrient); fluvoxamine (type of antidepressant); gastritis (inflammation of stomach lining); glycosuria (excretion of glucose in urine); haematuria (red blood cells in urine); halitosis (bad breath); hepatic (relating to the liver); hypertension (high blood pressure); hypertriglyceridaemia (fatty molecules in the blood); lacrimation (flow of tears); leucopenia (reduction of white blood cells); palpitation (abnormal heartbeat); paraesthesia (‘pins and needles’); polyuria (excessive production of urine); priapism (persistent and painful erection); prostatitis (inflammation of the prostate gland); proteinuria (protein in the urine); pruritus (itch); renal (relating to the kidneys); syncope (fainting); thrombocytopenia (abnormally low levels of red blood platelets).

Suppliers and Availability

Suppliers 

Melatonin is widely available within Europe and the USA but restrictions apply in some countries, such as Australia and the UK. According to the NICE website, accessed on 12 September 2017, 

“Only 1 form of melatonin (prolonged-release tablets) is currently licensed in the UK for the short-term treatment of primary insomnia, characterised by poor quality of sleep, in adults who are aged 55 years or over. Additional melatonin products are available from special-order manufacturers or specialist importing companies, or can be purchased directly online.”

You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.

Credentials

In the United States, melatonin is sold without a prescription in chemists and health food stores. Therefore some providers will have professional credentials and qualifications, while others will not. In the United Kingdom it can only be obtained by means of a private or National Health Service prescription, supplied by a suitably qualified and experienced medical practitioner.

 

History

Melatonin was first identified in 1958 by American physician Aaron Lerner and his colleagues at Yale University School of Medicine. Its potential for individuals with developmental disabilities and severe, intractable sleep disturbance was first suggested by Jan and colleagues in 1994.

Current Research

We have identified 15* studies of melatonin as a treatment for people on the autism spectrum published in English-language, peer-reviewed journals. Two of the studies (Appleton et al, 2011 and Gringras et al, 2011) reported on the same trial.

These studies included more than 450 individuals on the autism spectrum aged from two years old to 18 years old. Some of these studies looked at children with a range of neurodevelopmental disabilities including autism. Only one of these studies (Galli-Carminati et al, 2009) looked at adults on the autism spectrum.

Most of the group studies compared melatonin with a placebo treatment, although one study (Cortesi et al, 2012) compared melatonin with cognitive behavioural therapy, with a placebo, and with a combination of melatonin and cognitive behavioural therapy. 

The dosage of melatonin varied from 2m to 12 mg per day and the length of treatment varied from two weeks to six years, although only one study (De Leersnyder et al, 2011) lasted longer than a year.

All of the studies reported improvements in sleep problems in the majority of the participants. For example

  • Some of the studies (such as Garstang and Wallis 2006; Wasdell et al 2008; Wright et al 2011) reported reduced sleep problems (such as sleep latency, sleep duration, number of awakenings etc.) in the participants.
  • Some of the studies (such as Cortesi et al, 2012) reported other benefits such as improvements in behaviours and decreased stress (in parents of the participants).
  • The study by Gringras et al, 2011 reported positive but limited results, that is, melatonin increased total sleep time by an average of only 22.4 minutes per night. However they acknowledge that, for some people, “smaller increase in total sleep time might be worthwhile over cumulative nights.” 

*Please note: there are a number of research studies which looked at participants with Rett syndrome but we have not included these as Rett syndrome is no longer considered to be a form of autism.

Status Research

There are a number of limitations to all of the research studies published to date. For example

  • Three of the studies were retrospective case-series, with no form of experimental control, and two of these had fewer than ten participants on the autism spectrum.
  • Five of the studies used single-case designs (open trials) and two of these had fewer than ten participants on the autism spectrum.
  • Four of the randomised controlled trials had fewer than 20 participants on the autism spectrum.  One these (Garstang and Wallis, 2006) had a high level of drop outs (4 out of eleven participants).  One of the randomised controlled trials (Cortesi et al, 2012) was unbllnded.
  • Gringras et al (2011) reported a number of limitations to their study including “…. the relatively high number of participants who were either unable to tolerate actigraphy [portable measuring device attached to the child] or in whom actigraphy equipment failed.”  They also defined the minimum clinically important difference of sleep time at 60 minutes, when in fact most of the participants increased the amount of sleep by 22.4 minutes, which might be significant for those individuals.
  • Cortesi et al  (2012) reported a number of limitations to their study including the limited treatment period (12 weeks); the fact that they did not measure melatonin salivary and plasma level or its urinary metabolite before and during the treatment; the fact that some people were excluded (for example, if they had serious medical conditions); parents of participants had to comply with the treatment regimen; the fact that some people with conditions which could have influenced the results (such as obstructive sleep apnoea syndrome) may not have been excluded.
  • None of the studies appeared to involve people on the autism spectrum in the design, development and evaluation of those studies

For a comprehensive list of potential flaws in research studies, please see ‘Why some autism research studies are flawed’.

Ongoing Research

We been unable to identify any studies into melatonin that are currently underway.  If you know of any studies we should include please email info@researchautism.net with the details. 

 

Future Research

Summary of Existing Research

- Individual studies
  • There is some research which suggests that melatonin regulation may be impaired in some individuals on the autism spectrum. However the relationship between sleep problems and melatonin processing in people on the autism spectrum is complex and poorly understood.
  • There is a small amount of high quality research (seven controlled trials) and a small amount of low quality research (seven single case designs with three or more participants) into the use of melatonin as an intervention for people on the autism spectrum.
  • This research suggests that melatonin may be helpful in improving some sleep problems in some children and young people on the autism spectrum.
  • There isn’t enough high quality research to determine if melatonin is helpful in improving sleep problems in adults on the autism spectrum. 
  • There isn’t enough high quality research to determine if melatonin provides any other benefits to people on the autism spectrum.
- Research reviews

There have been a number of research reviews into the use of melatonin as a treatment for people on the autism spectrum.  Generally, these agree with our conclusions that there is some evidence for the benefits of melatonin, although they vary in their valuation of the quality of that evidence. For example

  • Guénolé F. et al. (2011) noted “As a whole, we found that the literature supports the existence of a beneficial effect of melatonin on sleep in individuals with ASD, with only few and minor side effects. However, considering the small number of studies and their methodological limits, these conclusions cannot yet be regarded as evidence-based. Randomized controlled trials and long-term follow-up data are still lacking to better assess efficacy and safety of exogenous melatonin for disordered sleep in individuals with ASD.
  • Rossignol et al (2011) noted “Melatonin administration in ASD is associated with improved sleep parameters, better daytime behavior, and minimal side effects. Additional studies of melatonin would be helpful to confirm and expand on these findings.”

Recommendations for Future Research

There is a need for more research into the relationship between sleep problems and melatonin processing in people on the autism spectrum.

There is also a need for more research into the use of melatonin as an intervention for people on the autism spectrum.  That research should

  • Use more scientifically robust, experimental methodologies with a wider range of participants. 
  • Provide more details about the participants, such as whether they had a formal diagnosis of autism, intellectual ability etc.
  • Investigate if specific individuals on the autism spectrum (such as those with circadian rhythm problems) might benefit most from the use of melatonin. 
  • Identify the optimal formulations, dosages and lengths of treatment for different individuals on the autism spectrum and for specific sleep problems.
  • Compare melatonin with other interventions which are designed to achieve similar results, such as tranquillisers.
  • Determine if melatonin can be used as one of the elements within comprehensive, multi-component, treatment models for sleep problems.
  • Make use of a wider range of standardised measurement tools including actigraphic devices, sleep diaries, quality of life measures etc.
  • Involve people on the autism spectrum in the design, development and evaluation of those studies.

Studies and Trials

This section provides details of scientific studies into the effectiveness of melatonin for people on the autism spectrum which have been published in English-language, peer-reviewed journals.

You may be able to find other studies on melatonin in our publications database.

If you know of any other studies we should include please email info@researchautism.net with the details. 

Please note that we are unable to supply publications unless we are listed as the publisher. However, if you are a UK resident you may be able to obtain them from your local public library, your college library or direct from the publisher.

Related Studies and Trials


Other Reading

This section provides details of other publications on melatonin.

You may be able to find other publications on melatonin in our publications database.

If you know of any other publications we should include please email info@researchautism.net with the details.

Please note that we are unable to supply publications unless we are listed as the publisher. However, if you are a UK resident you may be able to obtain them from your local public library, your college library or direct from the publisher.

Related Other Reading


Additional Information

The NICE website, accessed on 12 September 2017, provides the following information about melatonin,
 
“Melatonin is a naturally occurring hormone produced by the brain. It is involved in regulating a person's body clock and helping to regulate sleep patterns.

“Just 1 melatonin product, called Circadin, is licensed for use in the UK. It can only be obtained with a prescription and comes in the form of a 'prolonged-release' tablet. Prolonged-release means that the drug treatment continues working over a number of hours as the active ingredient is released slowly in the body. This tablet is licensed for treating sleep disorders over a short period of time in adults who are aged 55 or over. It is not licensed for use in any other age group, and so using prolonged-release melatonin in children and young people under 18 is described as 'off-label'.

“Other melatonin products, some in the form of 'immediate-release' capsules, tablets or liquids, are available from specialist suppliers and on the internet. These are not licensed for use in any patient group in the UK and so are known as 'unlicensed'.

“The main treatments available for children and young people with sleep disorders are non-drug treatments, including good 'sleep hygiene'. Good sleep hygiene includes day-to-day things that can be done at home to help children and young people sleep. This includes advice such as having fixed times for going to bed, avoiding exercise and eating a heavy meal near bedtime, keeping the bedroom comfortable and relaxing near bedtime”.

Related Additional Information


Updated
20 Dec 2017
Last Review
01 Nov 2017
Next Review
01 Jan 2020