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Melatonin for ADHD


Melatonin for ADHD

Melatonin is a hormone. It is produced by the pineal gland by converting tryptophan. The onset of darkness (the loss of light) is registered by the retina and stimulates melatonin production via the suprachiasmatic nucleus in the hypothalamus. Melatonin regulates the circadian rhythm. Blind people often have sleep problems and benefit from melatonin supplementation.1 In Germany, unretarded melatonin is freely available up to a dose of 1 mg.2 In the USA, melatonin is freely available as a dietary supplement. In other countries, such as Australia and Scandinavia, melatonin is only available on prescription.

Melatonin appears to be an effective, tolerable and safe treatment for comorbid sleep disorders in both adults and children with ADHD. We are not aware of any reports of inappropriate side effects.

Problems falling asleep and staying asleep occur in 15 % to 25 % of all children and adolescents and in 25 % to 50 % of those with ADHD. Several studies and reviews have shown the benefits of melatonin for sleep disorders in healthy children and adolescents as well as those with ADHD, ASD and other disorders, with minimal side effects.3 There is limited data on the safety and efficacy of long-term use of melatonin.45 Others report 75% circadian disruption in children and adults with ADHD.6
A systematic review of 62 studies with a total of 4,462 ADHD subjects found consistent evidence that ADHD is associated with an evening/late chronotype and a phase delay of circadian phase markers such as weak melatonin onset at dusk and delayed sleep onset. There is evidence that melatonin is an effective treatment for sleep problems in ADHD. A small number of genetic association studies reported links between polymorphisms in circadian clock genes and ADHD symptoms. Overall, there was consistent evidence of circadian rhythm disruption in ADHD7
Several other meta-studies and reviews on sleep problems in children and adults with ADHD have also confirmed that melatonin can shorten the time it takes to fall asleep and improve sleep quality without any significant side effects.891011

For problems falling asleep, unretarded melatonin between 0.5 and 3 mg is recommended (duration of action 3 to 4 hours), whereby it should be taken approx. 1 hour before going to bed and not after midnight.12
Slow-release melatonin can be useful if you have problems sleeping through the night.

1. Melatonin and dopamine and the circadian rhythm

Melatonin suppresses dopamine, while dopamine suppresses melatonin. The interaction between dopamine and melatonin is therefore part of the circadian system. Disruptions to the dopamine system therefore easily affect the melatonin system and vice versa. Against this background, the dopamine deficiency in ADHD and the high frequency of a delayed circadian rhythm in ADHD (which can be associated with melatonin deficiency) could be directly linked.
For more information, see Dopamine and melatonin: waking/sleeping behavior, circadian rhythm.

A regulatory mechanism connects dopamine D4 receptors and melatonin:13
D4R can form receptor heteromers with β1- and α1B-adrenoceptors (β1R and α1BR) in the pineal gland. In these receptor heteromers, D4R activation causes significant inhibition of the partner adrenoceptor. As a result, dopamine inhibits the effect of noradrenaline in the pineal gland. However, to date there is no clear evidence for a functionally relevant release of dopamine in the pineal gland.
At the beginning of the dark period, the initial noradrenergic activation of β1R and α1BR in the pineal gland increases melatonin synthesis and D4R expression. At the end of the dark period, increased D4R expression leads to increased formation of β1R-D4R and α1B-D4R heteromers, in which noradrenaline inhibits β1R and α1BR signaling, resulting in decreased synthesis and release of melatonin.

2. Melatonin for sleep disorders in children with ADHD

According to various studies, melatonin is also effective for sleep problems in children with ADHD,1415 16 17 18 while melatonin has no direct effect on the ADHD symptoms themselves.19
In a study of 74 children under the age of 12 with ADHD who received MPH, 60.8% showed a large or very large improvement in sleep behavior in response to melatonin treatment.20 A small study found improved sleep onset behavior, fewer sleep throughs and more sleep with melatonin in a group of children with mental disorders, including ADHD. There were no serious side effects.21

A systematic review on the treatment of sleep problems in ADHD found a positive effect of melatonin on falling asleep, sleep duration and sleep quality. Clonidine also improved insomnia (which is why we assume the same for guanfacine), while zolpidem and L-theanine hardly showed any improvement.22

A meta-analysis on the use of melatonin for the treatment of sleep problems in children with ADHD reports that melatonin is often prescribed as an adjunctive pharmacotherapy when optimization of stimulant adjustment, sleep hygiene and behavioral therapy have not been sufficient. Melatonin regulates sleep disorders in the circadian rhythm, such as difficulty falling asleep in children with ADHD. Four studies in children aged 6 to 14 years with ADHD and insomnia showed an improvement in sleep onset and sleep latency. Adverse events were transient and mild in all studies.23 Another meta-analysis also found a significant improvement in sleep duration and sleep onset latency in children with ADHD or ASD compared to placebo, with a high response rate. Melatonin was well tolerated in the dose range of 2 to 10 mg/day in children and adolescents in both short and long application tests with few side effects.24 Further reviews support these results.2526

A cohort study from Sweden showed that in 2017, around 2% of all children aged 0 to 17 had been prescribed melatonin at least once. Overall, melatonin prescriptions increased 15-fold for girls and 20-fold for boys between 2006 and 2017. 15% of girls and 17% of boys who were prescribed melatonin for the first time between the ages of 5 and 9 in 2009 continued to be prescribed melatonin for the following 8 years. Half of the children prescribed melatonin had at least one mental disorder. The most common mental disorder was ADHD, in all age groups and in both sexes.27
This is in line with another Swedish cohort study, according to which 40% of girls and 50% of boys aged 5 to 9 years who regularly received melatonin in 2010 continued to receive melatonin regularly after 3 years. Among 15 to 19-year-olds, only around 10% were still regular users 3 years later. In 2013, 65% of boys and 49% of girls who regularly took melatonin also regularly took ADHD medication. The daily dosage of melatonin appeared to have decreased by almost 30% between 2006 and 2012.28
A Norwegian cohort study also shows a continuous increase in the use of melatonin (off-label in Norway), whereby mainly sleep problems that occurred comorbidly with other disorders were treated. A large number of children continued treatment for 3 years with daily dosing. The average dosage in the third year was 1,080 milligrams (586 to 1,800 mg) for boys and 90o milligrams (402 to 1,620 mg) for girls.29
A very large cohort study of 48,296 ADHD sufferers between the ages of 0 and 17 from 2008 to 2012 found that 30% of them received other medications in addition to ADHD medications, with melatonin being the most commonly given other medication, ahead of antidepressants and antipsychotics.30

In view of these dimensions, it is difficult to imagine that melatonin would have been used without corresponding benefits or that serious side effects of melatonin would not have been noticed.

In a Canadian survey, melatonin was the most commonly used medication by doctors for sleep disorders in children (73%), regardless of coexisting ADHD.31

A Japanese survey showed that almost half of the children with difficulty falling asleep were treated with melatonin (n = 220). The following study showed effective doses between 0.2 and 8 mg, depending on age (n = 254).32

A meta-study found that melatonin brought forward the time taken to fall asleep by 40 minutes and reduced the time taken to fall asleep by 24 minutes in children and adults with sleep onset disorders.9

3. Melatonin for sleep disorders in adults with ADHD

A number of studies show that slow-release melatonin can alleviate sleep problems in older people aged 55 and over. A melatonin preparation (Circadin, 2 mg slow-release melatonin) has been approved for this purpose in Germany.

In a review of 41 studies, an international group of experts concluded that sustained-release melatonin (2 - 10 mg, 1 - 2 hours before bedtime) may be helpful in adults with insomnia symptoms or comorbid insomnia in affective disorders, schizophrenia, Autism spectrum disorders, neurocognitive disorders or during the discontinuation of sedative-hypnotics, while in adults with disorders associated with circadian sleep problems (such as ADHD), unretarded melatonin (1 mg and less) is more useful.33

A French expert commission found melatonin to be a helpful medication for adults with sleep disorders and comorbid mental disorders such as ADHD.34 A meta-study found that melatonin brought forward the time to fall asleep by 40 minutes and reduced the time to sleep by 24 minutes in children and adults with sleep onset disorders.9

4. Melatonin and stimulants

One study found that around 60% of children with ADHD taking methylphenidate responded to melatonin for sleep problems. No inappropriate side effects were found.35
Methylphenidate did not alter melatonin plasma levels, regardless of ADHD subtype.36
One study found children with ADHD who received ADHD medication were three times more likely to receive medication for sleep problems, with melatonin being the most common medication given. Further, ADHD-C was 2.5 times more likely to receive medication for sleep problems than the ADHD-I subtype.37

A study on the intake of MPH and melatonin found that melatonin not only shortened the time it took to fall asleep and reduced sleep disturbances, but also improved height growth and weight gain. Appetite correlated with sleep duration, but independently of melatonin intake.38

5. Deactivation of the HPA axis by melatonin

A study in rats with atopic dermatitis-induced psychological stress found evidence that high-dose melatonin (20 mg/kg) could equalize the stress effect on the HPA axis, the autonomic nervous system and the stress-induced changes in dopamine and noradrenaline levels, resulting in the elimination of ADHD symptoms.39 In humans, melatonin is given in doses of 1 to 5 mg in total (and not per kg), so the amount used in the study was several hundred times the dose usually used in humans. The use of melatonin as a stress inhibitor is therefore not foreseeable for the time being.
Nevertheless, it would be worthwhile investigating the question of stress reduction through melatonin in more detail.

Melatonin reduces the effects of cortisol in relation to dopamine and noradrenaline:

Melatonin effect on dopamine:
Cortisol reduced dopamine levels in the locus coeruleus, the PFC and the striatum.
20 mg/kg melatonin counteracted the dopamine reduction caused by cortisol in all three brain areas.39

Melatonin effect on noradrenaline:
Cortisol increased the noradrenaline level in the locus coeruleus, in the PFC and in the striatum.
20 mg/kg melatonin counteracted the noradrenaline increase caused by cortisol in all three brain areas.39

In both ADHD sufferers and people with sleep problems, the evening rise in melatonin is delayed.40 In children between the ages of 6 and 12 with ADHD and sleep problems, the onset of sleep was delayed by 50 minutes, which corresponded to the delay in the rise in melatonin. Otherwise, sleep did not differ significantly.
Since the start of school is the same for all children in everyday life, this explains why ADHD sufferers with sleep problems have considerably greater difficulties in everyday life.

The nocturnal rise in melatonin correlates with the nocturnal reduction of cortisol41 and occurs later in children than in older people. In addition, the time of sleep is shifted forward in older people in relation to the time of the evening melatonin rise.42

An elevated serum melatonin level was found in ADHD.43

6. Melatonin and improvement of ADHD symptoms

Despite the stress-relieving effect of very high doses of melatonin, melatonin is unlikely to improve ADHD symptoms directly (during the day). However, since sleep problems can make a significant contribution to ADHD symptoms and melatonin can effectively improve sleep problems, melatonin can indirectly contribute to an improvement in ADHD symptoms in this way. However, this also requires a certain amount of time.

One study found a significant improvement in sleep onset (27 minutes earlier) and sleep duration (20 minutes longer) with 3 or 6 mg melatonin in children with ADHD and sleep onset delay, but no effect on problematic behavior, cognitive performance or quality of life.44 However, the follow-up study conducted a good 3 1/2 years later showed that 65% of the children continued to take melatonin daily. 88% reported a high effectiveness of melatonin against problems with falling asleep. 71 % reported behavioral improvements, 61 % reported an improved mood.45 Discontinuation of the melatonin intake led to a return to delayed falling asleep in 92%. There were no serious side effects of long-term use.

A single study reported that melatonin reduced ADHD symptoms induced by psychological stress (via atopic dermatitis) in a mouse model.46 We are not aware of any other reports that melatonin directly reduces ADHD symptoms.

7. Miscellaneous about melatonin

The daily doses of melatonin as a medication range from 0.5 milligrams to 8 milligrams.

Retarded melatonin should only be used if melatonin production has completely ceased.47 Taking unretarded melatonin approx. 1 hour before going to bed can be helpful.

7.1. Measurement of melatonin

The measurement is carried out in serum, in the first morning urine or in saliva.
The measurement of the first morning urine is not suitable for determining the daily profile.

The melatonin release profile is determined by hourly measurement from dusk to 1 a.m. and on waking. If the chronobiorhythm is strongly shifted backwards, an even later nocturnal measurement may be necessary. Possible measurement targets are47

  • The speed of the increase from the start of release up to a level of 4 pg/ml
  • The amount of the increase
  • An early depletion of the melatonin level.

Melatonin is released from the time it gets dark, whereby the release initially increases slowly and usually more quickly between 10 and 11 p.m. (acrophase). The high melatonin level drops again from around 2 am to 4 am.47
The so-called twilight melatonin onset is determined when a value of 3 pg/ml is reached in the saliva. sleep usually sets in 2 to 3 hours after this value is reached.6

7.2. Risks and side effects of melatonin

Melatonin appears to be a safe remedy for improving sleep problems in children and adults with ADHD. The large amount of use, the long duration of use in the respective affected persons and the increasing numbers of use indicate evidence for successful use. The fact that there are only a few large clinical studies on the use of melatonin for sleep problems in ADHD is probably also due to the fact that off-patent active ingredients (such as melatonin) are understandably not of commercial interest to pharmaceutical companies. It is not the task of pharmaceutical companies to investigate the efficacy or safety of off-patent active ingredients. On the contrary, there would be more of an economic interest in identifying negative aspects of melatonin in order to avoid competition from melatonin as an active ingredient in the public domain. However, such reports are also lacking.

We were unable to find any studies documenting the occurrence of relevant side effects of melatonin. In view of the high number of users and the long history of use for the treatment of sleep problems, including in children and adults with ADHD, we consider the absence of reports of side effects to be an indication of good tolerability.
Nevertheless, there are reports of side effects of melatonin when taken continuously. In these cases, intermittent use is probably recommended, with a 1 to 2 day break every 1 to 2 weeks.

A review states that no relevant side effects of melatonin are known.48

Adults produce approximately 20 to 60 micrograms of melatonin daily. Melatonin is rapidly absorbed and metabolized during the first pass through the liver, with a half-life of 30 to 40 minutes (in 3- to 8-year-old children as well as adults, while newborns showed a half-life of up to 20 hours) and a bioavailability of 1 to 37%. In the liver, it is metabolized by CYP1A220 to 6-hydroxymelatonin and then sulfated to 6-sulfatoxymelatonin or conjugated to glucuronide and excreted.49

Too high a melatonin level can cause depression (winter depression).
Possible side effects can be

  • Night sweats50
  • Hot flushes at night50
  • Mood changes50
    • Restlessness
    • Nervousness
    • Fear
    • Lethargy
  • Nightmares
    • Occasionally (in one in one hundred to one thousand people treated) to rarely (in one in one thousand to ten thousand people treated)51
  • Very vivid dreams
    • Occasionally (in one in one hundred to one thousand people treated) to rarely (in one in one thousand to ten thousand people treated)51
  • Stomach cramps
    • Occasionally (in one in one hundred to one thousand people treated) to rarely (in one in one thousand to ten thousand people treated)51
  • Dizziness
    • Occasionally (in one in one hundred to one thousand people treated) to rarely (in one in one thousand to ten thousand people treated)51
  • Headache
    • Occasionally (in one in one hundred to one thousand people treated) to rarely (in one in one thousand to ten thousand people treated)51
  • Irritability
    • Occasionally (in one in one hundred to one thousand people treated) to rarely (in one in one thousand to ten thousand people treated)51
  • Reduced sexual desire
    • Occasionally (in one in one hundred to one thousand people treated) to rarely (in one in one thousand to ten thousand people treated)51

7.3. Degradation of melatonin

Due to the degradation of melatonin via CYP1A2 and (to a lesser extent) CYP2C19, increased caution should be exercised when combining melatonin with drugs that are also degraded via these pathways.
This mechanism also explains the fatigue-promoting effect of imipramine/desipramine, which, if severe, means that imipramine should be taken in the evening.

A decrease in the effect of melatonin could be due to CYP1A2 underactivity. In this case, a reduction in dosage is recommended.48

7.4. Interactions with melatonin

Interactions with antithrombotic and antiepileptic drugs are possible.

7.4.1. Reducing the effect of melatonin

  • Some psychotropic drugs47
  • Alpha blocker47
  • Beta blockers47
  • Alcohol
    • Even moderate doses of alcohol, one hour before bedtime, caused a significant reduction in melatonin levels in young adults.52

7.4.2. Increasing the effect of melatonin

Due to the degradation mechanism, inhibitors of CYP1A2 and CYP2C19 increase the plasma levels and bioavailability of melatonin:

  • Fluvoxamine5354
    • Inhibits the breakdown of melatonin in the liver; increases the duration and effectiveness of melatonin47
  • Desipramine53
    • Consequently also imipramine, as this is converted to desipramine
  • Caffeine55
  • Theophylline49
  • Citalopram / escitalopram as a CYP2C19 inhibitor56
  • Ciprofloxacin
    • Inhibits the breakdown of melatonin in the liver; increases the duration and effectiveness of melatonin47

7.4.3. Melatonin increases the effect of other medications

Melatonin enhances the dampening effect of, among other things:47

  • Benzodiazepines
  • Zaleplon
  • Zopiclone
  • Zolpidem
  • Imipramine
  • Thioridazine

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