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Melatonin for ADHD

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Melatonin for ADHD

Melatonin is a hormone. It is produced by the pineal gland through the conversion of tryptophan. The onset of darkness (the absence of brightness) is registered via the retina and stimulates melatonin production via the suprachiasmatic nucleus in the hypothalamus. Melatonin regulates the circadian rhythm. Blind people are more likely to have sleep problems and benefit from melatonin supplementation.1 In Germany, 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 available by prescription.

Melatonin appears to be an effective, tolerable, and safe agent for the treatment of comorbid sleep disorders in both adults and children with ADHD. We are not aware of 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 demonstrate the benefits of melatonin in sleep disorders for healthy children and adolescents as well as those with ADHD, ASD, and other disorders, while minimizing side effects.3 There are limited data on 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-night chronotype and a phase delay of circadian phase markers such as weak melatonin onset in dim light and delayed sleep onset. Evidence was found for effective treatment of sleep problems in ADHD by melatonin. A small number of genetic association studies reported links between polymorphisms in circadian clock genes and ADHD symptoms. Overall, consistent evidence was found for circadian rhythm disruption in ADHD7
Several other metastudies and reviews on sleep problems in children and adults with ADHD also confirmed that melatonin can shorten the time it takes to fall asleep and improve sleep quality without significant side effects.891011

1. Melatonin and dopamine and the circadian rhythm

Melatonin suppresses dopamine, while dopamine suppresses melatonin. The interaction between dopamine and melatonin are thus part of the circadian system. Disturbances of the dopamine system thus easily affect the melatonin system and vice versa. Against this background, the dopamine deficiency in ADHD and the high frequency of a retarded diurnal rhythm in ADHD (which may be associated with melatonin deficiency) could be directly linked.
See here: Dopamine and melatonin: wake/sleep behavior, circadian rhythm.

A regulatory mechanism links dopamine D4 receptors and melatonin:12
D4Rs can form receptor heteromers with β1- and α1B-adrenoceptors (β1R and α1BR) in the pineal gland. In these receptor heteromers, D4R activation causes marked inhibition of the partner adrenoceptor. As a result, dopamine inhibits the action of norepinephrine in the pineal gland. However, clear evidence for a functionally relevant dopamine release in the pineal gland is lacking so far.
At the beginning of the dark period, 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 norepinephrine inhibits β1R and α1BR signaling, resulting in decreased melatonin synthesis and release.

2. Melatonin against sleep disorders in children with ADHD

Melatonin is also effective for sleep problems in children with ADHD according to various studies,1314 15 16 while melatonin shows no direct effect on ADHD symptoms themselves.17
In a study of 74 children under 12 with ADHD who received MPH, 60.8% showed a great or very great improvement in sleep behavior in response to melatonin treatment.18 A small study found improved sleep onset, less sleep through, and more sleep on melatonin in a group of children with mental disorders, including ADHD. No serious side effects occurred.19

A systematic review on the treatment of sleep problems in ADHD found a positive effect for melatonin on falling asleep, sleep duration and sleep quality. Clonidine also improved insomnia (which is why we suspect the same for guanfacine), whereas zolpidem and L-theanine showed little improvement.20

A meta-analysis on the use of melatonin to treat sleep problems in children with ADHD reported that melatonin is often prescribed as a complementary pharmacotherapy when optimization of the stimulant setting, sleep hygiene, and behavioral therapy were not sufficient. Melatonin regulates sleep disturbances in circadian rhythms, such as difficulty falling asleep in children with ADHD. Four studies in children 6 to 14 years of age with ADHD and insomnia showed improvement in sleep onset and sleep latency. Adverse events were transient and mild in all studies.21 Another meta-analysis also found significant improvement in sleep duration and sleep onset in children with ADHD or ASD compared with placebo, while maintaining 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 use tests, with few side effects.22 Further reviews support these findings.2324

A cohort study from Sweden showed that in 2017, about 2% of all children aged 0 to 17 had been prescribed melatonin at least once. Overall, melatonin prescribing increased 15-fold for girls and 20-fold for boys from 2006 to 2017. 15% of girls and 17% of boys who were first prescribed melatonin in 2009 at age 5 to 9 continued to receive it consistently over 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.25
This is consistent with another Swedish cohort study, which found that 40% of girls and 50% of boys aged 5 to 9 years who received regular melatonin in 2010 continued to receive regular melatonin after 3 years. Among 15- to 19-year-olds, only about 10% were regular users 3 years later. In 2013, 65% of boys and 49% of girls taking melatonin regularly were also receiving ADHD medication regularly. Daily melatonin dosage levels appeared to have decreased by nearly 30% between 2006 and 2012.26
Similarly, a Norwegian cohort study showed a steady increase in melatonin use (off-label in Norway), primarily treating sleep problems comorbid with other disorders. A large number of children continued treatment for 3 years on daily dosing. Dosage in the third year averaged 1,080 milligrams (586 to 1,800 mg) in boys and 90o milligrams (402 to 1,620 mg) in girls.27
A very large cohort study of 48,296 ADHD sufferers aged 0 to 17 years 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.28

Given these dimensions, it is difficult to imagine that melatonin would have been used without corresponding benefit or that serious side effects of melatonin would not have been noted.

In a Canadian survey, melatonin was the most commonly used medication by physicians for sleep disorders in children, at 73%, regardless of co-existing ADHD.29

A Japanese survey showed that just under 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).30

One metastudy found melatonin advanced the time to fall asleep by 40 minutes and reduced the time to fall asleep by 24 minutes in children and adults with difficulty falling asleep.9

3. Melatonin for sleep disorders in adults with ADHD

Several studies show that sustained-release melatonin can correct sleep problems in older people aged 55 and over. A melatonin preparation is approved for this purpose in Germany (Circadin, 2 mg sustained-release melatonin).

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 discontinuation of sedative-hypnotics, whereas unretarded melatonin (1 mg and less) was more useful in adults with disorders associated with circadian sleep problems (such as ADHD).31

A French expert panel found melatonin to be a helpful medication for adults with sleep disorders and comorbid mental disorders such as ADHD.32 A metastudy found melatonin advanced the time to fall asleep by 40 minutes and reduced the time to fall asleep by 24 minutes in children and adults with insomnia.9

4. Melatonin and stimulants

One study found in children with ADHD taking methylphenidate, about 60% responded to melatonin for sleep problems. No inappropriate side effects were noted.33
Methylphenidate did not alter melatonin plasma levels, regardless of ADHD subtype.34
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.35

A study on the intake of MPH and melatonin found, in addition to a shortened duration of falling asleep and reduced sleep-through disturbances, an improvement in length growth and weight gain due to melatonin. Appetite correlated with sleep duration, but independently of melatonin intake.36

5. Deactivation of the HPA axis by melatonin

A study in rats that had mental stress induced by atopic dermatitis (neurodermatitis) 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 norepinephrine levels, and as a result eliminated ADHD symptoms.37 In humans, melatonin is given in dosages of 1 to 5 mg total (rather than per kg), so the amount used in the study was several hundred times the dosage commonly used in humans. Therefore, for the time being, a use of melatonin as a stress-buster is not foreseeable.
Nevertheless, it would be worthwhile to investigate the question of stress reduction by melatonin in more detail.

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

Melatonin effect on dopamine:
Cortisol decreased dopamine levels in the locus coeruleus, PFC, and striatum.
20 mg/kg melatonin counteracted dopamine reduction by cortisol in all three brain areas.37

Melatonin effect on norepinephrine:
Cortisol increased norepinephrine levels in the locus coeruleus, PFC, and striatum.
20 mg/kg melatonin counteracted noradrenaline elevation by cortisol in all three brain areas.37

In ADHD sufferers as in people with sleep problems, the evening rise of melatonin is delayed.38 In children between 6 and 12 years of age with ADHD and sleep problems, sleep onset was delayed by 50 minutes, which corresponded to the delay in melatonin rise. Otherwise, sleep did not differ significantly.
Since in everyday life the start of school is the same for all children, this explains that ADHD sufferers with sleep problems have considerably greater difficulties in everyday life.

The nocturnal melatonin rise correlates with the nocturnal depletion of cortisol39 and occurs later in children than in the elderly. In addition, the timing of sleep shifts forward in the elderly relative to the timing of the evening melatonin rise.40

Elevated serum melatonin levels have been found in ADHD.41

6. Melatonin and improvement of ADHD symptoms

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

One study did find a significant improvement in falling asleep (27 minutes earlier) and sleep duration (20 minutes longer) with 3 or 6 mg of melatonin in children with ADHD and delayed falling asleep, but no effect on problem behaviors, cognitive performance, or quality of life.42 However, the follow-up study conducted just over 3 1/2 years later showed that 65% of the children continued to take melatonin daily. 88% reported high effectiveness of melatonin against sleep onset problems. 71% reported behavioral improvements, and 61% reported improved mood.43 Discontinuation of melatonin use restored sleep delay in 92%. Serious side effects of long-term use were not found.

A single study reported that melatonin reduced ADHD symptoms induced by psychological stress (via atopic dermatitis) in a mouse model.44 We are not aware of any other reports that melatonin directly reduces ADHD symptoms.

7. Other about melatonin

Daily doses of melatonin as a drug range from 0.5 milligrams to 8 milligrams.

Retarded melatonin should be used only in case of complete failure of melatonin production.45 Taking unretarded melatonin about 1 hour before bedtime may be helpful.

7.1. Melatonin measurement

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

The melatonin release profile is determined by hourly measurement from dark until 1 a.m. as well as when waking up. An even later nocturnal measurement may be necessary in the case of a chronobiorhythm that is strongly shifted backwards. Possible measurement targets are45

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

Melatonin is secreted from darkness onwards, with the secretion increasing slowly at first and then more rapidly between 10 and 11 p.m. (acrophase). The high melatonin level drops again from about 2 to 4 o’clock.45
The so-called twilight melatonin onset is determined when a value of 3 pg/ml is reached in saliva. 2 to 3 hours after reaching this value, sleep usually occurs.6

7.2. Risks and side effects of melatonin

Melatonin appears to be a safe agent for improving sleep problems in children and adults with ADHD. The large amount of use, the long-lasting duration of use in the respective sufferers, and the increasing numbers of use suggest evidence for successful use. The fact that there are few large clinical trials on the use of melatonin for sleep problems in ADHD is likely due in part to the fact that off-patent agents (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, from an economic point of view, there would rather be an interest in identifying negative aspects of melatonin in order to avoid competition from melatonin as an off-patent active ingredient. However, such reports are also lacking.

We could not find any studies documenting the occurrence of relevant side effects of melatonin. Considering the high user numbers and the already longstanding use for the treatment of sleep problems also in children and adults with ADHD, we consider the absence of reports of side effects as an indication of good tolerability.
Nevertheless, there are reports of side effects of melatonin when taken continuously. In these cases, intermittent intake is probably recommended until every 1 to 2 weeks includes a 1- to 2-day interruption in intake.

A review states that no relevant side effects of melatonin are known.46

Adults produce approximately 20- to 60 micrograms of melatonin daily. Melatonin is rapidly absorbed and metabolized on first passage through the liver, with a half-life of 30 to 40 minutes (in 3- to 8-year-old children as well as adults, while neonates 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.47

Too high melatonin levels can cause depression (winter depression).
Possible side effects may include:

  • Night sweats48
  • Nightly hot flashes48
  • Mood changes48
    • Unrest
    • Nervousness
    • Fear
    • Lethargy
  • Nightmares
    • Occasionally (in one in one hundred to one thousand treated) to rarely (in one in one thousand to ten thousand treated)49
  • Very vivid dreams
    • Occasionally (in one in one hundred to one thousand treated) to rarely (in one in one thousand to ten thousand treated)49
  • Stomach cramps
    • Occasionally (in one in one hundred to one thousand treated) to rarely (in one in one thousand to ten thousand treated)49
  • Dizziness
    • Occasionally (in one in one hundred to one thousand treated) to rarely (in one in one thousand to ten thousand treated)49
  • Headache
    • Occasionally (in one in one hundred to one thousand treated) to rarely (in one in one thousand to ten thousand treated)49
  • Irritability
    • Occasionally (in one in one hundred to one thousand treated) to rarely (in one in one thousand to ten thousand treated)49
  • Reduced sexual desire
    • Occasionally (in one in one hundred to one thousand treated) to rarely (in one in one thousand to ten thousand treated)49

7.3. Melatonin degradation

Due to the degradation of melatonin via CYP1A2 as well as (less) CYP2C19, combination with drugs that are also degraded via this route should be done with increased caution.
This mechanism also explains the fatigue-promoting effect of imipramine/desipramine, which, when severe, means that imipramine should rather be taken in the evening.

A decrease in the effect of melatonin could be due to CYP1A2 underactivity. In this case, a dosage reduction is recommended.46

7.4. Interactions with melatonin

Interactions with antithrombotic and antiepileptic drugs are possible.

7.4.1. Reducing the effect of melatonin

  • Some psychotropic drugs45
  • Alpha Blocker45
  • Beta blocker45
  • Alcohol
    • Even moderate doses of alcohol, one hour before bedtime, caused a significant reduction in melatonin levels in young adults.50

7.4.2. Increase the effect of melatonin

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

  • Fluvoxamine5152
    • Inhibits the breakdown of melatonin in the liver; increases the duration of action and potency of melatonin45
  • Desipramine51
    • Consequently also imipramine, as this is converted to desipramine
  • Caffeine53
  • Theophylline47
  • Citalopram / escitalopram as a CYP2C19 inhibitor54
  • Ciprofloxacin
    • Inhibits the breakdown of melatonin in the liver; increases the duration of action and potency of melatonin45

7.4.3. Increase in the effect of other drugs due to melatonin

Melatonin enhances the depressant effects of, among others:45

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

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