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Wednesday, 22 January 2014

Melatonin for Kids with Autism, and indeed their Parents


I have long heard about kids with autism having sleeping problems; these range from difficulty falling asleep, waking frequently during the night and waking up very early in the morning.  The same problems apparently occur in ADHD.

I think some of the sleep related problems are behavioral in nature; some children with ASD live actually with less structure than typical kids.  Some kids with ASD do not get much physical exercise to tire them out by bed time.  
Having said all that, there does seem to be something else going on.
Long ago people found out that Melatonin, a hormone available cheaply without prescription in many countries, had a very positive effect on sleeping patterns.

What is also interesting, is the other properties of Melatonin and the other types of people who can benefit from it.  This does take us some way from our core theme of autism, towards treating cancer and other illnesses of older age.  I expect most my readers are parents of a child with ASD, well this time science has some news for you too.

What is Melatonin?
Melatonin is a hormone secreted by the Pineal Gland in the brain. It helps regulate other hormones and maintains the body's internal clock. The circadian rhythm is an internal 24-hour clock, that plays a critical role in when we fall asleep and when we wake up. When it is dark, your body produces more melatonin; when it is light, the production of melatonin drops. Being exposed to bright lights in the evening or too little light during the day can disrupt the body’s normal melatonin cycles.

Melatonin helps control the timing and release of female reproductive hormones. Some researchers also believe that melatonin levels may be related to aging.

Young children have the highest levels of night time melatonin. Researchers believe these levels drop as we age. Some people think lower levels of melatonin may explain why some older adults have sleep problems.

Melatonin has powerful antioxidant effects. Research suggests that it may help strengthen the immune system.

Melatonin is derived from serotonin. Serotonin levels in autism are often high in the blood, but can be low in the brain.  Serotonin cannot cross the blood brain barrier.  The Pineal Gland is inside the brain, but outside the blood brain barrier.

 
Dose Response
One clever study tried to establish the dose at which Melatonin had an effect on sleep.  It is interesting that they found the dosage was not correlated to weight.  The vast majority of drugs are dosed on how big you are, and often trials assume this to be the case.

Dose-response

All 24 children who completed study procedures obtained a satisfactory response (as defined above) to melatonin at doses between 1 mg and 6 mg. Seven children obtained a satisfactory response at 1 mg, 14 at 3 mg, and only 3 required 6 mg. The child’s age or weight was not associated with melatonin dose response. The mean age/weight (standard deviation) of children responding to 1 mg was 5.9 (1.9) years/26.4 (11.1) kg; and to 3 or 6 mg was 5.9 (2.3) years/25.4 (11.2) kg.

In effect you are treating a hormone deficiency, like any other.  Just as a small person may need more thyroid hormone than a very big person; the same appears to be true with Melatonin.
Much of the “specialist advice” from "doctors" on the web looks incorrect on this subject:-

Melatonin. This naturally occurring peptide released by the brain in response to the setting of the sun has some function in setting the circadian clock. It is available without prescription at most pharmacies and health food stores. Typically the dosage sizes sold are too large. Almost all of the published research on Melatonin is on doses of 1 mg or less, but the doses available on the shelves are either 3 or 6 mg. Nothing is gained by using doses greater than one milligram. Melatonin may not be effective the first night, so several nights' use may be necessary for effectiveness.
(this was advice for people with ADHD, which I regard as part of ASD)

 
Abnormal Melatonin Synthesis in ASD and in Parents
A surprising amount of work has been done looking at abnormalities in melatonin synthesis in both kids with ASD and their parents.  Hence the title of this post.
The low level of melatonin synthesis is acquired from one or more parent, who will probably also have a sleep disorder.  Not only that, but low melatonin is also linked to increased risk to some serious health conditions, more on that later. 

"In autism spectrum disorders (ASD), low melatonin levels have been reported by three independent groups,1315 but the underlying cause of this deficit and its relationship to susceptibility to ASD was unknown
the serotonin level was significantly higher in individuals with ASD (P=2×10−11) and their parents (P=10−8) than in controls
 Our results confirm that low plasma melatonin concentration (half the mean of the control values) is a frequent trait in ASD patients, as observed in 65% of the patients tested, a proportion very similar (63%) to that previously reported by Tordjman et al.15 We show for the first time that abnormal melatonin levels are also present in the unaffected parents of ASD patients, suggesting a genetic origin. Indeed, the melatonin deficit observed in the patients was associated with low ASMT activity, suggesting that variations in the ASMT gene could be the cause of this deficit."

Effect of Hormone Supplementation on the Pineal Gland
If you start interfering with human hormones, you need to be aware of the possible consequences.  For example, a relatively common autism therapy in the US is to give thyroid hormones T4 and T3 to children who are not clinically hypothyroid.  Some parents report great improvements, but some comment that over time they have to increase the dosage.  This is because the feedback loops that control the thyroid gland are telling it to gradually shut down.  Over time, such a child might become entirely dependent on the T4/T3 tablets.

So, if you have a pineal gland that does not produce enough melatonin, what happens to it when you take supplements?  I do not think anyone can tell you with certainty.
There have been long term trials over a few years in sleep disorders.  When supplementation stops the sleep disorder returns.  Nothing bad was reported.

Natural release of melatonin is controlled by exposure to light and dark.  To what extent does this change when supplements are added?
To what extent to supplements interfere with other less well understood melatonin mechanisms?  

On balance, common sense would tell you to leave a fully functioning pineal gland well alone; but if you have an autistic child with a challenging sleep disorder, this would be suggest that the pineal gland needs some external help.  In an ideal world, your doctor would test the pineal gland function and check Melatonin levels were age appropriate.

Melatonin and Behaviours
Research in ADHD suggests that while Melatonin improves sleep disorders it does not improve behaviour.
Abstract
OBJECTIVE:
To investigate the effect of melatonin treatment on sleep, behavior, cognition, and quality of life in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia.
METHOD:
A total of 105 medication-free children, ages 6 to 12 years, with rigorously diagnosed ADHD and chronic sleep onset insomnia participated in a randomized, double-blind, placebo-controlled trial using 3 or 6 mg melatonin (depending on body weight), or placebo for 4 weeks. Primary outcome parameters were actigraphy-derived sleep onset, total time asleep, and salivary dim light melatonin onset.
RESULTS:
Sleep onset advanced by 26.9 +/- 47.8 minutes with melatonin and delayed by 10.5 +/- 37.4 minutes with placebo (p < .0001). There was an advance in dim light melatonin onset of 44.4 +/- 67.9 minutes in melatonin and a delay of 12.8 +/- 60.0 minutes in placebo (p < .0001). Total time asleep increased with melatonin (19.8 +/- 61.9 minutes) as compared to placebo (-13.6 +/- 50.6 minutes; p = .01). There was no significant effect on behavior, cognition, and quality of life, and significant adverse events did not occur.
CONCLUSION:
Melatonin advanced circadian rhythms of sleep-wake and endogenous melatonin and enhanced total time asleep in children with ADHD and chronic sleep onset insomnia; however, no effect was found on problem behavior, cognitive performance, or quality of life.
 
The studies in autism indicate a different story; behaviours do improve.  After a good night’s sleep, most people’s behaviour improves; it would be odd if it did not.
I think this is another case of ADHD disorders being of a different magnitude to disorders further along the autistic spectrum.  
For the impact in autism, it best to read the studies; here is an excerpt from Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes:-

“The behavioral outcome measures that showed change with melatonin (e.g., attention-deficit hyperactivity, withdrawn, affective problems, stereotyped behaviors, compulsive behaviors) resemble that of prior work. The literature emphasizes that the behavioral construct of hyperactivity is affected by sleep disturbance—this had been documented in ASD populations (; ) as well as typically developing children treated for obstructive sleep apnea (). Other behavioral parameters which have been associated with poor sleep in children with ASD include repetitive behavior, including compulsive behavior, and oppositional and aggressive behavior, anxiety, depression, and mood variability (; ; ). In an intervention study of parent education, hyperactivity and restricted behaviors showed improvements with treatment ().”

Strangely, when it came to parental stress, they found less impact:-

“Parenting stress, as measured by the Difficult Child Subscale, improved with treatment. We did not find improvement in the PSI parent-related domains (Parental Distress or Parent-Child Dysfunctional Interaction) suggesting that parental stress in autism is multifactorial and may not be addressed with a single intervention.”
 

Why is Melatonin so good for the CNS (Central Nervous System)?
It appears that Melatonin does some very useful things

·        It is an antioxidant/free radical scavenger

·        It stimulates the production of the body’s other key antioxidants

·        It inhibits the production of pro-oxidative enzymes

·        Protects nuclear and mitochondrial DNA

Abstract

This review briefly summarizes the multiple actions by which melatonin reduces the damaging effects of free radicals and reactive oxygen and nitrogen species. It is well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments. This is consistent with the protection by melatonin of lipids and proteins, as well as both nuclear and mitochondrial DNA. Melatonin achieves this widespread protection by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. Thus, melatonin directly scavenges a variety of free radicals and reactive species including the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite anion, and peroxynitrous acid. Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Additionally, melatonin experimentally enhances intracellular glutathione (another important antioxidant) levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the proxidative enzymes nitric oxide synthase and lipoxygenase. Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.
 

Why is Melatonin good for the Immune System?
It is known that Melatonin interacts with the immune system, but the mechanism is not fully understood yet.  As you see below, Melatonin is not just produced in the Brain, it is also sythesized by the immune system. 
Abstract
This review summarizes the numerous observations published in recent years which have shown that one of the most significant of melatonin's pleiotropic effects is the regulation of the immune system. The overview summarizes the immune effects of pinealectomy and the association between rhythmic melatonin production and adjustments in the immune system as markers of melatonin's immunomodulatory actions. The effects of both in vivo and in vitromelatonin administration on non-specific, humoral, and cellular immune responses as well as on cellular proliferation and immune mediator production are presented. One of the main features that distinguishes melatonin from the classical hormones is its synthesis by a number of non-endocrine extrapineal organs, including the immune system. Herein, we summarize the presence of immune system-synthesized melatonin, its direct immunomodulatory effects on cytokine production, and its masking effects on exogenous melatonin action. The mechanisms of action of melatonin in the immune system are also discussed, focusing attention on the presence of membrane and nuclear receptors and the characterization of several physiological roles mediated by some receptor analogs in immune cells. The review focuses on melatonin's actions in several immune pathologies including infection, inflammation, and autoimmunity together with the relation between melatonin, immunity, and cancer.
 

Anti-aging Treatment
There are all sorts of products and therapies put forward to an eager public to combat the aging process; melatonin is one of these products.   I think, in this case, they may very well have got is right.  Yet again, a drug for older people seems to be effective for kids with ASD. 

In anti-aging, one well known practitioner, Dr Pierpaoli, recommends:-

30-39 years of age             1.5mg at bedtime
40-49 years of age             1.5mg to 3mg at bedtime
50-74 years of age             3mg at bedtime
Above 75 years                   3mg to 6mg at bedtime
 

Other use of Melatonin, related to subjects covered in this blog
Melatonin appears to help in Alzheimer’s by interfering with Amyloid beta, which was covered in an earlier post.

Melatonin appears to reduce symptoms in irritable bowel symptom.
Melatonin has been used to treat cluster headaches.


Information for Parents
We have seen earlier in this post that parents of a child with ASD also tend to have a low level of Melatonin.  If you read the layperson’s guide from the University of Maryland, you will see that a low Melatonin level in women is linked to increased risk of breast cancer and in men an increased risk of prostate cancer. 

“Studies show that men with prostate cancer have lower melatonin levels than men without the disease. In test tube studies, melatonin blocks the growth of prostate cancer cells.”
“Laboratory experiments have found that low levels of melatonin stimulate the growth of certain types of breast cancer cells, while adding melatonin to these cells slows their growth”
Since Melatonin is a powerful antioxidant, this may just mean that breast cancer and prostate cancer are linked to oxidative stress and so Melatonin is being used up; but it might also mean that Melatonin is somehow protective.
I read a long time ago that NAC improves outcomes in breast cancer and I expect it does on other types of cancer.

I already take NAC daily, I should probably take some Melatonin as well.  And you?

Conclusion
Melatonin would seem a good candidate for a drug that can make small positive improvements in autism.  Based on an earlier post, it is under consideration for the yellow side of the Polypill.


 
Note that Melatonin has to be given just before bed time.
Note that Melatonin interacts with some drugs used in autism and ADHD.

 

 

9 comments:

  1. Whether the pineal grand will further decrease Melatonin production after Melatonin being given to the children? _yi

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  2. Melatonin worked for my daughter Kirsten and enabled her to get into school in the morning. Increased my quality of life!. Interesting that dose of 1mg and less just as effective as higher one as she was prescribed 3mg. On a break from it at the mo - but if needs to be taken again will try breaking up tablet to see what happens. Am also interested, like previous commenter, to know whether supplementing melatonin for relatively long periods causes pineal to further decrease it's own production and whether effects permanent. Re in an ideal world melatonin levels would actually be tested - I will try asking for this. Thank you again Peter Lloyd-Thomas. Your blog is one of the most worthwhile on the net at the mo. Ben-Ari did reply and advised me to speak to Kirsten's specialists about bumetanide. Will leave comment on your relevant article if get to give it a go.

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    Replies
    1. Bumetanide is worth a quick trial. You will see within a few days whether it works for Kirsten. The effect ranges from zero to profound. It seems more effective in early onset classic autism, than regressive types. The only way to know, is to try it. It seems a safe druf for long term use.

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    2. I am wondering what might be best to help my son who has been waking between 2 and 3 for the past couple months. I upped his B vitamins because he is taking 3600 mg of NAC daily. I don't know if the B vitamins are waking him up. I give the last dose late morning or early afternoon for this reason.
      At this point, neither of us are sleeping again once he wakes up. Any advice would be great.
      Thanks.

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    3. Nancy, a known side effect of supplementing vitamin B12 in autism is hyperactivity (there was a clinical trial by the MIND Institute).
      If it was me, I would stop giving B vitamins and see if sleep goes back to normal. I am giving NAC without any B vitamins.
      B12 is interesting and there will be a new post on it because there has been a new study. Some people with autism have low B12 in their brain, but this would not show up in blood tests. It has long been known that a small percentage of people (circa 10%) do indeed benefit from extra B12, but 90% do not and some get side effects quoted as being hyperactivity and pica.

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  3. Grapefruit juice is known to interact with many prescription drugs like hormones.

    Do you have valide information if grapefuit interacts whith melatonine ?

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  4. Thanks for responding. Actually, when I ran out of B vitamins (my son and I both have homocysteine issues), his rages crept back up. I added the B vitamins back in and they dropped again somewhat. I added in second Homocysteine Supreme and mood stabilized even more.So I am fearful of removing them.

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    Replies
    1. Maybe some of the B vitamins are helpful and others are not. They all have different functions (and possible side effects). When you ran out of them, what happened to sleep? Perhaps NAC close to bedtime is the problem?

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  5. Hi nd,

    My daughter has never been able to handle a complete multi B. I used to supplement them all individually. The troublesome ones were the b3 and the b6. I used to give just a smidgeon of the nicotinamide and had to give p5p with magnesium. I only wanted to try the p5p for seizures and gave the others just so they wouldn't be depleted. I also used a methylcobalamin spray. I don't do any of it now. Here, the big mood stabilizer has been sytrinol.

    B12 also appears to act differently on people. Nothing for my daughter. I have tried injectable, buccal, oral. For me, in the daytime, even energy, clears my head if depressed. Interestingly, at night, it calms me and helps me fall asleep. It has also brought back the vivid, interesting dreams, sometimes nightmares, that I have had for for as long as I can remember, but that had stopped a couple of years ago.

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