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,13–15 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
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 (Goldman et al 2009; Mayes and Calhoun
2009) as well as typically developing children treated for obstructive
sleep apnea (Chervin
et al 2006). 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 (Malow et al 2006; Goldman et al, 2009; Mayes and Calhoun
2009). In an intervention study of parent education, hyperactivity and
restricted behaviors showed improvements with treatment (Reed 2009).”
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.