The over-activated Immune System in Autism or “why has NAC stopped working?”

 Organs of the Immune System

 Today’s post will combine some first class science from MGH (Massachusetts General Hospital) with some feedback that I have been receiving.

I have been receiving comments from parents who have tried some of the various new scientifically-based drug therapies for autism.  For some parents, none of them work.  This is not a surprise, since we have established that “autism” is just a general term for a collection of behavioral symptoms.  These symptoms can be caused by a remarkable variety of different factors and so a therapy can only be successful, if it is matched to the appropriate subject.  The lack of biomarkers currently makes it a case of trial and error.

What really draws my attention is when a successful therapy appears to “stop working”.  This has already happened to my son and it just happened to a reader of this blog; “NAC has stopped working”.

So I applied myself to figuring this out.  In fact, it is quite simple.  Here again we can learn from the comorbidities.  Asthma is another, sometimes nasty, auto-immune inflammatory condition.  Asthma often has flare-ups, but they are often quite predictable - icy cold air in winter and pollen in summer.  Most asthma sufferers in developed countries are very well cared for, and their medication is varied according to the magnitude of their symptoms.  A severe asthma attack may result in a visit to the nearest hospital and treatment with potent steroids, but the science is well understood.

When well-targeted, the current autism drugs can work reasonably well in treating the autism of “stable” subjects; just as a low dose of inhaled corticosteroid usually controls my son’s asthma.  However, when an external factor comes along and over activates the immune system, the medication is overwhelmed.  In asthma you would hear wheezing and have to make frequent use of a “rescue” inhaler like Ventolin and if that was overwhelmed, it would be a case of a nebulizer or an oral steroid, at home, or in hospital.

Unfortunately, you cannot call your doctor and say “my autism drug has stopped working”; he would not believe it worked in the first place.

Having been able to treat autism, it is quite a shock to see all those gains evaporate.  Fortunately, help is at hand in the scientific literature.  In the case of Monty, aged 10 with ASD, the problem was caused by something as simple as pollen.  The pollen triggered the “degranulation” of so-called mast cells that released histamine, serotonin and a whole host of inflammatory cytokines into the blood.  This results in the immune system being in a state of “over-activation”.  This takes the body back to the days in which such over-activation caused the damage that led to the child’s autism.

If I had the resources of the Massachusetts General Hospital (MGH), I would simply establish a base-line of inflammatory markers, like IL-6, for each subject; then, when the subject’s drugs “stopped working” I would measure them again.

Having recently come across a clever Italian called Alessio Fasano, a doctor specialized in Celiac Disease at MGH; I would also test serum Zonulin levels.  Now, Zonulin may sound like something out of Star Trek, and it has only a tiny entry in Wikipedia, but it is possibly the holy grail for those involved in the Gluten and Casein free diet.

Zonulin is a protein that controls the permeability of the gut (digestive tract).  It is also measurable and is indeed a very good indicator of who has a “leaky gut”.  According to Fasano, a leaky gut is a precondition for autism.  No leaky gut, no autism possible.

Now you might be thinking that this talk of leaky guts will then lead me to make crazy claims linking the gut to the brain and then to autism.  Well I am not going to make any such claims; I will leave the highly respected doctor from MGH to do that for me.

There are two videos.  The autism one is over an hour long, but is only a couple of weeks old.  The alternative film is much shorter, but is talking more generally about auto immune diseases.
 

Gut-brain interaction in Autism Spectrum Disorder

Then click on the film that looks like this:-

 

Or the short film:-

Unlocking the Connection Between Intestinal Permeability and Autoimmune Disease

 

Conclusion

This is all very interesting and clearly permeability of the gut looks like a big factor in some people’s day-to-day autism.  It may very well also be a factor in those “flare-ups”, which cause the immune system to “cancel out” the effects of otherwise effective autism drugs.  You may have noted in some of the more shocking autism news stories, that can even end in murder/suicide, ulcerative colitis had developed in the intestines of the autistic person, leading to a severe deterioration in behaviour, that then became unbearable for the carers.

Dr Fasano is a gastroenterologist and so has a lot to tell us about the gut, but some other areas are also involved. We also have the leaky blood brain barrier, a factor in other diseases like MS; a biomarker for that would also be handy.  We also have all the work on mast cell degranulation from Theoharides.  It just has to be fitted together.

So my advice to anyone whose “NAC has stopped working” is to look at what has re-activated your child’s immune system.  It might be Seasonal Autistic Mastocytosis, but it might very well be a related to Fasano’s leaky gut or at the extreme, some kind of colitis (Dr W’s autistic enterocolitis, perhaps).

Perhaps some of those children who do not respond to any of the current autism drugs are in a chronic state of immune system over-activation.  For them, no drug can help, unless the immune system is first re-set. (pass the prednisone or even some TSO; more on immunomodulation here)

 

 

Fibromyalgia, Autism and President Putin

 

I introduced Fibromyalgia in my last post; it is an neurological condition that can cause some very strange symptoms, in addition to pain and fatigue.  I imagine that there are various different underlying causes and so, like autism, it is really a family of disorders with overlapping symptoms.

Surprisingly, at least one type of Fibromyalgia would appear to have similar causes to classic autism, but its onset is after the brain has fully developed.  As with autism, the approved medical treatments are all for the symptoms, rather than the underlying condition.  The underlying condition seems to be a neuro-endocrine inflammatory disorder, sometimes with channelopathies.

One very interesting finding is that exercise consistently helps with the symptoms of Fibromyalgia.  I was reading a paper just last week that showed that exercise (jogging) reduced autistic behaviors.  It has already been well established that exercise is almost as effective as drugs at treating people with depression.

Here are some links:-

Can exercise improve behavior? Help encouraging a child who has autism

Exercise in fibromyalgia and related inflammatory disorders: Known effects and unknown chances.

 

Exercise may be Just as Effective as Medication for Treating Major Depression

So what is the wonderful power behind jogging or swimming, you might be wondering?  Exercise and even passively experiencing a roller-coaster, or motor bike ride, releases certain hormones in your brain, which causes a cascade of changes to many other hormones and neurotransmitters.  Depression, fibromyalgia and indeed autism all include some central hormone dysfunction; shaking up the homeostasis by exercise seems to do good.

I did look, a long time ago, for studies that showed precisely which hormones are affected.  The problem is that hormone levels in the blood do not tell you the hormone levels in the brain; if they did, then there would be a lot of demand for neuro-endocrinologists.    The problem is the blood brain barrier  (BBB).

You can of course measure hormone levels in the spinal fluid, but I do not suppose many people would volunteer for such clinical trials.  As a result, any intervention in brain hormone levels is likely to be a hit and miss affair.  People have tried to do it, but unless you can measure the result scientifically, it will remain voodoo science.

Some expert autism physicians continue to maintain classic autism is not treatable; that would suggest to me, they have never tried.  You can very easily change brain homeostasis, but it might be for better or might be for worse - but you can certainly change it.  Even if you make it worse, you know that you have been able to change it; then it is just a matter of rethinking and trying again.  As a patient, you naturally expect the specialist to get it right with 90+% certainty.  Without being able to measure hormone levels in the brain, it is rather like target shooting, while wearing a blindfold.  Maybe there are some safe interventions that will work in everyone.  I prefer to limit this blog to things I can prove scientifically, so I will keep the rest for my polypill.

For the risk averse amongst you, I suggest you rely on exercise.  Unless you are completely unfit, it seems that exercise can only do good.  You will never know which hormone levels changed, or what neurotransmitter did what, but then you do not need to know.

President Putin

Monty, aged 10 with ASD, has an elder brother Ted, aged 13.  Ted loves history and is also learning Russian; he very much wants to go to visit Moscow and also Putin’s home town of St Petersburg.  Given the choice, he would undoubtedly go to Izhevsk , a city in the western Urals, home of the Kalashnikov factory and museum.

Ted was very impressed to hear Putin telling journalists in Sochi that he swims 1,000 metres every day.  Even the journalists were surprised, “every day?”; “yes, every day”.

So I told Ted, who does have some of the stranger symptoms of fibromyalgia, that I listed in my previous post, if Putin can swim 1,000 metres, then you can swim 500 metres every day.

Today was the first day of the new regime.


 

Fibromyalgia and, perhaps, What Happened to the Missing Females with Autism

This post is about a condition about Fibromyalgia, a condition that affects 2-4% of the population. It affects women eight times more often than men, but it does, bizarrely, appear to be related to autism and is seen by some as a comorbidity.  I would go further and suggest that perhaps I have stumbled upon the missing females with autism. 

When you look at all the proposed drugs and supplements, there is a 90% overlap between the two conditions, even things like low dose naltrexone and flavonoids, like quercetin, crop up.

As we have seen earlier in this blog, autism is a disease related to the auto-immune system and inflammatory pathways.  There are many other diseases with similar origins, one example being arthritis.  Fibromyalgia tends to get lumped together with arthritis.  Families with autism present tend to have higher levels of arthritis and there are even some overlapping therapies, such as vagus nerve stimulation.

Fibromyalgia caught my attention, because it seems to be uncannily closely related to autism, but there are some distinct differences.  Classic “full-on” fibromyalgia is a disease about pain, whereas in autism people tend to have a high pain threshold.  Nonetheless, if you Google “Fibromyalgia with Autism” you will find no shortage of people suffering from both and pondering a connection.

Comorbidities are interesting, because they can indicate possible new therapies.  The people researching fibromyalgia are not generally the same people as the autism researchers.  The underlying pathologies though are very likely overlapping, even though neither is fully understood.

Fibromyalgia is neither degenerative nor curable, but it is treatable.

Here is a link to an article by a US doctor who came to the same conclusion.  (The article itself is not great)

Symptoms of Fibromyalgia

We can split these into two categories, pain-related and pain-unrelated.  In the case of autism we should look at pain-unrelated, but in the case of relatives we should look at both.  You will probably be able to diagnose a non-autistic family member with symptoms of this syndrome.

 
Pain-related:-

·        Widespread muscle pain and joint pain, the effects of these symptoms varies from person to person and from day to day.  Many people have flare-ups.  There are specific pain areas, and these are shown below:

 

·        Long-term studies suggest that it is not progressive, it does not cause permanent damage to your muscles, bones, joints or organs.

 

Pain-unrelated:-

This is a long list and typically only some will apply to any one person:-

·        Cognitive dysfunction, such as:

o   Difficulty following directions when driving

o   Losing your train of thought in the middle of a sentence

o   Difficulty paying attention

o   Memory problems

o   Difficulty expressing ideas in words

·        Depression, anxiety, irritability,  overreaction, anger outbursts, unpredictable mood swings, phobias and personality changes

·        Difficulty swallowing

·        Headaches

·        Restless leg syndrome

·        Sensitivity to the cold, and/or having cold hands and feet

·        Palpitations

·        Chest pain and costochondritis    

·        Sensitivity to light and noise intolerance.

·        Clumsy walking, dropping things

·        Hair loss

Fibromyalgia vs autism

There are some other similarities/differences with autism.

·        It often takes years to get a diagnosis and some doctors do not believe the condition exists

·        There is a specialist doctor that should know about it – the Rheumatologist, although Neurologists sometimes get involved

·        It is not curable, but it is treatable

·        It is usually diagnosed on very subjective measures

·        A blood test does now exist in the US  - the FM/a test  

The firm with the blood test is called, interestingly, “Epigenetics”.  If you make a blood test for Fibromyalgia, there is a good chance that the same researchers could develop one for autism.  They are measuring the level of pro-inflammatory cytokines.

The test is expensive, about $750.  Who knows how accurate the result is; they claim 99%.

In the UK, the National Health Service maintains that no test for Fibromyalgia exists.

A Neuro-immuno-endocrine disorder

Evidence exists that fibromyalgia is a neuro-immuno-endocrine disorder. Elevations in substance P, IL-6 and IL-8 as well as corticotropin-releasing hormone have been found in the cerebral spinal fluid of fibromyalgia suffering individuals. Increased numbers of mast cell numbers have been found in skin biopsies of some individuals with fibromyalgia.

Theoharides, who I have quoted extensively in early post on mast cells and autism, appears here too:- 

Fibromyalgia--new concepts of pathogenesis and treatment.

Lucas HJ, Brauch CM, Settas L, Theoharides TC.

Abstract

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.

Treatment

Classic treatment involves tricyclic antidepressants, which are actually very closely related to the early antihistamine drugs. 

Even though low brain serotonin is a feature of the disease, counter-intuitively, it has been found that serotonin-3 receptor antagonists are effective; this is the opposite of what was expected.  Tropisetron is a favoured antagonist, but there are several others.  Tropisetron is also a α₇-nicotinic receptor agonist, which you may recall, I highlighted as interesting in posts on the cholinergic system and autism.

Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain.

This blog is about autism, so let us go back to a previous paper I looked at.

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

 

In that paper tropisetron is put forward as a potential autism treatment.

 

10.1.2 ᾳ7 nAChRs

It is possible to use ᾳ7 nAChR agonists to treat neuroinflammation in ASD. There is strong evidence that activation of the ᾳ7 nAChR expressed on monocytes and macrophage, by inhibiting NF-kappaB nuclear translocation, suppresses cytokine release by them, and that this cholinergic anti-inflammatory pathway that provides a bidirectional link between the nervous and immune system, inhibits the innate immune response. Hence, a reasonable case can be made for the use of ᾳ7 nAChR agonists to treat neuroinflammation in ASD.

A second candidate drug, Tropisetron is a partial agonist of the ᾳ7 nAChR. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. In a clinical trial with 33 schizophrenic patients administration of tropisetron, without placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. In mice, the early postnatal period represents a critical time window essential for brain development. The administration of tropisetron from postnatal days 2-12

(P2-P12) in mice did not induce significant cognitive, schizophrenia-like or emotional alterations in tropisetron-treated animals as compared to controls, when tested in multiple behavioral assays.

 

It is the non-conventional treatments that overlap with autism, things like GH, IGF-1 and low dose naltrexone etc.  The interesting therapies relate to treating the non-pain symptoms. There are many such therapies and some have been used for decades, one or two may be interesting for autism; they may indeed be more effective in autism that in fibromyalgia.  There is even an overlap with therapies I am already investigating.

 

 

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.

Melatonin for Sleep in Childrenwith Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

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. 

Abnormal Melatonin Synthesis in ASD

"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

 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.

Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. 

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

Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.

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. 

A review of the multiple actions of melatonin on 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.

Amyloids, APP, ADAM17 and Autism

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.