Monday, 30 September 2013

Biomarkers in Autism: Mercury – Science, Bad Science & GSH (again)

You do not need to have any particular view about vaccines and autism; but there are some very strange connections between mercury and autism.

I came back to look at this subject, having noticed that one of the more rational/objective researchers included a chelating agent in his patent for autism treatment.   Chelating agents remove heavy metals like mercury or lead from the body, but they also remove important elements like calcium.  Very high or low levels of electrolytes like Ca or K can kill you.

In 2006 clinical trials on chelation therapy in autism were halted by the US National Institute of Health on “safety reasons”.  But in 2012, a much bigger 5 year long, $30 million study called Trial to Assess ChelationTherapy (TACT) in coronary heart disease reported back that this “fringe” therapy did indeed work, though for reasons unknown.

The autism trial was to use a chemical called DMSA,  while the coronary heart disease trial used a chemical called EDTA.  The 5 year trial appeared to show EDTA was safe.

Measuring Mercury

There are various ways of measuring for mercury; you can measure for it directly in urine, blood, hair and even teeth.  You can also measure for biomarkers of mercury and the popular one is called Porphyrin Testing.

The problem is that if you have been subject of some serious heavy metal contamination the metal may no longer be in your blood or urine in elevated levels.  This is why forensic science laboratories look at hair and teeth.

At this point the bad science and the science start to get mixed up.  There is a chemical called precoproporphyrin, an atypical porphyrin previously identified only in adult humans and animals with prolonged exposure to Mercury or compounds containing mercury.  It is often present in substantial concentrations in urine of younger children with autism.

This has created a nice business with laboratories charging $120 to measure porphyrin in the urine of autistic children.  A handful of researchers keep writing studies about mercury in autism, using porphyrin to “measure” them.

One of the labs used is surprisingly in France.  It seems many US citizens are mailing samples to Laboratoire Philippe Auguste in Paris.

But, at the same time, another group of scientists take the opposite approach and say that urinary porphyrins are biomarkers of autistic spectrum disorder, because a subset of people with ASD have disordered porphyrin excretion as a metabolic characteristic.  They have gone so far as to patent their idea as a test for autism.  By this logic paying $120 to test a kid known to have ASD would be pretty pointless.

The researcher suggests that the elevated Urinary porphyrins have nothing to do with mercury at all.

… Several possibilities might account for these differences. Not to be bound by theory, Hg exposure appears unlikely to play a role in this effect, because no significant differences were observed between NT and AUT subjects for indices of past exposure to Hg from dental or medical sources, as reported by parents/caregivers. Additionally, urinary Hg concentrations, measures of recent Hg exposure, were very low among all subjects in this study (Table 2), and no significant differences between diagnostic groups were observed …

… the present findings indicate that porphyrin metabolism, particularly in preadolescent children, may be too disordered or differently regulated to permit detection of the Hg-mediated changes in urinary porphyrin excretion that are apparent in adult subjects …

… another factor that may account for the differences in urinary porphyrin levels between AUT and NT children is mitochondrial dysfunction, a disorder commonly associated with autism …

Where is the Mercury coming from?

The sources put forward as to where the mercury is coming from include:-

·        Mother’s dental fillings containing mercury

·        Any amalgam fillings the child has

·        Mercury in the environment

·        Mercury in vaccines

If your body is unable remove mercury as fast as it is absorbing it, then the total amount of mercury in your body will increase.  So it is your cumulative past exposure, minus what you have removed, that is the key figure.

The body’s main antioxidant, glutathione (GSH), is its key resource to deal with disposing of heavy metals.  It has been established for years that GSH levels are reduced in almost all cases of autism.  Incidentally, GSH levels are also reduced in old age and so those subjects in the TACT clinical trial for chelation in heart disease that benefited, did do (according to Peter) because the chelator is an antioxidant.  It lowered their oxidative stress and raised their GSH level.

Mercury in Hair Samples

An interesting study measured the level of mercury in babies’ first haircuts.  This is about when the baby is 17 months old.

The study showed much lower levels of mercury in the ASD babies than in the control babies.  This is probably the opposite of what you might have expected.  There is also a nice chart correlating the level of mercury in the control babies with the number of amalgam fillings in the mother.

The authors proposed that the kids with ASD must have higher levels of mercury in their bodies, because they are unable to eliminate mercury like typical children.

“If reduced overall mercury elimination is related to hair elimination, then autistic infants will retain significantly higher levels of mercury in tissue, including the brain, than normal infants.”

A later study has some equally surprising findings.  The study in Poland, looked at kids aged 3-4 and also 7-9.  They found, as in the baby study, that the youngest kids had lower levels of mercury in their hair than the typical kids.  But the older kids had higher mercury levels in their hair than the kids in the control group. 

The conclusion was that:-
The results suggest that autistic children differ from healthy children in metabolism of mercury, which seems to change with age.

Mercury in baby teeth

 So now we come to teeth.  If the ASD kids have low mercury, it will be claimed that this means they must have high internal levels since they have not eliminated it in their teeth.  If they have high mercury then they will say that this proves there is a high level of mercury in kids with ASD.  Read on and find out.

Well the study tells us that baby teeth are a good measure of cumulative exposure to toxic metals during fetal development and early infancy.  They found that 6 year old children with autism had twice as much mercury in their teeth as neurotypical children.

This study determined the level of mercury, lead, and zinc in baby teeth of children with autism spectrum disorder (n = 15, age 6.1 +/- 2.2 yr) and typically developing children (n = 11, age = 7 +/- 1.7 yr). Children with autism had significantly (2.1-fold) higher levels of mercury but similar levels of lead and similar levels of zinc. Children with autism also had significantly higher usage of oral antibiotics during their first 12 mo of life, and possibly higher usage of oral antibiotics during their first 36 mo of life. Baby teeth are a good measure of cumulative exposure to toxic metals during fetal development and early infancy, so this study suggests that children with autism had a higher body burden of mercury during fetal/infant development. Antibiotic use is known to almost completely inhibit excretion of mercury in rats due to alteration of gut flora. Thus, higher use of oral antibiotics in the children with autism may have reduced their ability to excrete mercury, and hence may partially explain the higher level in baby teeth. Higher usage of oral antibiotics in infancy may also partially explain the high incidence of chronic gastrointestinal problems in individuals with autism.

How much Mercury is bad for you?

Mercury is definitely not good for you, but just how much is actually bad for you?

Eating a lot of fish will raise maternal levels of mercury, so in the US women are advised to eat less fish during pregnancy.

In the Seychelles (islands in the Indian Ocean) the diet included 10 times as much fish and since they eat big fish, mercury consumption is 20 times higher.  The level of vaccination was near 100% and the vaccines contained thimerosal.

Using linear and nonlinear regression analyses, the researchers found no consistent correlation between prenatal exposure to methyl mercury and scores on ASD screening instruments.

Parent feedback

If you look on the web, it is pretty clear that many parents think their chelation therapy had a positive impact.  There is even a very unscientific survey showing this somewhere; I cannot find it today.

Since the chelation is like a big anti-oxidant infusion, I would expect to see a big positive improvement, regardless of whether mercury has anything at all to do with it.

Big Sceptics

There are some big sceptics about chelation.  Here is one site called chelation watch
and here is an interesting article by a Doctor who followed ”his dark side” into the world of alternative therapy and emerged a big sceptic.

James R. Laidler, MD    -  My Involvement with Autism Quackery

My personal journey through the looking glass has ended. I stepped into “alternative” medicine up to my neck and waded out again, poorer but wiser. I now realize that the thing the “alternative” practitioners are really selling is hope—usually false hope—and hope is a very seductive thing to those who have lost it.

Other research

There is plenty of other research on the subject of my post.  Normally you can tell by who funded the study or who worked on it, what the likely conclusion is to be.

This paper again shows that urinary porphyrins are a biomarker for autism, rather than mercury.

This paper repeats the story about urinary porphyrins indicating high mercury in autism  


If the US National Institute of Health removed its ban on the clinical trial of chelation in autism, then there would be some high quality facts to judge.  Sadly, this all seems to be linked to “big brother” trying to halt the debate about autism and vaccinations, all for the very sound reason of public health.

I think it is quite possible that the culprit is oxidative stress and low GSH and that the bizarre results of mercury levels in hair, teeth and urine are in fact no more than a consequence of low levels of GSH.  The oxidative stress is clearly damaging, perhaps the slightly elevated levels of heavy metals are themselves harmless.

Perhaps the best thing would be to measure the level of GSH (GSH redox) in babies, children and then again after middle age.  High levels of oxidative stress, whether linked to autism or other conditions could then be treated.

There is a cheap and effective antioxidant called NAC (N-acetyl cysteine), it is known to raise GSH.  If you want to call it a chelating agent, you would also be correct.

Since mercury is known to be a very harmful substance, we should of course try to minimize it in humans.

Sunday, 29 September 2013

Autism in Iran: Piracetam, Periactin & Pentoxifylline

This may sound like a very odd subject for my blog.
In 2002 US President George Bush first used the term “Axis of Evil” to refer collectively to Ian, Iraq and North Korea.  Later that year the then-Undersecretary of State John Bolton gave a speech entitled "Beyond the Axis of Evil"; in it he added three more nations to be grouped together: Cuba, Libya and Syria. Finally, in 2005 Bush’s Secretary of State came up with “Outposts of tyranny” to refer to Cuba, Belarus, Burma and Zimbabwe.

Many readers of my blog are from the US and may think that not much good can be going on in Iran.  The reality is quite the reverse, at least in the field of autism.

In spite being under all kinds of economic sanctions, Iran has generated a substantial body of insightful research.  There are 75 million Iranians which is just under the population of Germany.  I do not recall seeing much German research into autism. 

One particular researcher, Shahin Akhondzadeh, has done several very interesting studies. His CV lists 128 research papers, including autism, ADHD, schizophrenia, Alzheimer’s and other conditions.  He also writes about herbal medicine for mental health, which I know is popular among readers of this blog, so I included links to some of those papers.

Piracetam, Periactin/ Cyproheptadine & Pentoxifylline

Akhondzadeh is unusual in that he actual makes repeated clinical trials of existing drugs that the science shows could be effective.  In the case of autism he trialled three interesting drugs (with similar names):-

·        Piracetam

·        Periactin/Cyproheptadine

·        Pentoxifylline

Unfortunately his three trials combined them with an anti-psychotic.  But I think it is still interesting to look at the net impact of each of the three drugs.  I did just that.

You have to look at the data and compare the impact after 8 weeks to be consistent and you have to adjust for the fact that in the Periactin/Cyproheptadine trial at week 0 the placebo group was out of line with the trial group.
Net improvements:-
Piracetam                                        7 points on ABC

Periactin/Cyproheptadine           7 points on ABC

Pentoxifylline                                 3 points on ABC

This tells us that Piracetam and Periactin had the greater incremental impact over the antipsychotic and that the change was 7 points on the aberrant behaviour checklist (ABC).  The ABC is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54. It is a 58 item checklist. There are five subscales: a) Irritability and Agitation b) Lethargy and Social Withdrawal c) Stereotypic Behavior d) Hyperactivity and Noncompliance and e) Inappropriate Speech.




I have written about this drug in my recent post on Serotonin.  Periactin is an old first generation H1 antihistamine that happens to have additional anticholinergic, antiserotonergic properties.  It is the effect on serotonin that appears to reduce aberrant behaviours in autism

Periactin is available OTC in the UK.  In the US it is sometimes prescribed to increase appetite.
The link to Akhondzadeh’s full study is later in the post.



Piracetam was first synthesized in 1964 by scientists at the Belgian pharmaceutical company UCB; struck by its apparent ability to boost mental functioning in even healthy individuals and by its safety, they coined the term nootropic to describe it and other substances. Piracetam (trade name "Nootropil") was launched clinically by UCB in the early 1970s, and currently is in use in many European countries.

Piracetam is a cyclic derivative of the neurotransmitter GABA.

Akhondzadeh writes:-

In addition to serotonergic abnormalities, the strongest evidence implicates the glutamatergic and GABAergic systems are important biochemical factors in autism. One current hypothesis is that autism is a hypoglutamatergic disorder. This hypothesis is based on neuroanatomical and neuroimaging studies and supported by similarities between symptoms produced by N-methyl-D-aspartate (NMDA) antagonists in healthy subjects and those seen in autism. If there is deficient glutamatergic transmission in autism, the most logical treatment would of course be a glutamatergic agent. In the treatment of schizophrenia, that has many similarities with autism either D-cycloserine (glycine agonist) or Piracetam showed promising results. Indeed, autism and schizophrenia have some similarities regarding the role of serotonin and glutamate in their pathophysiology.

Piracetam is a member of the nootropic class of drugs, which have cognition enhancing effects, it appears to modulate AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acids)-sensitive glutamate receptors positively and has been used in many countries in the management of dementia. Although its mode of action is not certain, it is said to protect the cerebral cortex against hypoxia and has been used following trauma or surgery and in a variety disorders including senile dementia and behavioral disorders in children. In addition, it is used in the treatment of dyslexia and some type of myoclonus in adults. Indeed. Piracetam is the most studied nootropic in children.

Piracetam was freely available in the US as a supplement until three years ago.  You will see on the web that people were using it, combined with another supplement called choline, to improve their mental functioning.  It had been shown to work in rats, as you can see in this trial.
In the Ukraine it seems that Piracetam has long been given as a therapy in autism.  No mention of choline.

The full study is listed later in this post.


Pentoxifylline is a drug that targets the immune system, well established to play a key role in autism.  It is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF  and leukotriene  synthesis, and reduces inflammation and innate immunity.

So it would be fair to classify it as an immunological treatment for autism.

It is hard to find much about Pentoxifylline and autism.  It was trialled in the 1970s in Japan.

Japanese Journal of Child Psychiatry, Vol 19(3), 1978, 137-144

Describes the successful use of Pentoxifylline (150–600 mg/day) with 3–15 yr old children with abnormal behaviour (e.g., self-mutilation, aggressiveness, and hyperkinesis) and with autism. It is noted that while the drug was effective in reducing symptoms of autism, developmental factors in the disorder should not be ignored. (English abstract)

Unfortunately I gave not found the full text version of Akhondzadeh’s study on this drug.

Autism in Iran

A paper actually entitled “Autism in Iran”, makes very interesting reading and was co-authored by  Akhondzadeh.


Links to my selection of Akhondzadeh’s Research


Herbal medicine and women's mental health


Autism spectrumdisorders: etiology and pharmacotherapy

Herbal Medicine in the Treatment of Alzheimer’sdisease

Cyproheptadine in the treatment of autism 

Authors: GUDARZI S., YASAMYM. and AKHONDZADEH S Eur. Psychiatry, Vol.17, Year. 2002, Page: 230-231,    NO ABSTRACT

A Double-blind Placebo Controlled Trial of Piracetam


All three drugs would seem worthy of further investigation, but particularly Piracetam and Periactin.  Both seem to be widely used with children and were/are OTC.


Thursday, 26 September 2013

Controlling Anger in Autism - Part 2

I wrote extensive earlier posts about using H1 anti-histamine drugs to control autism flare-ups.  Summertime allergies can result in anger, loss of control and ultimately, self-injury.

Although this blog is about pharmacological interventions that can help in autism, I am firmly in the ABA behavioural intervention camp.  The drugs can indeed help, but are always going to be secondary to a very labour intensive intervention.

Anger in autism

Depending on how lucky you are, parents experience widely differing levels of anger from kids with ASD.  For those who have not experienced the extremes, here is my summary:-

Level 1           Bad temper

Level 2           Tantrum with screaming, maybe rolling around on the floor but no  violence

Level 3           Self-injury, like hitting head with fist, but no external “objects”

Level 4           Violent self-injury like banging head into a wall

Level 5           Violence towards care givers (punching, kicking, biting etc.)

There seems to be little correlation between anger and intellect.  Some highly verbal kids with ASD exhibit self-injurious behaviours.


This post is about alternatives to antipsychotic drugs such as risperidone and haloperidol, which I personally do not believe should be given to children.

ABA (Applied Behavioural Analysis)

The underlying principle of ABA is to reward good behaviours and, in effect, ignore the bad behaviours.  You are taught to understand behaviours with the “ABC” of antecedent, behaviour and then consequence.

If you take your 4 year old to the Mall and he rolls around screaming on the floor, the typical embarrassed parent would make a swift exit to the car and back home.  So the kid has won and gets to avoid a boring visit to the Mall.  The same behaviour will repeat the following weekend.  Kids quickly learn which adults this behaviour works with and who the hard cases are.  Consistency among the adults is a key part of successful ABA. 

When children are still very small, a violent tantrum can be extinguished by the care giver physically restraining the child.  In some countries, in special schools this is still being done with quite big kids.   Monty’s former therapist, Dule, used to work in the local special school and as one of the few male staff members was regularly the one called upon to do the “restraining”. 

Generally, ABA is more useful for understanding the reason for tantrums and violence, so that it can be avoided in future.  The child can be redirected towards some other activity and thus calm is restored.

Alternative Strategies

Faced with a child who has lost control and the tantrum has become self-reinforcing, you are faced with the choice of letting it runs its course, or doing something about it.  This does rather depend on how big the child is, how big you are and where you are at the time.

My son Monty is only 10 years old and so my policy of zero tolerance to violence is still easy to enforce.  It is clear that once bad behaviours (violence) are learned (or self-taught) they can only very gradually fade away and be forgotten.  If violence is allowed to persist, the child will turn to it more readily and as he grows up, big problems will surely lie ahead.

Hit the reset button

I learned a long time ago that if you do something totally unexpected to a child (with or without ASD) it is like pressing the “reset button”.  It clearly depends how old the child is, but what still works for me is picking up my son and holding him upside down, or when he was very small, getting down on all fours and get right in front of him and bark like a dog.  It may sound crazy, it is crazy, but it works.

Chewing Gum

I noticed a long time ago that giving Monty a toy pipe to play with, intended for blowing bubbles, had a strange calming influence.  When I look at people smoking, I think that many of them have no need to inhale at all.  The mere ritual of lighting up, puffing and stubbing might be enough.

Then a few weeks ago Ted, Monty’s older brother, told me that a friend of his had told him something very funny.  She told him that she always has to be chewing something or have something in her mouth, otherwise she gets very stressed.  This fitted with what her Mother had being telling us adults; she declared that she (the Mother) is like Monk in the crime series on TV, where the character Monk has obsessive behaviour and many traits of Asperger’s.  Not surprising, the mother is a smoker, as will be the daughter in due course.

This brings me to our latest experiment, chewing gum.  Not as a reward, but as a therapy.

You may have seen from earlier posts that summertime allergies affect Monty’s behaviour.  With plenty of antihistamine we have the allergy under control, but the associated behaviours are not fully controlled.  It is much better than at the start of the pollen season, but not perfect.  I still do not have the optimal H1 antihistamines.

We just had a visit from our American ABA consultant, who flew in to see us and fine tune Monty’s programme at school and then his home programme.  This spurred me to think further how to give Monty the ability to fully control his behaviour by himself.  He is now able to tell us when he is about to “lose it”, so we have the three minute warning.  We need to give him the ability to himself subdue whatever is going on inside his head.

With an active and stimulating day at school, the problem now only arises at home, and hopefully ,with no pollen in a couple of months, the problem will disappear until next June.  But for now, the new secret weapon is “unlimited” chewing gum.  I say “unlimited” because it is not supposed to be a reinforcer (reward), if it was, the result would likely be the opposite of what I want.  The “calm down son here’s a gummy bear” method would be a disaster  and just prompt future tantrums to “earn” gummy bears.

Calming a tantrum

Giving gum to calm a self-injurious tantrum seems to work .  No restraint is required, just “here’s your gum”.  One minute later all is calm and Monty is joking, “Monty was hitting his head”.

Avoiding/anticipating a tantrum
The warning signs Monty gives are all verbal; “I want to be nice”; “I want to be happy”; “to hit your head”.  I just need to promptly offer the chewing gum.  Monty starts chewing and indeed calm is gradually restored.

I have since learned that Michael Jordan started a huge trend for basketball players to chew gum, it supposedly helps them be calm and concentrate.  There are actually studies showing health benefits of chewing gum, and not just for your teeth.

Here are some chewing gum facts.


I was already a regular buyer of gummy bears, now I am loading up with kid’s chewing gum as well.  If it works, I am happy to continue doing so.  The only side effects are clean teeth and sticky fingers.