Modified Use of Anti-Epileptic Drugs (AEDs) at Low Doses in Autism

As readers will be aware, many people with more severe autism are also affected by epilepsy.  Siblings of those with autism also seem to be at greater risk of epilepsy.

There are frequent comments that once starting on AEDs (Anti-Epileptic Drugs) aspects of autism also seem to improve.  This should not be surprising given the suggested action of these drugs and the overlapping causes of epilepsy and autism.

Today’s post is prompted by the observation that in very low, apparently sub-therapeutic, doses some AEDs seem to improve autism in some cases.  This is relevant because the usual high doses of these drugs are associated with some side effects and indeed a small number can be habit forming.

What is epilepsy?

The cause of most cases of epilepsy is unknown.

Genetics is believed to be involved in the majority of cases, either directly or indirectly. Some epilepsies are due to a single gene defect (1–2%); most are due to the interaction of multiple genes and environmental factors.  Each of the single gene defects is rare, with more than 200 in all described.  Most genes involved affect ion channels, either directly or indirectly. These include genes for ion channels themselves, enzymes, GABA, and G protein-coupled receptors.

Much of the above applies equally to autism, including the genetic dysfunctions associated with GABA.  The ion channel dysfunctions in epilepsy are thought to be mainly sodium channels, like Nav1.1.  We previously came across this channel when looking at Dravet Syndrome.

Dravet Syndrome

Dravet Syndrome is rare form of epilepsy, but is highly comorbid with autism.  It is cause by dysfunctions of the SCN1A gene, which encodes the sodium ion channel Nav1.1.  There is a mouse model of this condition, used in autism research.  Dravet Syndrome is known to cause a down-regulation of GABA (the neurotransmitter) signaling.  We saw how tiny doses of Clonazepam corrected this dysfunction in mice.

Known ASD-associated mutations occur in the genes CACNA1C, CACNA1F, CACNA1G, and CACNA1H, which encode the L-type calcium channels Cav1.2 and Cav1.4 and the T-type calcium channels Cav3.1 and Cav3.2, respectively; the sodium channel genes SCN1A and SCN2A, which encode the channels Nav1.1 and Nav1.2, respectively; and the potassium channel genes KCNMA1 and KCNJ10, which encode the channels BKCa and Kir4.1, respectively.

Channelopathies in Autism - Treating Nav1.1 with Clonazepam

Dr Catterall, the researcher, then went on to test low dose clonazepam in a different mouse of autism model and found it equally effective.  It also appears to work in some human forms of autism.

Sodium Valproate

Valproate is a long established epilepsy drug that has also been used widely as a mood stabilizer and particularly to treat Bipolar Disorder.

One side effect can be hair loss.  Hair loss/growth and also hair greying are frequently connected with drugs and genes linked to autism (BCL-2, biotin, TRH etc).

One regular reader of this blog has pointed out that a tiny dose of Valproate, when combined with Bumetanide, appeared to have a significant and positive effect.  We know that bumetanide works via NKCC1 and the GABA_A receptor to make GABA more inhibitory.

Many modes of action are proposed for Valproate, but the most mentioned one is that it increases GABA “turnover”; so it would make sense that having shifted the balance from excitatory to inhibitory, a stimulation to increase GABA signaling might be beneficial.

What is odd is that this is happening at a dose 20 times less than used in epilepsy, bipolar or mood disorders.

The use of Clonazepam, discovered by Dr Catterall, is also at a dose 20 to 50 times less than the typical dose.

Clonazepam and Valproate are both AEDs.  There are not so many of these drugs and while using them at high doses, without dire need, might be highly questionable, their potential effectiveness at tiny doses is very interesting.

Clonazepam is a Benzodiazepine in the table below.

The above table is from the following paper:-

 Mechanisms of action of antiepileptic drugs

Low Dose Clonazepam

Low dose Clonazepam was shown to be effective by its action of modulating the GABA_A receptor to make it more inhibitory.  There are different types of GABA_A receptor and the low dose effect was sub-unit specific.  Other benzodiazepine drugs were found to have the opposite effect.

The mouse research showed that the effect only appeared with a narrow range of low dosages.

Low Dose Valproate

Valproate is known to affect sodium channels like Nav1.1, but also some calcium channels.

For an insight into some known potential effects of Valproate, here is a paper from the US National Institute of Mental Health:-

Therapeutic Potential of MoodStabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

In the paper it highlights the less well known effects of Valproate:-

inhibits HDACs

Modulates Neurotrophic and Angiogenic Factors (BDNF, GDNF, VEGF)

PI3K/Akt Pathway

Wnt/β-Catenin Pathway

MEK/ERK Pathway

Oxidative Stress Pathways

Enhanced Neuroprotection

Enhancing the Homing and Migratory Capacity of Stem Cells

Here is a list of the suggested new applications of Valproate, many highly appropriate to many types of autism:-

       Repurposing Mood Stabilizers for CNS Disorders Beyond BD

       A. Stroke

       1. Lithium-Induced Effects in Experimental Stroke Models

       a. Neuroprotection and behavioral improvement

       b. Anti-excitotoxic and anti-apoptotic effects

       c. Anti-inflammation

       d. Angiogenesis

       e. Neurogenesis

       f. Effects on MSC migration after transplantation

       2. VPA-Induced Effects in Experimental Stroke Models

       a. Neuroprotective effects and behavioral benefits

       b. Anti-inflammation

       c. BBB protection

       d. Angiogenesis

       e. Neurogenesis

       B. TBI

       1. Lithium-Induced Effects on Neurodegeneration, Neuroinflammation, Behavioral Improvement, and Aβ Accumulation in Models of TBI

       2. VPA-Induced Effects on Neurodegeneration, Neuroinflammation, and Functional Recovery in Models of TBI

       3. Clinical Trials of VPA Treatment in TBI

Having read that paper I am now not surprised that a tiny dose of valproate can have a positive behavioral effect in autism.  What would be interesting to know is how the effects and dominant modes of action vary with dosage.  I presume the dosage has been optimized to control/prevent seizures.

Valproate is a cheap drug and is available as a liquid, so accurate low dosing is possible.  It has been shown to be neuro-protective, even shown promise as a treatment for traumatic brain injury.

While not written about autism, some of you may find the following collection of research interesting:-

Brain Protection in Schizophrenia, Mood and Cognitive Disorders

It does talk about the wider potential use of Valproate, but not at tiny doses.

Stiripentol

Interestingly, an orphan drug was developed in the European Union to treat Dravet Syndrome.  It is included on the list of AEDs above.

Even though that drug, Stiripentol, is not approved by the FDA, most sufferers in the US are able to acquire it under the FDA’s Personal Importation Policy(PIP).

So it is indeed possible to acquire drugs prior to approval in your home country.

Hopefully, once Bumetanide is approved for autism in Europe, similarly people will be able to access it easily in the US.

I wonder if anybody with Dravet Syndrome has tried low dose Clonazepam.  In theory it should be helpful.

Cytokines from the Eruption of Permanent Teeth causing Flare-ups in Autism

A recent post looked again at inflammation in autism and some possible therapies to try.  Over Christmas and New Year, Monty, aged 11 with ASD, had occasional outbursts, more typical of his summertime raging, which was later solved using allergy /mast cell therapies.

At least it did let me establish whether Verapamil was a universal “cure” for SIB.  It is not.  It works great for allergy-driven aggressive behaviors, but had no effect on these ones.

Christmas is often a stressful period for many people with, or without, autism; but Monty likes presents and he loves food.

Having pulled out a wobbly tooth on Boxing Day and noticed an apparent behavior change, I thought that perhaps the loss of milk teeth and development of permanent teeth might cause an effect similar to that of his mild pollen allergy.  Monty, in common with many people with autism, has a high pain threshold.  While teething causes well known problems in babies, most children have minimal problems when their milk teeth are replaced by their permanent ones.

I just wondered if perhaps the underlying biological mechanism might provide an inflammatory insult to the highly inflammation-sensitive autistic brain.

Just as histamine provokes a release of inflammatory cytokines like IL-6, perhaps losing your milk teeth does something similar.

Ibuprofen experiment

I decided that I would buy some Ibuprofen, the least problematic NSAID.   A day or two later, Monty declared that another tooth was wobbly and needed to be pulled out.  This tooth was, and remains, well and truly attached.

So I decided that in advance of another, potentially stressful, Christmas event, I would give 10 ml of Ibuprofen.  I did not give it in response to any comment about pain.

It did indeed seem to work.

Skiing

A few days later we were in the Alps for skiing.

Monty can ski, but we always give him a 1:1 instructor.  On the first day, without Ibuprofen, he got agitated during the queuing at the bottom of the beginners’ ski lift.  The instructor thought it was the loud booming music.  It was clear that by the end of the lesson, it was no fun at all.

The following days, I gave 10 ml of Ibuprofen, 20 minutes before the lesson started.  He had a great time, going up by cable car to the top of the mountain and skiing along the blue/red slopes and coming down in a neighboring resort a couple of hours later.  Even a change of instructor on one day, passed without issue.

It might not be scientific proof of the effectiveness of Ibuprofen, but it was enough for me.

The Science

Since this is a scientific blog, arriving home I did some checking on the biology of what happens when you lose your milk teeth.

There is more written about “teething” when you first get your milk teeth, but there is information about “root resorption” of milk teeth and “eruption” of the permanent teeth.  The process is indeed modulated by inflammatory cytokines and transcription factors.

These cytokines will then circulate around the body and cross the blood brain barrier.

Cytokine levels in gingival crevicular fluid of erupting primary teeth correlated with systemic disturbances accompanying teething.

Abstract

PURPOSE:

The aim of this study was to investigate whether there are increased levels of the inflammatory cytokines IL-1beta, IL-8, and TNF alpha in the gingival crevicular fluid (GCF) of erupting primary teeth. This increase could explain such clinical manifestations as fever, diarrhea, increased crying, and sleeping and eating disturbances that occur at this time.

METHODS:

Sixteen healthy children aged 5 to 14 months (mean=9.8 months) were examined twice a week over 5 months. Gingival crevicular fluid samples were taken from erupting teeth. As a control, GCF was collected from the same teeth 1 month later. Cytokine production was measured by ELISA. Signs and clinical symptoms were listed. Pearson correlation coefficients were used in the comparisons described below. A paired t test was used to analyze the same variable at different times.

RESULTS:

Fifty teeth of the 16 children were studied. GCF samples were collected from 21 of these teeth. Statistically significant differences (P<.05) were found with regard to the occurrence of fever, behavioral problems, and coughing during the teething period and the control period. During the control period, 72% of the children did not exhibit any clinical manifestations, whereas during the teething period only 22% of the children did not exhibit any clinical manifestations. The study revealed high levels of inflammatory cytokines during the teething period, with a statistically significant difference in TNF alpha levels (P<.05) between the teething period and the control period. Correlations were found between cytokine levels and some of the clinical symptoms of teething: IL-1beta and TNF alpha were correlated with fever and sleep disturbances; IL-beta and IL-8 were correlated with gastrointestinal disturbances; IL-1beta was correlated with appetite disturbances.

CONCLUSIONS:

Cytokines appear in the GCF of erupting primary teeth. The cytokine levels are correlated to some symptoms of teething.

Mechanism of Human Tooth Eruption: Review Article Including a New Theory for Future Studies on the Eruption Process

Physiologic root resorption in primary teeth: molecular and histological events

Root resorption is a physiologic event for the primary teeth. It is still unclear whether odontoclasts, the cells which resorb the dental hard tissue, are different from the osteoclasts, the cells that resorb bone. Root resorption seems to be initiated and regulated by the stellate reticulum and the dental follicle of the underlying permanent tooth via the secretion of stimulatory molecules, i.e. cytokines and transcription factors. The primary root resorption process is regulated in a manner similar to bone remodeling, involving the same receptor ligand system known as RANK/RANKL (receptor activator of nuclear factor-kappa B/ RANK Ligand). Primary teeth without a permanent successor eventually exfoliate as well, but our current understanding on the underlying mechanism is slim. The literature is also vague on how resorption of the pulp and periodontal ligament of the primary teeth occurs. Knowledge on the mechanisms involved in the physiologic root resorption process may enable us to delay or even inhibit exfoliation of primary teeth in those cases that the permanent successor teeth are not present and thus preservation of the primary teeth is desirable. (J. Oral Sci. 49, 1-12, 2007)

Nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, work by inhibiting the enzyme COX which converts arachidonic acid to prostaglandin H₂ (PGH₂). PGH₂, in turn, is converted by other enzymes to several other prostaglandins ,which are mediators of pain, inflammation, and fever.

Prostaglandin E synthase

Prostaglandin E₂ (PGE₂) is generated from the action of prostaglandin E synthases on prostaglandin H₂ (PGH₂).

PGE₂ has various known effects, but one known effect is to increase the pro-inflammatory cytokine IL-6.  The same one that is increased by histamine released from mast cells during allergic reactions.

Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.

Abstract

Injection of mineral oils such as pristane into the peritoneal cavities of BALB/c mice results in a chronic peritonitis associated with high tissue levels of interleukin 6 (IL-6). Here we show that increased prostaglandin E2 (PGE2) synthesis causes induction of IL-6 and that expression of an inducible cyclooxygenase, Cox-2, may mediate this process. Levels of both PGE2 and IL-6 are elevated in inflammatory exudates from pristane-treated mice compared with lavage samples from untreated mice. The Cox-2 gene is induced in the peritoneal macrophage fraction isolated from the mice. A cause and effect relationship between increased macrophage PGE2 and IL-6 production is shown in vitro. When peritoneal macrophages are activated with an inflammatory stimulus (polymerized albumin), the Cox-2 gene is induced and secretion of PGE2 and IL-6 increases, with elevated PGE2 appearing before IL-6. Cotreatment with 1 microM indomethacin inhibits PGE2 production by the cells and reduces the induction of IL-6 mRNA but has no effect on Cox-2 mRNA, consistent with the fact that the drug inhibits catalytic activity of the cyclooxygenase but does not affect expression of the gene. Addition of exogenous PGE2 to macrophages induces IL-6 protein and mRNA synthesis, indicating that the eicosanoid stimulates IL-6 production at the level of gene expression. PGE2-stimulated IL-6 production is unaffected by addition of indomethacin. Taken together with the earlier finding that indomethacin diminishes the elevation of IL-6 in pristane-treated mice, the results show that PGE2 can induce IL-6 production in vivo and implicate expression of the Cox-2 gene in the regulation of this cytokine

Indomethacin is another NSAID, like Ibuprofen.

Implications

If, as seems likely, many incidents of anxiety, aggression, explosive behavior, or "meltdowns" are made possible by elevated levels of the pro-inflammatory cytokine IL-6, then the occasional use of drugs known to inhibit IL-6 makes a lot of sense.

Ibuprofen is an NSAID and it is known that some people respond much better to certain NSAIDs and suffer side effects from others.   NSAID drugs work by affecting both COX-1 and COX-2.  It appears that desired effect of NSAIDs comes from their effect on COX-2, while the side effects come from changes made to COX-1.  So it is logical that some NSAIDs are better tolerated than others and for some people a different NSAID may be more appropriate.

Other common drugs also lower IL-6;  leukotriene receptor antagonists like Montelukast (Singulair)  being an example.  This drug is used in autism, but a known side-effect in typical people is to worsen behavior, sometimes severely.  There are plenty of reports of Singulair in autism, some good and some bad.  Since almost all drugs have multiple effects, this is not surprising.

Interestingly, one of the drugs in my Polypill, NAC, is also known to reduce IL-6; but it also reduces the “good” anti-inflammatory cytokines like IL-10.  Perhaps this is why NAC is not beneficial to some people with autism?

Occasional use of Ibuprofen at times anticipated to be stressful makes a lot of sense. 

Conclusion

While it is well known that Ibuprofen relieves pain from teething, low level pain is often completely ignored by people with ASD.  The cytokine release associated with the resorption of the milk teeth and the eruption of the permanent tooth appears to be much more problematic.

Ibuprofen, available OTC, limits the production of pain mediators, called prostaglandins, which in turn stimulate production of the inflammatory cytokine IL-6.

Ibuprofen will reduce both pain and the level of cytokines like IL-6.

In earlier extensive posts on mast cell degranulation in autism, I concluded that the resulting elevated levels of IL-6 likely produced behaviors ranging from anxiety, through aggression, all the way to self-injury.

A protocol for treatment of common autism phenotype(s)

This is a guest post written by Seth Bittker, who previously wrote about Vitamin D in Autsim.

Your child has just been diagnosed with autism.  Now what?  Start some form of behavioral therapy and research autism biochemistry.  You will soon realize by reading blogs like Peter’s that biochemical dysfunction is fundamental to most cases of autism.   For example, some biochemical characteristics that are common in autism are:

1)       Immune dysfunction.  Often this shows up as comorbidity with allergic or autoimmune diseases. http://europepmc.org/abstract/med/16512356

2)       Elevations in monoamine neurotransmitters in the young.  http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.1994.tb11911.x/abstract

3)       Methylation deficits.  Often the oxidized to reduced glutathione ratios are high. http://www.ncbi.nlm.nih.gov/pubmed/15585776

4)       Low plasma cysteine and higher sulfate excretion than controls.  This means there is a functional sulfation deficit. http://informahealthcare.com/doi/abs/10.1080/13590840050000861

5)       Lower levels of fatty acids in blood plasma than controls. http://www.lipidworld.com/content/10/1/62

6)       Higher testosterone than controls. http://www.nature.com/srep/2014/140926/srep06478/full/srep06478.html

7)       Oxidative stress as demonstrated by markers.

http://www.ncbi.nlm.nih.gov/pubmed/22005342

8)       Vascular damage as demonstrated by markers. http://archneur.jamanetwork.com/article.aspx?articleid=792009

9)       Intestinal dysbiosis.  http://www.biomedcentral.com/1471-230X/11/22  

Given this background, it makes sense to determine whether there are issues in your child’s biochemistry that may be involved in inducing autism and how his biochemistry compares to others with autism.  After all if his biochemistry is similar to what is common it may be that therapies that have proven useful in others with autism will prove useful in the case of your child as well.

How can you get an understanding of your child’s biochemistry?  You can have tests run on your child’s urine and blood.  This typically involves finding a medical doctor who can order such tests and has the inclination to do so.  One test that I believe everybody with autism of an unknown cause should have done is a quantitative urine organic acid test.  A good organic acid test will provide information on fatty acid and carbohydrate metabolism, Krebs cycle function, B vitamin deficiencies, neurotransmitter metabolism, oxidative stress, detoxification, and bacterial and fungal activity in the digestive tract, as well as methylation and sulfation processes.  In short it will provide information on a lot of the biochemistry that is often dysfunctional in autism.  Different providers of organic acid tests include different compounds and provide different information on them.  I recommend Genova’s comprehensive test because it includes a number of metabolites that are of interest in autism, it is quantitative, and the data is displayed in a logical manner.  Here is a link: https://www.gdx.net/product/organix-comprehensive-profile-metabolic-function-test-urine.  To be clear I have no relationship to Genova and I do not recommend that you follow the supplementation guidelines that they typically include with test results.  After reviewing the information from your child’s organic acid test and googling various metabolites, you may have some leads on whether the biochemistry of your child is similar to the biochemistry that is common with autism as described above.

What to do next?  The next step especially if there are indications that your child’s autism is similar to what is common in the medical literature is to develop a food and supplement protocol for your child by experimentation.  To mitigate risk you should find a physician who you can collaborate with, experiment with one therapy at a time, use your child’s biochemistry as determined by tests as a guide, use supplements that have generally found to be helpful in others with autism, and carefully control any experiments.  Always use low doses of any supplements at first.  In fact to obtain positive effects with most supplements, you need not provide large doses and in my view the amounts used in supplement trials are often excessive.

Below are some supplements and experiments and a reasonable order in which to try them.  I recommend that you try these (or some subset of them) if your child’s biochemistry suggests they may be helpful.  If you find significant issues in your child’s biochemistry that may be ameliorated with a single supplement, you should certainly consider trying that supplement first.  Also if something does not work well for your child, leave it out of the protocol that you are developing independent of biologic rationale.  The objective is to improve the functional level and health of your child.  If something does not work, discard it.  You need not do everything.

1)       Fatty acids.  As mentioned previously fatty acids are often low in autism.  You could get a fatty acid panel on your child to determine if they are low in your child.  Two double blinded trials have been done with fish oil (omega 3 fatty acids) in the context of autism with generally positive results.   http://www.ncbi.nlm.nih.gov/pubmed/16920077  Interestingly it seems some omega 6 and omega 9 fatty acids are often more deficient than omega 3s in autism.  As omega 6s like omega 3s are essential fatty acids, deficiency can be problematic.  While controlled trials have not been done with omega 6s or omega 9s in the context of autism, it makes sense to experiment with borage oil (omega 6) and olive oil (omega 9) if deficiency is suggested based on a fatty acid panel.

2)       Methylation cofactors.  Are there elevations (even mild ones) of methylmalonic acid or forminoglutamic acid from your child’s organic acid test?  Does your child have a high ratio of oxidized to reduced glutathione (a test by the European Laboratory of Nutrients can measure this)?  If so, then your child may have a methylation deficit.  Jill James among others has found that shots of methylB12 and oral supplementation of folinic acid can help normalize this biochemistry.  http://ajcn.nutrition.org/content/89/1/425.long  MethylB12 is absorbed well orally even in those with dysbiosis.  In addition the methylfolate form of folate is absorbed well and is the active form used in the body.  Also it is methylated which is a plus for those with methylation deficits.  Therefore, if there is any indication of need, I recommend supplementation with oral methylB12 and oral methylfolate rather than the forms that were used by James.  In my experience high doses of methylcobalamin can cause insomnia but low doses are therapeutic.  So be wary of inducing insomnia.

3)       Thiamine.  Deficiencies of this vitamin lead to a disease known as beriberi.  If you set aside the rashes that typically characterize it, there is significant overlap between the symptoms of beriberi and those that are common in autism.  In fact some with autism have rashes as well.  The word thiamine means sulfur containing vitamin and thiamine does indeed contain sulfur.  Sulfur deficits are common in autism as previously noted.  So this is another hint in my view that thiamine may be helpful in general in autism.  Indeed a trial from 2002 of thiamine suppositories found that thiamine deficiency was fairly common in autism and supplementation even in those without obvious signs of deficiency could lead to improvement in behavior.  http://www.ncbi.nlm.nih.gov/pubmed/12195231 It is my belief that this vitamin is significantly underutilized in treatment of autism.  Some signs that thiamine may be warranted include high levels of lactate or pyruvate, issues of fatty acid or carbohydrate metabolism and rashes.

4)       Vitamin C.  A double blinded placebo controlled trial from 1993 found some improvement in behavior could be attributed to supplementing vitamin C in the context of autism.  http://www.ncbi.nlm.nih.gov/pubmed/8255984  This is not surprising given that oxidative stress is common in autism.  Are there indications of oxidative stress from your child’s organic acid test or other sources such as high levels of 8-Hydroxy-2’-deoxyguanosine?  Then a trial of vitamin C is warranted.  I think low doses are preferable to high doses as high doses have effects on digestion as well as neurotransmitters that may be undesirable.  In addition high doses can induce copper deficiency.  Too much copper is not uncommon with autism but copper deficiency can be as problematic as too much copper.

5)       Removal of supplementary and fortified sources of fat soluble vitamins and particularly vitamin D.  This is controversial and the vast majority of practitioners would recommend supplementation with vitamin D.  I believe getting rid of supplemental and fortified sources of vitamin D was vital to improving my son’s biochemistry.  In addition processing oral vitamin D requires sulfation and sulfation deficits are common in autism.  Also many of the biochemical characteristics of autism including excessive levels of neurotransmitters, excessive levels of hormones, and a Th2 skew to the immune system are exacerbated by significant supplementation of oral vitamin D.  I wrote a paper on this available here: http://omicsgroup.org/journals/infant-exposure-to-excessive-vitamin-d-a-risk-factor-for-autism-2165-7890.1000125.pdf If you think there is merit to this view, some indications that excessive fat soluble vitamins could be a problem for your child include elevation in glucarate and sulfate on an organic acid test.  Please note sun exposure is positive for those with autism.  My concern is only with significant supplemental oral sources of fat soluble vitamins and particularly vitamin D.

6)       Probiotics.  A number of excellent studies support the notion that dysbiosis is common in autism.  In addition a double blinded trial from 2010 found marginal improvement in those with autism from supplementation with a probiotic.  http://centaur.reading.ac.uk/17353/  If your child has elevations in dysbiosis markers, this is worth a try.  I recommend a trial of a probiotic that is high in bifidobacteria and lactobacilli as there are indications that these are typically lower than controls in the digestive tracts of those with autism.  In addition if there are indications that your child may have clostridia from an organic acid test or other test, it probably makes sense to try the probiotic yeast saccharomyces boulardii as it has proven helpful in cases of clostridia.  Clostridia is common in autism and can lead to dysfunction.

7)       Carnitine.  One study found that about 17% of those with autism have abnormal carnitine metabolism.  In addition a double blinded placebo controlled trial found significant improvements in behavior from carnitine supplementation in the context of autism.  http://www.ncbi.nlm.nih.gov/pubmed/21629200  One indication carnitine may be useful is a high lactate to pyruvate ratio.  In addition one can measure the level of carnitine in the blood and low carnitine is an indication that supplementation could be benefical.  I do not use carnitine in supplementation with my son as I have not found it to be helpful but the trial mentioned suggests it will be helpful to a number of others.

8)        Removal of milk from the diet.  I do not believe there have been double-blinded trials showing efficacy for this treatment.  However some open label trials have resulted in positive results and I attest to the importance of this intervention in the case of my son.  Issues of digestion such as diarrhea and especially constipation are indicators that a trial of this may be beneficial.

9)       Removal of gluten from the diet.  As with milk free diets, I do not believe there have been double blinded trials showing efficacy.  However some open label trials have resulted in positive results and it seems helpful to my child.  In addition there does appear to be some comorbidity between celiac (autoimmune disease of the small intestine initiated by reaction to gluten) and autism. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884520/ Again issues of digestion such as diarrhea or constipation can be good indicators that a trial may be beneficial.

10)   Cruciferous vegetables.  Sulfur deficits are common in autism as previously noted.  In addition a number of trials with sulfur containing compounds have had tantalizingly positive results in the context of autism.  Such trials include: NAC, DMSA, and sulforaphane as well as thiamine (mentioned above).  We have tried small doses of all of these with my son and with the exception of thiamine I have not felt the long term results were positive.  NAC and DMSA both tend to exacerbate dysbiosis in some cases as well.  As dysbiosis can be such a huge issue in those with autism, I am hesitant to recommend them.   We also tried a tiny dose of a sulforaphane supplement with my son and I believe it induced a temporary verbal tick, which was awful.  In fact the researchers who conducted the sulforaphane trial acknowledgement that it might raise the risk of seizures in some.  http://www.pnas.org/content/111/43/15550.short?rss=1&ssource=mfr  Seeing the results in my son, I think this caution is warranted and for this reason I feel sulforaphane supplementation can be dangerous despite the positive results that many have seen.  Cruciferous vegetables such as broccoli (which contain sulforaphane) seem to have a marginally positive effect on my son.  As these are foods I also have less fear of negative side effects.  Thus, I recommend inclusion of a trial of cruciferous vegetables  in your child’s diet if there are any indications of sulfation deficits (low cysteine) or high sulfur excretion (high sulfate in urine).

Some other supplements that I believe are useful in autism include biotin, riboflavin, milk thistle, melatonin (for sleep), and prunes (for constipation).  One could write a book about treatment protocols for those with autism and a number of good books have already been written on this topic.  What appears above is a summary of an ebook that I wrote describing this protocol which is available here:  http://www.amazon.com/Autism-Getting-Biomedical-Protocol-Biochemistry-ebook/dp/B00R298YNW/.  If you have any interest, please feel to preview it on amazon.

In interest of full disclosure, I am not a doctor, I do not consider my son “recovered” from autism, the autism literature I have consulted as well as my own views may later be shown to be incorrect, and independent of what is true generally your child may have negative reactions to the supplements mentioned above.  I thank Peter for the opportunity to describe this protocol here and for his wonderful blog on cutting edge treatments for autism and the science behind them.  I wish you success in your efforts to improve the health of your child.