ABA Strikes Again

This blog is mainly about clever pills and potions that may improve some people’s autism, but I do like to remind people of the power of behavioral interventions.

Monty, aged 11 with ASD, has had three behavioral consultants since we began his home ABA program when he was aged about four.  Since there are no ABA consultants in our part of the world, we have to fly them in.  We have our local therapists/assistants, who then work with some support from the foreign consultant.  The net result is a mixture of approaches, which admittedly becomes more “ABA” when the consultant comes to visit.  We now have a vast collection of ABA books, manuals and training materials.

Last week our excellent American-Greek behavioral consultant came for a two day visit and so it was a good opportunity to look at progress.

Monty went to the airport to wait for her and then we went home for some discussions and Monty showed off his piano playing.  Later everyone went out to a pizza restaurant; all went well and Monty quietly devoured his full-sized margarita pizza.

The next day the consultant went to school with Monty and his assistant, to see how things are handled there.  The last time she came, she pointed out that there was little interaction with the other kids.  Now things are much better in that area.  In class, she noted than he can now sit attentively and follow much of what the class teacher is saying/doing.

Then back home to see Monty’s afternoon home program with his other assistant.

Another school visit the next day and the visit was over.  Now we wait to find the suggested items to work on at home, as we work our way through one of the ABA bibles, which in our case is:-

Behavioral Intervention for Young Children with Autism

We have lots of other material, but we still often use this book.

Academically and socially we have moved on a fair way since the last visit.  Back home our consultant runs more intensive clinic-based ABA programs and she was wondering out loud how come we are making all this progress.

“Our other kids have six times as much intervention”; I am not sure exactly how the six figure was picked, but I do get her point.

Near the end of the visit she did ask “are you giving him any drugs?”

The answer was “yes, but not any ones you will have heard of”.  I did then give a brief explanation of my "extra-curricular" activities.

I have learnt it is best not to mix messages with different audiences.  ABA people are great, but do tend to think nothing else can help.  Equally, people convinced that the problem is candida or vaccines, have also already made up their minds.

It is, of course, not a good idea to compare one child with ASD’s performance against another, but everybody still does it.

It looks like the kind of people our consultant works with now and encountered at a leading center in the US, where she trained until 10 years ago, are generally more affected by autism than Monty.  Most of the people I read about today with “autism” (mainly from the US) are clearly much less affected than Monty.  This does rather suggest that what passes for “autism” there has really changed a lot in 10 years.  Now that Asperger’s has ceased to exist in the US, under their latest DSM, this process will continue yet further.

Conclusion

My conclusion is that ABA works great and so does the Polypill.

Hopefully, next time we go to the airport to meet our ABA consultant, or even drop by her in Athens, we will again have moved forward nicely.

For now everyone is happy.

Treatment of Autism with low-dose Phenytoin, yet another AED

I do like coincidences and I do like not struggling to find a picture for my posts. 

Phenytoin (Dilantin) is a drug that appeared in the novel and film, One Flew Over the Cuckoo's Nest, but then it was not used in low-doses.

Today’s post follows from a comment I received about using very low doses of anti-epileptic drugs (AEDs) in autism.

First of all a quick recap.

Clonazepam was discovered by Professor Catterall, over in Seattle, to have the effect of modifying the action of the neurotransmitter GABA to make it inhibitory, at tiny doses that would be considered to be sub-clinical (i.e. ineffective).

Valproate, another AED, was discovered by one of this blog’s readers also to have an “anti-autism” effect in tiny doses of 1 mg/kg.

A psychiatrist from Australia, Dr Bird, specialized in adults with ADHD has just published a paper about the benefit of low-dose phenytoin in adult autism.  The same psychiatrist has also earlier encountered the effect of low dose valproate in ADHD (autism lite).

The treatment of autism with low-dose phenytoin: a case report

Significantly, this beneficial effect of sodium valproate appeared to have a narrow therapeutic window, with the optimal range between 50 and 200mg daily. A complete loss of efficacy frequently occurred above a dose of 400mg.

Case presentation

My patient was a 19-year-old man diagnosed in early childhood with ADHD and ASD

a sublingual test dose of approximately 2mg phenytoin was administered

Within 10 minutes of taking the sublingual phenytoin he reported a reduction in the effort required to contribute to conversation and was able to sustain eye contact both when listening and speaking. He was surprised about the effortless nature of his eye gaze and also commented that he had never done this before.

The following day he started taking compounded 2mg phenytoin capsules in the morning in conjunction with his methylphenidate.

After two weeks both he and his mother stated that his communication with the family had improved and there had been no aggressive outbursts.

Over the next four weeks he became inconsistent in taking the phenytoin, and then ceased altogether. His behavior reverted to the previous pattern of poor social interaction; he became oppositional with outbursts of anger and physical violence.

Nine months later he resumed taking the phenytoin, this time as a single 4mg capsule in the morning. After his first dose there was an improvement of his social behavior similar to his previous response, although there was an apparent deterioration in the late afternoon. The dose was increased from 4mg to 5mg and a larger capsule formulated to try and prolong the release of the phenytoin. This appeared to achieve a more consistent improvement in behavior throughout the day, evident both at home and at work. Increases in the dose above 5mg were not associated with any additional benefit. He remained on the 5mg dose of phenytoin for over 18 months and reported that his work performance had consistently improved sufficient to increase his working hours and his level of responsibility. The violence and destruction at home abated. His confidence improved and for the first time he has established and sustained peer-appropriate friendships.

I hypothesize that, in a similar mechanism to the low-dose clonazepam in this animal model of autism, low-dose phenytoin may enhance GABA neurotransmission, thereby correcting the imbalance between the GABAergic and glutaminergic systems.

Phenytoin

Now let us look at Phenytoin and see if we agree with Dr Bird's hypothesis that the mechanism is the same as low dose clonazepam. 

The accepted method of action is that working as a voltage gate sodium channel blocker.  GABA is not mentioned.

Phenytoin, by acting on the intracellular part of the voltage-dependent sodium channels, decreases the sodium influx into neurons and thus decreases excitability.

The antiepileptic activity of phenytoin was found during systematic research in animals: it suppresses the tonic phase but not the clonic phase elicited by an electric discharge and is not very active against the attacks caused by pentylenetetrazol.

Phenytoin was the first non-sedative antiepileptic to be used in therapeutics.

It decreases the intensity of facial neuralgia and has an antiarrhythmic effect.

 But as I dug a little deeper, I found from 1995:-

Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin

 Abstract

We report here that carbamazepine and phenytoin, two widely used antiepileptic drugs, potentiate gamma-aminobutyric acid (GABA)-induced Cl- currents in human embryonic kidney cells transiently expressing the alpha 1 beta 2 gamma 2 subtype of the GABAA receptor and in cultured rat cortical neurons. In cortical neuron recordings, the current induced by 1 microM GABA was enhanced by carbamazepine and phenytoin with EC50 values of 24.5 nM and 19.6 nM and maximal potentiations of 45.6% and 90%, respectively. The potentiation by these compounds was dependent upon the concentration of GABA, suggesting an allosteric modulation of the receptor, but was not antagonized by the benzodiazepine (omega) modulatory site antagonist flumazenil. Carbamazepine and phenytoin did not modify GABA-induced currents in human embryonic kidney cells transiently expressing binary alpha 1 beta 2 recombinant GABAA receptors. The alpha 1 beta 2 recombinant is known to possess functional barbiturate, steroid, and picrotoxin sites, indicating that these sites are not involved in the modulatory effects of carbamazepine and phenytoin. When tested in cells containing recombinant alpha 1 beta 2 gamma 2, alpha 3 beta 2 gamma 2, or alpha 5 beta 2 gamma 2 GABAA receptors, carbamazepine and phenytoin potentiated the GABA-induced current only in those cells expressing the alpha 1 beta 2 gamma 2 receptor subtype. This indicates that the nature of the alpha subunit isoform plays a critical role in determining the carbamazepine/phenytoin pharmacophore. Our results therefore illustrate the existence of one or more new allosteric regulatory sites for carbamazepine and phenytoin on the GABAA receptor. These sites could be implicated in the known anticonvulsant properties of these drugs and thus may offer new targets in the search for novel antiepileptic drugs.

So not only is it possible that phenytoin can modulate the behaviour of the GABA_A receptor like Dr Catterall did with Clonazepam, but carbamazepine is yet another known AED with this effect.

So I expect someone will also go and patent low-dose carbamazepine for autism.

We potentially now have a wide range of low dose AEDs for autism.

·        Valproate (1000 to 2000 mg for adults as AED) at a dose of 1-2 mg/kg

·        Clonazepam (up to 20 mg for adults as an AED)   at a dose of 1.7mcg/kg

·        Phenytoin (up to 600 mg for adults as an AED) at a dose of 0.05 mg/kg

·        Carbamazepine (up to 1,200 mg for adults as an AED) no data for the low dose!

We also have two other drugs that are used as AEDs in high doses and have been used in autism with much lower doses.  I do not have any evidence to show that they affect GABA_A receptors.  I think their method of action is unrelated to GABA, or sodium channels.

  

·        Piracetam (up to 24 g as an AED) at a dose of 400 to 800 mg

·        Vinpocetine (up to 45mg for adults as an AED)  at a dose of 1 to 5 mg

Both Piracetam and Vinpocetine are classed as drugs in Europe and supplements in the US.  Both are also used as cognitive enhancers. Both have numerous possible modes of action.  They may not help with behavioral problems, but may well improve cognition.

Interestingly, a clinical trial is underway to look at the cognitive effect of moderate doses of Vinpocetine in epilepsy.

Cognitive Effects of Vinpocetine in Healthy Adults and Patients With Epilepsy

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.