Friday, 8 October 2021

Alpha-lactalbumin Whey Protein – Treating Neurological Dysfunction, including Epilepsy and Autism, via the Gut (Eubiosis)


Moo! α-Lactalbumin is a whey protein constituting 22% of the proteins in human milk and 3.5% of those in cow milk.


Most parents love the idea of treating their child with autism or epilepsy with diet.

Diet is so popular because you do not need a doctor - no drugs, no prescriptions, just healthy food.

This blog is about the science, which often takes us to drugs that need a prescription, but when talking about using the gut to fine-tune how the brain works, much can be achieved with nutraceuticals.

We previously saw how the ketogenic diet, which has been reducing epilepsy for one hundred years, actually works by modifying which bacteria grow in the gut.  The super high fat diet encourages specific bacteria to flourish and it is these bacteria which indirectly cause the cessation in seizures. You can replicate the effect with probiotic bacteria, without needing the highly restrictive diet at all.

Today I will introduce Alpha-lactalbumin, which is a commercially available whey protein found in mother’s milk and to a lesser extent in cow milk. 

Alpha-lactalbumin when combined with another regular in this blog, sodium butyrate, has been shown to improve autism, epilepsy and indeed depression.

The research also suggests that Alpha-lactalbumin may improve sleep and mood disorders.


Whey protein vs NAC

I recall reading about whey protein as an antioxidant back in 2013, when I was deciding what to try next after Bumetanide, as I developed by son's personalized polytherapy for autism. I did choose NAC, but I still recall the surprising option of whey protein.

Whey protein is popular among athletes and body builders.

Whey protein is a mixture of proteins isolated from whey, the liquid material created as a by-product of cheese production. The proteins consist of α-lactalbumin (ALAC)β-lactoglobulin, serum albumin and immunoglobulins.


Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein

We sought to increase glutathione levels in stable patients with cystic fibrosis by supplementation with a whey-based protein.

 After supplementation, we observed a 46.6% increase from baseline (P<0.05) in the lymphocyte GSH levels in the supplemented group. No other changes were observed. 

Conclusion: The results show that dietary supplementation with a whey-based product can increase glutathione levels in cystic fibrosis. This nutritional approach may be useful in maintaining optimal levels of GSH and counteract the deleterious effects of oxidative stress 


The Antioxidant Effects of Whey Protein Peptide on Learning and Memory Improvement in Aging Mice Models

The results showed that WHP could significantly improve the accumulation of MDA and PC, increase the activities of SOD and GSH-Px, resist oxidative stress injury, and enhance the potential of endogenous antioxidant defense mechanisms. WHP can significantly improve the decline of aging-related spatial exploration, body movement, and spatial and non-spatial learning/memory ability. Its specific mechanism may be related to reducing the degeneration of hippocampal nerve cells, reducing the apoptosis of nerve cells, improving the activity of AChE, reducing the expression of inflammatory factors (TNF-α and IL-1β) in brain tissue, reducing oxidative stress injury, and improving the expression of p-CaMK and BDNF synaptic plasticity protein.

These results indicate that WHP can improve aging-related oxidative stress, as well as learning and memory impairment.



 α-lactalbumin (ALAC)

Today we are really focused on one specific whey protein, α-lactalbumin (ALAC), which is actually sold commercially as a nutraceutical.



Applications for α-lactalbumin in human nutrition

α-Lactalbumin is a whey protein that constitutes approximately 22% of the proteins in human milk and approximately 3.5% of those in bovine milk. Within the mammary gland, α-lactalbumin plays a central role in milk production as part of the lactose synthase complex required for lactose formation, which drives milk volume. It is an important source of bioactive peptides and essential amino acids, including tryptophan, lysine, branched-chain amino acids, and sulfur-containing amino acids, all of which are crucial for infant nutrition. α-Lactalbumin contributes to infant development, and the commercial availability of α-lactalbumin allows infant formulas to be reformulated to have a reduced protein content. Likewise, because of its physical characteristics, which include water solubility and heat stability, α-lactalbumin has the potential to be added to food products as a supplemental protein. It also has potential as a nutritional supplement to support neurological function and sleep in adults, owing to its unique tryptophan content. Other components of α-lactalbumin that may have usefulness in nutritional supplements include the branched-chain amino acid leucine, which promotes protein accretion in skeletal muscle, and bioactive peptides, which possess prebiotic and antibacterial properties. This review describes the characteristics of α-lactalbumin and examines the potential applications of α-lactalbumin for human health.


α-Lactalbumin constitutes approximately 22% of total protein and approximately 36% of the whey proteins in human milk and approximately 3.5% of total protein and approximately 17% of whey proteins in bovine milk (Figure 1)1,2. It has an amino acid composition that is high in essential amino acids and comparatively rich in tryptophan, lysine, cysteine, and the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine.3 (Table 1)4. Because of its unique amino acid profile, α-lactalbumin has potential for multiple uses: (1) as a component of infant formulas, to make them more similar to breast milk; (2) as a supplement to promote gastrointestinal health or modulate neurological function, including sleep and depression; and (3) as a therapeutic agent with applications in conditions or diseases such as sarcopenia, mood disorders, seizures, and cancer. 


Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy.


Increased efficacy of combining prebiotic and postbiotic in mouse models relevant to autism and depression


·        Prebiotic/postbiotic combination is a suitable approach in manipulating the Microbiota Gut Brain Axis. 

·        Prebiotic/postbiotic combination is more effective than single drug administration. 

·        α-lactalbumin/sodium butyrate combination improves animal behaviour in autistic (BTBR) mice. 

·        α-lactalbumin/sodium butyrate combination improves animal behaviour in the depression chronic unexpected mild stress model.



It is not by chance that mother’s milk has evolved to be rich in Alpha-lactalbumin (ALAC).

ALAC has wide-ranging health benefits. People with gut dysbiosis would seem likely to benefit from it, particularly if they have co-occurring neurological symptoms (epilepsy, ASD, depression) that are made worse by GI inflammation.

NaB (Sodium Benzoate) has some overlapping benefits with ALAC and the research shows that the combined effect is better than either alone,

The increase in production of glutathione (GSH), the body’s main antioxidant is clearly a benefit of whey protein in general and we assume its effect extends to ALAC.

NaB seems to have an effect that can be very dose dependent.  Too little has no benefit and, at least in some people, too much and you lose the benefit.

NaB is producing butyric acid and depending on your fiber intake and gut bacteria you are already producing your own butyric acid.  As a result, it makes sense that the effective dose of NaB will vary from person to person.

This continues the earlier subject of eubiosis vs dysbiosis.  The graphic below looks nice, but really is an oversimplification.  You can modify the microbiome to produce a specifically targeted change in the brain, which has nothing to do with allergic diseases.  All  very clever and a little hard to believe at first.



Source : The Role of Prebiotics and Probiotics in Prevention of Allergic Diseases in Infants

I think ALAC is an interesting choice for autism and hopefully one day there will be a clinical trial.  In that trial do not exclude those with epilepsy, but collect data of the impact of ALAC on the frequency/intensity of seizures.


Friday, 17 September 2021

Bumetanide – Maths Test ✔✔✔ Clinical trial ✖✖✖


Memantine, Arbaclofen 
and now Bumetanide stumble in clinical trials

(also the less well known Balovaptan, which Roche dropped in 2020).

Place your bets on Suramin, anyone?


Plus ça changeplus c'est la même chose

The more things change, the more they stay the same

The first week of the school year brought two big surprises. 

Monty, aged 18 with autism, came top of the class in the math test.  This is a big win for bumetanide treatment, because 9 years ago Monty was effectively innumerate.  With a huge effort by his Assistant, he had learnt how to read and write, but even the most basic maths was beyond him.  That all changed in 2012 thanks to Professor Ben-Ari’s published research on Bumetanide in autism.

The sad news that week was that the Phase 3 clinical trial of Bumetanide for autism had been terminated early.  

Servier and Neurochlore announce the main results of the two phase 3 clinical studies assessing bumetanide in the treatment of Autism Spectrum Disorders in children and adolescents

Paris, 7 September 2021 – Servier and Neurochlore announce that no sign of effectiveness was observed in their two phase 3 clinical studies assessing bumetanide versus placebo in the treatment of Autism Spectrum Disorders (ASD) in children and adolescents. As a consequence, Servier and Neurochlore have decided, by mutual agreement, on an early termination of the two clinical studies in progress.

“The results of the phase 3 clinical studies are a major disappointment,” declares Professor Yehezkel Ben-Ari, President of Neurochlore. “Neurochlore’s teams will now analyze in detail the results of the studies and potentially explore new approaches based on artificial intelligence, which may enable us to identify sub-populations of people suffering from Autism Spectrum Disorders, for whom bumetanide could be effective.


Bumetanide also did not pass the NEMO clinical trial, as a treatment for neonatal seizures back in 2015.  This then made it a bit awkward to suggest that children with severe autism might lower their risk of developing epilepsy by taking bumetanide. Since this is a blog, I can speculate.  I would imagine children with severe autism, who are bumetanide-responders, and who are treated from early childhood through to adulthood with this drug, will have a low incidence of developing seizures. Seizures develop in about 30% of those with severe autism (DSM3 autism) and are the leading cause of their early death.  

 A Poorly Constructed Trial?

If such an effective therapy shows no benefit in a trial with 400 participants, something has gone seriously wrong.

I did ask one researcher friend, who just replied bluntly that the trial must have been poorly constructed.  I thought that was a bit brutal, even by my standards.


Be honest and admit your limitations

Monty, aged 18, came top in maths among 15 neurotypical 16 year olds.  But the 45 pupils in the year had been split into sub-groups. Two groups of 15 taking extended maths and one group of 15 taking core maths.  For some reason, because Monty has autism they put him in the lower group.

Not to worry, after his coming top in the math test, the school agreed that he can move to one of the upper groups taking the wider math curriculum.

So Monty is no maths genius, he came top among the weakest group of typical kids.  That is the whole truth, which is different to the partial truth.

In a similar way, autism researchers need to accept that there may never be a unifying therapy for autism, one that benefits everyone.

Concentrate on the responders to your treatment and forget the rest.  If you over-sell your therapy, you will fail.

As I have said in this blog many times, most people with an autism diagnosis are not bumetanide-responders.  However, a significant minority of those with severe autism are responders to bumetanide and they will experience a transformative benefit.

Going from a basket case to a Maths Whizz even?


Apply common sense and don’t outsource everything

In previous clinical trials of bumetanide, critics said it was all a placebo effect because the parents knew when they were giving bumetanide rather than a placebo.  The bumetanide pill causes the diuresis and placebo does not.

Why can you not use a different diuretic as the placebo?  Answer that one!

Many people using bumetanide give up because of the diuresis.  With schoolkids, the parents will receive complaints from school about excessive toilet breaks.  There will be wetting of trousers, car seats etc.  There will be anxiety caused by urgently needing a toilet, when none is nearby.

So you need a strategy in advance of how to deal with the diuresis.

I was told that people in the one trial centre I know about, were told nothing about the diuresis and how to cope with it.  I was even told the clinician basically told the parents that it was a stupid trial.  Not a good way to ensure compliance with the trial protocol.

So what happens? Some parents will decide to stop giving the diuretic drug, at least on school days.  Maybe they think that a “double-dose” at the weekend will make up the difference.

Clinical trials are a business these days and are outsourced to companies that do this and nothing else.  Don't outsource the most critical part of your work, or at least supervise it.


Why, oh why, oh why?

I was contacted by a mother from the southern hemisphere who managed to get Bumetanide prescribed by a pediatrician, based on Ben-Ari's earlier publications.  The diuresis is proving a problem for her family, but the positive effects are clear, for example her son now uses the word “Mummy”, but only while taking Bumetanide.  If you are a Mum/Mom, that is a big deal.  He also now responds to his own name and is "more present", the hallmark sign of a bumetanide-responder.

She saw me on YouTube and sent me a long email, including the “why, oh why, oh why?” are more people not giving bumetanide to their child with severe autism.  There is no good answer.

This Mum, now realizing she is not alone, plans to continue Bumetanide therapy.

Good for her!


Who dares wins, or at least stands a chance

I was recently sent an email version of an old post I had written on myelination. The sender had read it and convinced her doctor to prescribe her son Clemastine.

Her son has a single gene autism that is known to feature impaired myelination.

I pointed out that in my blog there are many references to therapies shown to benefit different aspects of the myelination process, clemastine is just one.  Some of these therapies are OTC, like alpha lipoic acid (ALA) and the N-Acetyl glucosamine (NAG), that Tyler brought to everyone’s attention.

Is the young man in question going to improve in function taking one or all of these 3 therapies? At least the mother in question is going to give them all a good shot.

Good for her.



I have received quite a few comments and messages about the Bumetanide trial failure.  Many are along the lines of “what do we do now?” and “how long will we have to wait?”

It looks like it pays to be an early adopter, rather than having faith that clinical trials will be structured and implemented properly. 

It has been suggested in the research that a large, 10g, daily dose of the OTC supplement TMG (trimethylglycine) may have an equivalent chloride lowering effect to bumetanide.  There is only anecdotal evidence to support this, but it seems to work for our reader Nancy's adult son - good job Nancy!  The other potentially chloride lowering drugs are more difficult to obtain than bumetanide itself.

There likely will never be a single unifying therapy for autism, just like there can never be for cancer.  In both conditions it is all about specific sub-types.

You would think that the previous trial failures in autism would have caused people to learn this important lesson.  

Hopefully, in the future Suramin clinical trials, where two competing companies are using the same therapy, it will not be assumed that everyone must be a responder for the therapy to be valid.  From the data, it does look like Suramin improves symptoms in a significant percentage of those with severe autism; but the same can also be said of Bumetanide, based on the earlier trials

In December Monty will commence his 10th year of Bumetanide therapy. We have made short breaks periodically to check it is still needed. For our case of autism, Professor Ben-Ari clearly got the science right and transformed a little boy's future life, something Ben-Ari can always be proud of. 

Tuesday, 7 September 2021

The Kynurenine Pathway in Autism and its modification using Sulforaphane or the probiotic Lactobacillus Plantarum 299v


 A pathway to somewhere, hopefully

Today’s post was prompted by our reader George’s observation that the probiotic Lactobacillus Plantarum 299v increased speech in his adult son.  This widely available probiotic is commonly used to treat IBS (Irritable Bowel Syndrome) and I did mention it in a recent post about Eubiotics.

Eubiotics for GI Dysfunction and some Autism

Increased speech is a target for many people treating autism and this probiotic is known to be safely used long term - so it is interesting.

Since I already had this probiotic at home, I made a trial and I observed a very similar effect to what happened several years ago when Monty started to use Sulforaphane / broccoli sprout powder. 

The effect of broccoli powder was a brief period of euphoria about 20 minutes later and a then a marked increase in verbalization.  The effect on mood was seen by some other readers, but not the majority. I recall back then a very happy parent who was feeding broccoli powder to his child via a G-tube. A gastrostomy tube, often called a G-tube, is a surgically placed device used to give direct access to your child's stomach for supplemental feeding, hydration or medication.  Some children with autism will not eat and so are fed via a G-tube.

Broccoli powder tastes pretty bad, but this is one problem you will not experience when taking it via a G tube.

I was surprised that even some people with mild autism found broccoli powder beneficial. In diabetics it improves insulin sensitivity and so reduces the amount of insulin they need to inject.

This post is about the science, but before reading all the science, I made my trial of Lactobacillus Plantarum 299v.  One capsule a day works very nicely. The science is optional.

I wondered what might be the shared effect of these two very different therapies - broccoli and L.P. 299v.  There is indeed a plausible explanation, the Kynurenine pathway.


Click on the graphic, to enlarge

This may all look rather complicated, but there are some terms we are already very familiar with. We know that Serotonin is the happy hormone and we know that Melatonin is the sleep hormone.

It all starts with Tryptophan, one of those amino acids. It is essential in humans, meaning that the body cannot synthesize it and it must be obtained from the diet. Good sources include milk, turkey and bananas. If you take bumetanide, you likely already eat a lot of bananas due to their potassium content.

95% of tryptophan is metabolized to Kynurenine, a very odd sounding word. So it must be that less than 5% becomes Serotonin and Melatonin. Two enzymes, namely indoleamine 2,3-dioxygenase (IDO) in the immune system and the brain, and tryptophan dioxygenase (TDO) in the liver, are responsible for the synthesis of kynurenine from tryptophan.

The so-called kynurenine pathway of tryptophan is altered in several diseases, including psychiatric disorders such as autism, schizophrenia, major depressive disorder and bipolar disorder.

The supplements Tryptophan and 5-hydroxytryptophan (5-HTP) are widely used for many conditions ranging from depression to autism.


The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+).


NAD+ is very important.


Increasing the level of NAD is itself an autism therapy in the research. 

New Preclinical Study Finds Niagen® Corrects Social Deficits in Mouse Model of Autism

First-of-its-kind preclinical study shows that Niagen® (nicotinamide riboside) resolves social deficits and anxiety-like behaviors in male mice

The amount of Tryptophan that ends up as the cute-sounding Picolinic acid is determined by how much of the enzyme ACMSD is present.

Quinolinic acid (QUIN) and Kynurenic acid (KYNA) are two neuroactive KP metabolites that have received considerable attention for their modulation of the NMDA receptor. While QUIN shows neurotoxic effects by over activation of the NMDA receptor, KYNA offers neuro-protection by blocking receptor function. Emphasis has been placed upon the importance of maintaining a balanced ratio between these two metabolites.

Picolinic acid (PIC) also shows antagonistic properties towards the toxic effects of QUIN via an unknown mechanism.  There are a number of biological factors that can potentially affect PIC levels and synthesis in the CNS including age, circadian rhythms and hormonal and nutritional factors.


 Source: The Physiological Action of Picolinic Acid in the Human Brain

Anthranilic acid (AA), once thought to be vitamin L, is very elevated in schizophrenia, and also in type-1 diabetes and arthritis.  AA is seen as a treatment target in these conditions. 

Now for the interesting part, the effect of the probiotic Lactobacillus Plantarum 299v on the Kynurenine pathway:


Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study


· There was an improvement in cognitive functions in group of depressed patients receiving probiotic Lactobacillus Plantarum 299v (LP299v) compared to the placebo group.

 · There was a significant decrease in kynurenine concentration in the LP299v group compared to the placebo group.

 · There was a significant increase in 3-hydroxykynurenine : kynurenine ratio in the LP299v group compared with the placebo group.

· Decreased kynurenine concentration due to probiotic could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group.


And, the effect of Sulforaphane on the Kynurenine pathway: 


Altered kynurenine pathway metabolism in autism:Implication for immune-induced glutamatergic activity

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, Quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased Quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD.


QA = Quinolinic Acid

KP = Kynurenine Pathway


The increased concentration of QA in ASD is also likely to be associated with increased oxidative stress. We previously showed that QA can significantly potentiate oxidative stress in human primary neuron cultures and that oxidative stress markers are increased in children with ASD.  Recently, a clinical study effectively used sulforaphane derived from the broccoli sprout to treat ASD resulting in improved behaviour.  Interestingly, sulforaphane was shown to attenuate the effect of QA-induced toxicity in rat brain by enhancing the antioxidant, glutathione. This study is coherent with our current finding of increased QA in children with ASD and our previous work showing decreased glutathione in the children with ASD.  Hence, the possibility that sulforaphane may act by attenuating QA-induce oxidative stress in ASD warrants further investigation.



Too much Quinolinic Acid (QA) does appear to be a damaging feature of autism and is produced by a malfunctioning Kynurenine pathway (KP).

The exact relevance of each part of the KP in diseases of the brain is still a work in progress, but it is clearly disturbed in a specific way in each particular CNS disorder, autism being just one.

Modifying the KP does look like a useful therapeutic avenue to follow, but it is not so simple to understand all of it.

It appears that Lactobacillus Plantarum 299v may improve some people’s autism via a mechanism that includes modification of the Kynurenine pathway (KP). It may also be the case that sulforaphane / broccoli powder has an effect that counters the disturbed KP. For whatever biological reason, the visible/audible effects of the two therapies appear to be remarkably similar.

As usual, you do not have to fully understand biological pathways, like the KP, to benefit from them.  In effect, it is all a question of where all the Tryptophan from your diet ends up – and for some people it does seem to matter.

Lactobacillus Plantarum 299v and sulforaphane / broccoli are not wonder autism therapies for most responders, but if there is an incremental benefit available, you may want to take it.

Another low hanging fruit? 


Monday, 16 August 2021

Pioglitazone for Autism and Specifically Summertime Raging and Verapamil-responsive Autism?


Adult-sized people with autism can cause property damage and much worse.

I am told that summertime raging is a common problem encountered by neurologists, but it remains poorly understood and usually remains untreated.

The most common worry for parents of toddlers diagnosed with severe autism is their lack of speech.

By the time these children reach adulthood, the biggest worry for parents is often aggression and self-injury. Often it is the mother who faces the worst episodes of aggression, which is a really cruel turn of events.

Aggression is usually not present in young children with autism, in some people it never develops, but in others it later becomes established as a learned behavior and then you are stuck with how to deal with it.

One of my own therapy targets has long been to improve cognitive function; this can indeed be achieved and then you can improve important daily living skills (adaptive function). Some steps that you can take to improve cognition, and indeed speech, have a downside in that they increase anxiety, which may lead to aggression. Calcium Folinate (Leucovorin) does cause aggression in a significant minority of people.  I think that low dose Roflumilast (60mcg) is cognitive enhancing, as proposed by the researchers at 100mcg, but it does seem to increase edginess/anxiety. DMF (Dimethyl fumarate) increases alertness, which is a good thing, but too much alertness will make you anxious.

When dealing with a full sized adult, which is more important, increased cognition/speech or avoiding explosive aggression?

Clearly there is a need for a compromise.

In adults with severe autism, living at home, entirely extinguishing aggressive behavior looks like the number one treatment goal.

For children in mainstream school, following the regular curriculum, cognitive function has to be a top priority.  Fortunately, this is our case, but only after starting Bumetanide therapy in 2012.

It looks like you can potentially have the best of both worlds - increased IQ and adaptive function, but without aggressive behavior. That is my own experience, but it was not simple.

Pioglitazone has been covered quite extensively in this blog and it is again featuring in the research. Pioglitazone is an interesting old drug used to treat people with type 2 diabetes; the phase 2 trial for autism has been completed.  I doubt there will be a phase 3 trial due to the high costs. Pioglitazone is broadly anti-inflammatory; it reduces the pro-inflammatory cytokine IL-6 and increases the anti-inflammatory cytokine IL-10.

We have seen in early posts how important is IL-6 and that it plays a key role in both allergy and even how milk teeth roots “dissolve” and then permanent teeth erupt. This transition to permanent teeth is another common cause of raging in autism, in our case it was mostly wintertime raging. 

IL-6, either directly or indirectly, seems to negatively affect behavior.


PPAR gamma

In earlier posts there was a lot about the various PPARs. These are used in medicine as targets to treat conditions like high cholesterol and type 2 diabetes.

Resveratrol and Pterostilbene are the OTC supplements that some readers are using. Sytrinol is another such supplement, but its cognitive benefit unfortunately just lasts a few days.

Here is a relatively recent paper on the subject, for those seeking the details. 


Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder


Or just look up the old posts in this blog:-

PPARs are rather complicated, but do seem to be very relevant.  For example, the master regulator of mitochondrial biogenesis, something called PGC-1 alpha, is activated by PPAR gamma. If you have mitochondrial dysfunction that included a reduced number of mitochondria, you might want to make more mitochondria. A PPAR gamma agonist might be beneficial.

Dysregulation of PGC-1 alpha is associated with neurodegenerative and metabolic disorders including Parkinson's, Alzheimer's and Huntington's.

Outside this blog, there is some interest in PGC-1 alpha and autism, particularly in connection with oxidative stress and mitochondrial dysfunction.


“In conclusion, we demonstrated mitochondrial oxidative stress may affect a significant subgroup of ASD children and that the SIRT1/PGC-1α signaling pathway may be a promising medical treatment for ASD.”

Source: Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder

It does look like PPARs can be targeted and provide a benefit for at least some types of autism. My choice is Pioglitazone.


Dumber in the Summer

In parallel with summertime raging comes the phenomenon I called “Dumber in the Summer”, where cognitive function regresses.

Monty’s assistant told me recently there is no “Dumber in the Summer” this year, and I opened my medicine cupboard and explained why this is indeed the case.

At least in our case, when you resolve summertime raging, you also protect against cognitive regression. That therapy involves Verapamil, Pioglitazone and allergy therapies, Dymista spray (azelastine + fluticasone) plus Ceterizine and Clemastine. Clemastine also has the pro-myelination effect and stabilizes microglia.


Pioglitazone Side effects

In the stage 2 trials for autism doses of 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg were all found to be safe and well tolerated.

As a summertime add-on therapy it appears very well tolerated.

In adults with type 2 diabetes, who will tend to be overweight and not so healthy, there are common side effects.  At one point, it was thought that there was an association between this drug and bladder cancer. Now this is thought not to be the case.

For adults with severe untreated autism, who are aggressive and self-injure, these behaviors very much limit where they can live and what they can do during the day. Life expectancy is also severely reduced. If Pioglitazone can help control these behaviors, some side effects are likely a price worth paying. 



Pioglitazone, by the standards of autism drugs, has plenty of evidence in the literature, regarding both mouse models and humans, to support an n=1 trial.  It addresses neuro-inflammation, one key feature of autism and it has beneficial effects on mitochondria.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

In a small cohort of autistic children, daily treatment with pioglitazone eased some autistic behaviors, such as irritability, lethargy, stereotypy, and hyperactivity, without significant side effects

 pioglitazone treatment inhibits the secretion of proinflammatory factors, such as nitric oxide and IL-6, and enhances the levels of the secretion of anti-inflammatory factors IL-4 and IL-10. Therefore, considering the results of Qiu and Li and our present findings, pioglitazone acted to benefit autistic-like behaviors possibly via the inhibition of IL-6 secretion in astrocytes stimulated by LPS, which inhibited the neuroinflammatory response.


I think for people whose child with autism has a behavioural or cognitive regression in summer, there is good reason to expect a benefit.  They very likely have allergies or other autoimmune conditions.

For people who deal with aggression and self-injury in a person who responds partially, but not 100%, to Verapamil, they may find that Pioglitazone helps to complete their anti-aggression therapy.

Our doctor reader Agnieszka did her best to collect case studies of people with autism responsive to Verapamil, but not enough parents wanted to participate.

Based on the comments section in this blog, it would look like our reader George in Romania has a son whose son’s aggression is reduced by Verapamil.  If some aggression persists in summer, I think there is a very good chance that Pioglitazone will help reduce it.  George did recently share with us the the anti-inflammatory Probiotic Lactobacillus Plantarum 299v, from the previous post and widely used for irritable bowel syndrome (IBS), improved his son's speech.  

Note that the research clearly shows that most autism has an "inflammatory" element, but the exact nature varies (for details read the work of Paul Ashwood at the MIND Institute).  There are very many different anti-inflammatory therapies that are reported to benefit specific people, but there are no unifying therapies that work for all. Some will inevitably make non-responders worse and potentially dramatically so, like L.reuteri ATCC PTA 6475, found in Biogaia Gastrus. Trial and error seems unavoidable if you want to find an effective therapy.

The research proposes Pioglitazone as a year round therapy for idiopathic autism.  In the phase 2 trial almost half of the children were deemed to be responders to the treatment; not a bad result. I think it also has potential as just a summertime add-on therapy. We used it last summer and now again this summer.

People with a diagnosis of mitochondrial disease, who also present with lethargy, might be another target group because of PGC-1 alpha.