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Thursday 21 January 2016

2016 To-do List

I expect many readers of this blog have a list of things to trial in 2016; I certainly do.

Monty’s older brother, codenamed Ted, did say to me recently, “I thought you said you’d be all finished with this, in a couple of years”; that was indeed the intention.  


A medicine cabinet to be proud of, but not mine


It has now been three years.  I never really intended to go so deeply into the science, and I never expected there to be so many “obvious” things un/under-investigated by researchers.

Most people diagnosed these days with “autism” are fortunate to be relatively mildly affected.  Parents of those kids likely find this blog rather shocking; how can so many pills be needed and still you want more?

Some other people also diagnosed with autism, face really big challenges, not limited to:-
  
     ·        Unable to talk
·        Unable to walk
·        Unable to eat (must use G tube)
·        Unable to be toilet trained
·        Unable to read
·        Unable to write
·        Have seizures 

So when asked by a teacher at school, if Monty, now aged 12, has severe autism I responded in the negative.  He does not tick any of the above boxes.

If you have more than “mild autism” it seems that there are likely many dysfunctions and the more you treat, the better the result.  A quest without an end.


School

Ted hates his relatives discussing his school grades and I agree with him that they are entirely his business.  We all know that typical kids vary in how smart they are and how motivated they are.  NT kids tend to get the grades they deserve.

I do break these rules with Monty, but that is because I really want to show that when a person has numerous neurological dysfunctions, as those found in classic autism, if you treat them with science (not with bleach and other nonsense), you can end up in a different, better place. 99.99999% of the world do not know this; perhaps 500 people do know.

 Improving IQ will improve the person’s ability to understand and compensate for the dysfunctions that have not been treated.  

Grading academic performance at school is something we all understand and along with its limitations.  We have all been there, so let's use it.

Kids with classic autism do not get the grades they potentially deserve.  Most can be made smarter and it is easy to measure.

Before coming to my to-do list, I did receive another question about what exactly is the effect of bumetanide. 

When I collected Monty from school the other day, his assistant was proudly holding up the latest “quick fire” math test, where speed is seemingly even more important than the right answer.

So Monty, the only one with autism, came first and by a long way. 3 minutes and 35 seconds, with the runner up taking 3:56.  He got 90% correct, but that is enough to keep first place.   The previous test before Christmas he got 100%, but finished 7th out of 16 on speed.  It must be the turkey.

The questions are very simple, since you have to be very fast; but until the age of 9, and the introduction of Bumetanide, the class teacher would never have dreamt of having Monty compete at all.  Coming a distant last in everything would be disheartening, for the teacher. Monty would not have even noticed, let alone cared.

People with Classic Autism, or what Knut termed SDA (strict definition autism), are usually hopeless academically; but with Bumetanide, it does not have to be that way. 

Many people with classic autism leave school 18 years old, still at the level of single digit addition and subtraction, or perhaps up to 20.

If you reach the academic level of Grade 2 (Year 3 in the UK system), that of a typical 7 or 8 year old, by the time you “graduate” high school, you are doing above average.









So Ted is not alone in being able to get good grades.  The PolyPill is indeed worth all the bother.



To-do list


I did have to go through by supply cupboard to see what I had not got round to testing and that I still think has some potential merit.  Some things did get thrown out.

Some old ideas are worth revisiting.

·        Biotin (high dose)
This did seem to have a marginal positive effect and is both cheap and harmless. 

·        Pregnenolone (very low dose)
This also appeared to have some positive effect and should affect GABA subunit expression. High doses have been used in a Stanford clinical trial. We saw in earlier posts that allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor, meaning that a tiny dose can have the same effect as a large dose.
 I like low doses.  

Old ideas worth developing:-

·        Miyairi 588 bacteria, but at higher doses

This is the bacteria used as a probiotic in Japan for humans, since the 1940s.  It is also added to animal feed to avoid inflammatory disease and so produce healthier animals.

The science showed that it should be helpful to raise Butyrate levels.  It can be achieved directly via supplementation, with sodium butyrate, and indirectly by adding a butyrate-producing bacteria, such as Clostridium Butyricum or Miyari 588.

I have been using a tiny dose of Miyari 588 for months.  It achieves what it is sold for in Japan, in that it reduces gas, which is the only obvious negative side effect of Monty’s Polypill, other than diuresis.

The positive side effect of the Polypill is near perfect asthma control.  Asthma is an auto-immune/inflammatory disease, highly comorbid with autism. 

The effect of Miyari 588 is reversible because this bacteria cannot survive long in the intestines, which is why you have to take it every day.  It crowds out some of the other bacteria in the intestines, but they will soon grow back.


New ideas already in this blog:-

·        Diamox

I did suggest on several occasions that it might be possible to get a “Bumetanide plus” effect by adding Diamox.

Diamox (Acetazolamide) is another diuretic and it is a carbonic anhydrase inhibitor


Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid Carbonic anhydrase is an enzyme found in red blood cells that catalyses the following reaction:



hence lowering blood pH, by means of the following reaction that carbonic acid undergoes:


The mechanism of diuresis involves the proximal tubule of the kidney. The enzyme carbonic anhydrase is found here, allowing the reabsorption of bicarbonate, sodium, and chloride. By inhibiting this enzyme, these ions are excreted, along with excess water, lowering blood pressure, intracranial pressure, and intraocular pressure. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation, increasing levels of oxygen and decreasing levels of carbon dioxide in the blood

This change in bicarbonate will also affect the AE3 and NDAE exchangers.

As you will see in the figure below the regulation of bicarbonate HCO3- and pH is directly connected to chloride Cl- homeostasis.  This means that via AE3 and NDAE you can affect intracellular chloride levels by change the level of HCO3-

In turns this means that Diamox (Acetazolamide) really should have an effect on the level of intracellular chloride.

This in turn suggested to me that Diamox could augment the effect that bumetanide has on NKCC1.

 In the case that Bumetanide can lower intracellular chloride, but not to the optimal level to correct the GABA dysfunction, Diamox might be able to lower chloride levels a little further so further shifting GABA to inhibitory.










http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1317631/

Neuronal activity results in significant pH shifts in neurons, glia, and interstitial space. Several transport mechanisms are involved in the fine-tuning and regulation of extra- and intracellular pH. The sodium-independent electroneutral anion exchangers (AEs) exchange intracellular bicarbonate for extracellular chloride and thereby lower the intracellular pH. Recently, a significant association was found with the variant Ala867Asp of the anion exchanger AE3, which is predominantly expressed in brain and heart, in a large cohort of patients with idiopathic generalized epilepsy. To analyze a possible involvement of AE3 dysfunction in the pathogenesis of seizures, we generated an AE3-knockout mouse model by targeted disruption of Slc4a3. AE3-knockout mice were apparently healthy, and neither displayed gross histological and behavioral abnormalities nor spontaneous seizures or spike wave complexes in electrocorticograms. 



After only a couple of days of Diamox, it is pretty clear that there is indeed a “bumetanide plus” effect.  So the same changes that were noted when starting bumetanide appear again.

A promising start to 2016.



·        Ponstan

This is the NSAID that is also suggested to be useful to affect the ion channels expressed by the genes ANO 2/4/7 & KCNMA1.  We saw in this post

http://epiphanyasd.blogspot.com/2015/12/autism-treatments-proposed-by-clinical.html

where Knut highlighted that Fenamates act as CaCC inhibitors and also stimulate BKCa channel activity.  Ponstan is a Fenamate.



·        Vitamin A

This was Maja’s discovery, that in some people vitamin A will stimulate oxytocin, via upregulation of CD38.


·        Zinc

Zinc should affect GABA, particularly in immature neurons.  Zinc homeostasis is disturbed in some autism and perhaps, in some people, a small dose of zinc may actually have a positive effect.  Simple to check.

Clioquinol, the drug that shifts zinc to the “right” place, is not without risks.


·        Picamilon

Once the GABA switch has been repaired, it may be time for a little extra GABA.  GABA should not be able to cross the blood brain barrier (BBB), but in the form of Picamilion, it does cross the BBB.


·        Inositol

This it naturally produced in the body from glucose and used to be known as vitamin B8.  In some people Inositol reduces OCD and stereotypy.  Simple to check.


·        Montelukast

This is an asthma drug, considered very safe in children, that Dr Kelley (formerly of Johns Hopkins and likely the cleverest autism clinician)  uses in children with AMD, as a short term therapy, when they are sick and, very interestingly, before immunizations.  This is to avoid further mitochondrial damage.  Montelukast is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies.

Dr Kelley also uses Ibuprofen as a short term therapy to counter the effects of increased cytokine production.  Montelukast is more potent and has different side effects, meaning it might be a better choice than ibuprofen for some people.

Ibuprofen may be OTC, but, more than very occasional use, can cause side effects in many people.  These side effects are caused by NSAIDs also being COX-2 inhibitors, which leads to stomach and intestinal adverse reactions.

Since I have determined that in the case of autism I deal with, the surge in cytokines like IL6 causes behavioral regression, Montelukast might be a good alternative to Ibuprofen to treat some types of autism flare.  

 So a new addition to the autism flare-up toolkit, I hope.

  

Ideas not yet in this blog:-

·        Curcumin

Curcumin, and particularly some of the substances within it, have been shown to have very interesting autism-relevant effects, particularly in vitro (in test tubes).  Whether taking curcumin orally, in reasonable doses, produces any of these effects in humans is a big question.  Many such substances like luteolin and resveratrol fail to meet expectations in humans, due to poor bioavailability.

There are various ways to improve the bioavailability of curcumin, so it seems worth investigating.



·        5-loxin

Frankincense has been used for 5,000 years.  More recently, two thousand years ago, three wise men did bring gifts of gold, frankincense, and myrrh.

Frankincense is an aromatic resin obtained from trees of the genus Boswellia.  Boswellia is used for inflammatory conditions like arthritis in a similar way to curcumin.

There are six boswellic acids, one is most active. This fraction is called AKBA. 5-Loxin is a boswellia supplement claiming to deliver a high standardized level of AKBA.

5-Loxin does seem to help some people with arthritis, but does it have any benefit for the pro-inflammatory aspects found in some autism?  I am not expecting much, but you never know.

  
Ideas suggested to me by others, that look interesting:-


·        Mint/Menthol

This is Natasa’s discovery and there is evidence to show that Menthol does indeed affect GABAA receptors.

Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons


These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABAA receptors in native PAG neurons. The development of agents that potentiate GABAA-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABAA-related pharmacotherapies.

  
·        NIAGEN / Nicotinamide Riboside

This was highlighted by Tyler and is another potential therapy for oxidative stress.  Not as cheap as peppermint, but definitely interesting, perhaps particularly for those with autism and mitochondrial dysfunction.

Also note that there are odd recurring links between some autism and obesity. This is not the first anti-obesity therapy that potentially has some benefit for autism.


The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity

Summary
As NAD+ is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38—both NAD+ consumers—increases NAD+ bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD+ precursor with the ability to increase NAD+ levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD+ levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function.
  

Nicotinamide Riboside Ameliorates Hepatic Metaflammation by Modulating NLRP3 Inflammasome in a RodentModel of Type 2 Diabetes


Low-grade chronic inflammation (metaflammation) is a major contributing factor for the onset and development of metabolic diseases, such as type 2 diabetes, obesity, and cardiovascular disease. Nicotinamide riboside (NR), which is present in milk and beer, is a functional vitamin B3 having advantageous effects on metabolic regulation. However, the anti-inflammatory capacity of NR is unknown. This study evaluated whether NR modulates hepatic nucleotide binding and oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Male, 8-week-old KK/HlJ mice were allocated to the control or NR group. NR (100 mg/kg/day) or vehicle (phosphate-buffered saline) was administrated by an osmotic pump for 7 days. Glucose control, lipid profiles, NLRP3 inflammasome, and inflammation markers were analyzed, and structural and histological analyses were conducted. NR treatment did not affect body weight gain, food intake, and liver function. Glucose control based on the oral glucose tolerance test and levels of serum insulin and adiponectin was improved by NR treatment. Among tested lipid profiles, NR lowered the total cholesterol concentration in the liver. Histological and structural analysis by hematoxylin and eosin staining and transmission electron microscopy, respectively, showed that NR rescued the disrupted cellular integrity of the mitochondria and nucleus in the livers of obese and diabetic KK mice. In addition, NR treatment significantly improved hepatic proinflammatory markers, including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1. These ameliorations were accompanied by significant shifts of NLRP3 inflammasome components (NLRP3, ASC, and caspase1). These results demonstrate that NR attenuates hepatic metaflammation by modulating the NLRP3 inflammasome

  
NLRP3 inflammasome and itsinhibitors: a review

  
Activation and regulation of the inflammasomes

  

An apparently crazy idea of my own, but actually serious:-


·        Propolis tincture, without the propolis

The BIO 30 Propolis from New Zealand is a (mild) PAK1 inhibitor.  One reader is convinced of its cognitive enhancing effects in autism .  I also think it had an effect, but in our case not as potent as that reader.  Now I am wondering what was it that produced this effect. 

Most propolis is made as a tincture with ethanol.  Propolis is not soluble in water.  They typically use 70% ethanol to make propolis tincture.  “Non-alcoholic” tinctures use glycol.

In the last post we saw ethanol has pronounced effects on several GABAA receptor subunits, mainly delta but also alpha, including possibly down regulating alpha 5.

So was it the propolis, or the ethanol that has the effect?

Propolis tincture is either made with ethanol (grain alcohol) or if it is “alcohol free” they use propylene glycol.  Propylene glycol actually is a food ingredient but it is also used to de-ice aircraft in winter.  Ethylene glycol is the antifreeze in your car and you would not want to drink that.

Compared to ethanol, glycol can dissolve less propolis, 

A quick check of school chemistry reminds us that if it is an –ol , it’s an alcohol.

·        Alcohols have at least one hydroxyl group
·        Diols have two hydroxyl groups

Propylene glycol is  C3H8O2  and as you can see below it has two hydroxyl groups (the – OH), so it is both a diol and an alcohol. 






So your Propolis tincture can be ethanol-free, but it cannot be alcohol-free.  Someone might point that out to the supplement makers.

It also should be noted that propylene glycol has known effects on GABA very similar to ethanol.

Propylene glycol elicits anxiolytic responses to the elevated plus-maze in male mice

  
This suggests that the users of ethanol-free BIO30 may also be seeing responses unrelated to propolis.

Propylene glycol even has an E-number, it is E1520.  It is cheap and they even sell it on Amazon.

Food grade ethanol is normally not sold to the public.

In lay terms, ethanol and alcohol are interchangeable, so one corner of the supermarket contains food grade ethanol, with some impurities.

Japanese research suggests that these impurities are much more potent than ethanol in modulating GABA receptors.  It is the fragrant compounds that accumulate over the years on wooden barrels that cause this effect.

The twenty drops of propolis suggested to me by the Japanese PAK1 researcher/doctor contained about 1ml of ethanol.  It seems that to get an effect on GABA similar to this amount of ethanol would require a much smaller amount to well-aged Japanese whiskey.

So if someone over 18 responds well to twenty drops of BIO 30 propolis, it would helpful if they could compare the effect with 1ml of Propylene glycol (E1520), 1ml of ethanol, if they find it, and with a few drops of well-aged whiskey.








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80 comments:

  1. Anonymous23 January 2016 at 12:42

    Congratulations to you and Monty on doing so exceptionally well. I look forward to hearing how your experiences go with the new things you plan to trial this year.
    Nina

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    1. Unknown4 February 2016 at 13:50

      Love this blog! Stumbled on it this morning. My soon to be 25 year old son is severely 'autistic', no speech at all, no real effective means of communication, no academic skills, limited personal care skills, very limited social skills. He must be supervised 24/7 for his own safety. He cannot live independently. I am still searching for the keys to unlock him from'autism' so he can have a real life that he can enjoy... Thank you for this blog and sharing your experiences!❤

      Delete
  2. RG23 January 2016 at 15:41

    A couple of parents on the MAD seizure group have reported that frankincense reduces seizures.

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas23 January 2016 at 17:48

      If you look up frankincense and epilepsy, very many people say that seizures are markedly reduced using frankincense oil applied to the skin. I doubt they are making this up.

      Delete
    2. Peter Lloyd-Thomas23 January 2016 at 18:27

      This paper even suggests Boswellia to increase the learning in those (rats) with epilepsy.

      "Based on the obtained findings from this study and other relevant studies, it can be argued that the consumption of Boswellia extract increases the learning ability in epileptic animals"


      The Therapeutic Effect of the Aqueous Extract of Boswellia Serrata on the Learning Deficit in Kindled Rats
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050676/

      Delete
  3. Unknown23 January 2016 at 21:31

    Peter, my son likes vinegar made from red wine. Once I bought him a nice home made vinegar grown in special barrels with lots of "impurities" inside but he didn't like the strong taste. He only likes the cheap vinegar from supermarkets. Do you think that it contains ethanol?
    As for the E1520, could we use some sweeteners in his drinks?

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    1. Peter Lloyd-Thomas24 January 2016 at 13:18

      In theory the ethanol should become ethanoic acid (acetic acid), but perhaps not all does. Propylene glycol is supposed to have a sweet taste, but I have not tried it.

      Delete
  4. Unknown24 January 2016 at 00:18

    Hi Peter,
    For all subjects related to Propolis please visit www.PropolisScience.org
    In addition, www.NaturaNectar.com has a Patented Pure Water Extraction http://naturanectar.com/solomon-propolis-four-decades-1
    as well as all raw materials coming from Brazil, no envirnomental toxins (protected land), cGMP in USA.
    Extraction method, botanical source and environment, and what the bee's are feeding on are key to constituents of propolis!
    I welcome any questions that you may have, and best to you!
    Jodi

    ReplyDelete
  5. BK28 January 2016 at 19:58

    Hi Peter,
    That maths was so impressive, we discussed about it in our household.
    I am also preparing a spreadsheet for 2016, but we went for testing recently, from DAN and also geneticist/metabolic doctor.
    We have been told by DAN that our son has high deficieny of vitamin Bs (all of them), Vit A and mitochondrial dysfunction.
    We have started on Deplin 15mg (methy folate) as per our genetic metabolist for folate deficiency as a first trial for 2016 - have you heard about it.
    We have been recommended B12 shots to help start speech (main issue) - do you have any idea about B12 shots.

    We are confused with high supplements recommendation, do the high doses of vitamins B & A, E, l-carnitine have side effects?

    Thanks
    BK

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    1. Peter Lloyd-Thomas28 January 2016 at 23:07

      B vitamins are important and there are cases in autism where strange deficiencies exist. Generally blood testing does not show up these deficiencies, it is much more complex.

      There is a new study showing B12 deficiency in the brain of some people, but this does not show up in blood tests.

      Only about 10% of people respond to B12 shots and those people would need them forever. Some people do get side effects.

      The DAN type doctors are treating all their patients as if they have every rare disorder, and all at the same time.

      Delete
  6. Nat30 January 2016 at 10:28

    Peter, what do you think about adding PEA to the list? You wrote about it a while ago, have you tried it yet?

    This case report paper is from 2015:

    "In this original report of two cases, we show PEA-mediated effects may be beneficial for treating core symptoms of autism. PEA is a well-studied, apparently safe even in the pediatric population, anti-inflammatory capable of regulating mast cells and modulating immune chemistry. It is manufactured in the EU and prepared under strict standards according to Good Manufacturing Practice (GMP). PEA also appears to be an atypical endocannabinoid, with additional anti-inflammatory effects mediated via the PPAR pathway..."
    http://www.hindawi.com/journals/crips/2015/325061/

    ReplyDelete
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    1. Peter Lloyd-Thomas30 January 2016 at 14:16

      Nat,PPARα PPARβ and PPARγ are all interesting.

      In our case PEA did not have any effect, but a PPARγ agonist (tangeretin/sytrinol) did have an effect.

      Another reader of this blog, RG, is a big fan of Sytrinol.

      But I can believe in other people PEA may help. I seemed plausible when I was writing about it.

      PEA was shown in the wider population to stop people getting the flu. It was a big study using employees in factory, those on PEA did not get sick.

      PEA is safe, as is Sytrinol.

      Delete
  7. Unknown30 January 2016 at 22:36

    Hello Peter, there is a lot of discussion about the possible benefit of zinc in autism. You mention it in yout articles and it's on your 2016-to do list.
    I am sure you have read the literature and know most of the things that I am going to say here.
    A great deal of autistic population was found deficient in zinc, which takes place in countless metabolic and signaling pathways. Zinc affects immune system, brain function and the "second" brain, the GI system. It is used for digestion of carbohydrates and saccharides. Decreased levels of zinc in the body lead to malabsorption of cholesterol and fats. It even plays a role in the oxytocin regulation. ERK kinase upregulates oxytocin and low ERK kinase signaling may be due to zinc deficiency.
    Lots of our multivitamin complex supplements that we use, including broccoli supplements, contain zinc. However, they also contain cooper and other minerals that work as antagonists to zinc, therefore we might not get the mere benefit of zinc.
    I would like to trial zinc in the form of amino acid and a bacteroides frangilis probiotic for better absorption, so I need your help to find the right product and dosage. Do you have anything in mind?
    Thank you very much

    ReplyDelete
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    1. Peter Lloyd-Thomas1 February 2016 at 11:10

      Petra, if Zinc has a role to play it is likely more complex, so not the amount of zinc but where it is. We are not able to safely move it to the "right place". All we could do is to increase/decrease zinc in the diet on the small chance that this might help. It probably will do nothing, but giving 10mg Zinc a day (the recommended dietary allowance) for a few days will do no harm. Higher doses are used for all kinds of conditions, but there are side effects.

      Delete
  8. BK1 February 2016 at 17:16

    Hi Peter,
    What are the side effects of zinc, my son was recommended 60 mg per day, he is 3.5 and weighs 38 pounds, we did not start on it yet, but we were worried it is too high a dose
    Thank BK

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas2 February 2016 at 10:12

      If you look on google you will find things like this from Mayo Clinic

      http://www.mayoclinic.org/drugs-supplements/zinc/safety/hrb-20060638


      Zinc may cause anorexia, asthma-related symptoms, blood disorders, changes in attention, changes in copper metabolism, changes in iron levels, changes in skin pigmentation, changes in thyroid function, changes in zinc levels, bad or different taste, bloating, changes in cholesterol levels, constipation, decreased zinc absorption, diarrhea, dizziness, drowsiness, dry mouth or nose, fatigue, feeling of burning or tingling, genital or urinary complications, headache, hormone changes, immune changes, increased risk of cancer, increased risk of lung or breathing disorders or infections, increased zinc in the urine, indigestion, kidney inflammation, liver failure or inflammation, loss of smell, mouth ulcers, nausea, skin symptoms, stomach cramps or bleeding, throat irritation, tingling in the nose, tissue death, and vomiting.

      Zinc may increase the risk of bleeding. Caution is advised in people with bleeding disorders or taking drugs that may increase the risk of bleeding. Dosing adjustments may be necessary.

      Zinc may lower blood sugar levels. Caution is advised in people with diabetes or low blood sugar, and in those taking drugs, herbs, or supplements that affect blood sugar. Blood sugar levels may need to be monitored by a qualified healthcare professional, including a pharmacist, and medication adjustments may be necessary

      Delete
  9. BK1 February 2016 at 21:56

    Hi Peter & RG,
    I was wondering if there was a better way to search for comments, I wanted to reply to comment from RG about SCD diet, but cant find it as it is not recent any more.
    Any way, RG & Bhuvaneswari, my son had eczema today, it has almost gone away and his asthma is better since we changed our diet to avoid milk, gluten & grains, we still do fruits. (almost SCD or keto diet)
    Q to RG: I thought berries and fruits were supposed to be avoided in SCD diet, isnt that true?

    ReplyDelete
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    1. RG2 February 2016 at 09:41

      Hi Bhaskar,

      Fruits are allowed on the SCD. All monosaccharides can be eaten, no polysaccharides. That is the reason honey is included, but not sugar, molasses or maple syrup or agave. There are a few other restrictions as well, such as avoiding mucilaginous foods like okra, some lentils and beans, soft cheese, etc. I also avoided nuts, because in sensitive people, they often tend to be a problem. It is also recommended that raw and difficult to digest foods not be included initially.

      I should mention that the best acute intervention I have for eczema, gi difficulties, for both my husband and daughter, is a two to three day ultra simple scd. Homemade chicken broth, a little bit of chicken meat, carrots and zucchini cooked in the same broth, avocado. Only salt and pepper, no other spices. Only bananas, no other fruits. No restriction on quantity. If you are serious about trying the SCD, I recommend the book by Dr. Haas, published in the 50's. My librarian got hold of a copy for me since it was out of print.

      The SCD itself is not a low carb diet, especially with all the fruits. The MAD/Ketogenic Diet can be made SCD compliant which is what my daughter follows. A low carb diet is not necessarily MAD/KD. There has to be ketosis to qualify. This is achieved through a combination of low carbs and high fat. Ketosis can also be achieved by adding mct oil, this way the carb count could be a bit higher. It is very individual though and you can only know through testing several times a day with Keto strips. It is best to do the MAD/KD with some help from your doctor. There are some tests you need to run before beginning and there is a standard panel that has to be done every few months. You also need to watch for acidosis, kidney stones etc.

      I have the same problem with reading comments, I am sure I miss some of them. My feed reader is only loading posts, not comments.

      Delete
  10. Abdul2 February 2016 at 00:27

    Hi Peter,
    Have you tried propanolol also?

    http://www.sciencedaily.com/releases/2016/02/160201122836.htm

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    1. Peter Lloyd-Thomas2 February 2016 at 10:49

      Hi Abdul

      Thanks for highlighting this research.

      I have not tried Propranolol. It has been mentioned on this blog as a therapy for anxiety in autism/Aspergers.

      Some people have found it very helpful and others found no improvement.

      Delete
  11. Unknown2 February 2016 at 17:23

    Peter, you say that Sytrinol helps with inflammation and at first I thought it's a painkiller-anti-inflammatory drug that we don't have it in Greece. Then I saw that it is a citrus supplement.
    It's true that we cannot give ibuprofen or ponstan almost every other day, so Sytrinol seems a good alternative, as long as it works. Do you give it every day, or only when there is a flare up? How much do you think I could use daily?
    Also I give spirulina from times to times, about 2-3 tabs, and I can see benefit. I don't know if it's from years of malnutrition or metabolic dysfunction, or both, but my son seems to lack everything. Would you consider spirulina for autism?
    Peter, my son's first milk (he was also brestfed- my milk seemed awful, like magnesia milk but kept him for 6 months) was fortified with taurine. That milk fed him well, he looked sound and healthy. Have you ever thought the benefits of taurine? There is a product that has magnesium 150mg, potassium 100mg, taurine 100mg per tablet. Would it be better than just taurine 500mg?
    My doctor, the one who makes biotin trials and implies the ketogenic diet for autism, told me that he has some things in mind for my son. I am going to talk to him tonight to see what his suggestions are and let you know.

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    1. Peter Lloyd-Thomas3 February 2016 at 10:13

      Sytrinol shares one mode of action with ibuprofen (both are PPAR gamma agonists), but ibuprofen has other mechanisms of action and the Ponstan affects some relevant ion channels.

      I found Sytrinol to have similar positive effects to ibuprofen, but less potent.

      You need to try it and see if it helps. Your son will be able to decide. Some people find it highly beneficial, others less so. At the moment I use it (150mg) once a day.

      I think 150mg once a day has an effect, but there is a greater effect with 2 or 3 doses a day. Unlike ibuprofen there are no GI side effects, because it is not a COX2 inhibitor.

      Ibuprofen is remarkably effective against certain types of flare up, in our case. A pity it has to used very sparingly.

      I have not looked at spirulina.

      I think your doctor, from the biotin research, should have plenty of relevant ideas for you to try to fine-tune the metabolism.

      Delete
  12. Unknown3 February 2016 at 12:11

    Hi Peter, thanks for your reply.
    Peter, doctor said that my son has very low levels of cholesterol and this has a negative effect on his brain as it is not 'fed' properly. I asked him if there is an underlying mitochondrial dysfunction and said there must be.
    He asked some feedback on biotin supplementation and I replied that something is happening, but it's not always obvious. By the way, as I am running out of biotin, I lowered the dose from 20mg/day to 10mg/day and saw again the benefit. Strange, isn't it?
    Then he advised me on magnesium and vitamin 6 trial, which I have already been doing and it seems positive.
    Today I have to trial carnitine, in the form of acetyl-carnitine which crosses the blood-brain barrier directly and it is more effective. For a start the dose is 1gram/day, for 10 days, if it works raises to 2 grams/day.
    I told him that I ordered L-carnitine and said that I should take it myself. He cured many of his patients out of anxiety and depression with carnitine.
    There will be an autism/metabolic dysfunctions conference in England, on 18 of June, where he is invited to give a lecture. He told me that he will send me an invitation.

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    1. Peter Lloyd-Thomas3 February 2016 at 13:36

      Petra, since you have found such a nice doctor, might I suggest you show him the following paper:-

      Treatment of Smith-Lemli-Opitz Syndrome and Other Sterol Disorders
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890258/

      Your son dose not have SLOS, but he might well benefit from therapies in that paper.

      To the surprise of regular of most readers of this blog, one therapy for these low cholesterol disorders was a statin. This is the classic cholesterol lowering drug, but is actually raised cholesterol levels.

      "Statins have also been suggested for treatment of SLOS. Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that crosses the BBB. It inhibits the cholesterol pathway proximal to the enzymatic defect in SLOS. In unaffected individuals taking statins, there is reduction in endogenous cholesterol synthesis. Although it might seem counterintuitive to use a cholesterol lowering medication such as simvastatin in a syndrome of cholesterol deficiency, investigators hope that by blocking the cholesterol biosynthesis pathway proximal to the location of the defect in SLOS, the abnormally high levels of potentially toxic 7DHC and 8DHC can be reduced [Jira et al., 2000]. Statins upregulate DHCR7 in animal models and in vitro in human cell lines, which could be therapeutic if a similar upregulation can be achieved in vivo [Correa-Cerro et al., 2006; Wassif et al., 2005]. SLOS fibroblast cell lines with residual DHCR7 enzymatic activity treated with simvastatin increased fractional cholesterol synthesis and decreased 7DHC levels [Wassif et al., 2005]. The seemingly incongruous increase in cholesterol from simvastatin in SLOS might be due in part to sterol regulatory element-binding proteins (SREBPs). SREBP-2 regulates the metabolism of cholesterol, and in an individual with SLOS prescribed simvastatin, SREBP-2 increased the expression of DHCR7 [Porter and Herman, 2011]. Statins also have antioxidant effects that may provide additional benefits"

      The change in biotin is interesting. With potassium, it only a quick change that has an effect, eating a banana has none. Perhaps biotin every other day might also work well.

      Delete
  13. Agnieszka Wroczyńska5 February 2016 at 14:33

    Hi Peter,

    I think your 2016 to-do list is a good answer for my previous question about "how many pills...?". As many as needed based on risk-benefit assessment? The more pills I use however, the more I appreciate non-pharmacological interventions like Nat's idea of mint leaves, which my son eats like crazy.

    I have one question from another reader, which I also was wondering about: does Bumetanide effect reduce over the time? You wrote in this post that with Diamox "the same changes that were noted when starting bumetanide appear again". Does it mean that some early Bumetanide effects have been lost in the meantime or one just gets used to some kind of "new level" in terms of behavior or cognition? Some effects are obviously persistent in my son (sensory issues improvement), while I am not that sure for others.

    If there is any feedback loop involved, then maybe temporary withdrawal of Bumetanide would make sense? Once we run out of Bumetanide and indeed restarting it was very remarkable, although it was on holidays and I thought it's because of that.

    And another question from another parent: if the child benefits from Picamilon, could we say anything about the chance for Bumetanide effects? (I don't think we can say for sure unless try). And that's perhaps a question to Tyler: did you start Picamilon before Bumetanide? I can't find your comments about it and about the dose. I would appreciate your help with that.

    With regard to the 2016 list, I've recently found some old paper suggesting that: "Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.":
    http://www.ncbi.nlm.nih.gov/pubmed/15635412

    And it had been used for autism already:
    http://www.ncbi.nlm.nih.gov/pubmed/25767546

    Do you think that it may be relevant to what parents see when the child is put on typical antibiotic for example for common Strep infections? Could that be an indicator that a child may benefit "glutamate" targeted treatments? In the paper below many glutamate transporter EAAT2/GLT-1 “neuroprotective activators” are suggested:
    http://www.ncbi.nlm.nih.gov/pubmed/26096891

    Including nicergoline (Sermion) which was - if I remeber well - here by Maja long ago. One more pill to think about?

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    1. Peter Lloyd-Thomas7 February 2016 at 17:18

      I tried Picamilon and it had a bad, agitating, effect almost straight away. It looks like a Selective Extrasynaptic GABA Receptor Agonist might potentially have a beneficial effect. These are being developed for Angelman and Fragile X, the science behind them is quite clever. There will be a post on it.

      I think we likely take for granted the cognitive enhancing effects of Bumetanide, however very many interventions seem to work best at the start.

      Biotin seems to make a difference, but the greatest improvement is when you start, or change (even reduce) the dosage.

      Occasionally stopping, and then restarting, may well optimize the results of many therapies.

      Your case report is very interesting. Being on antibiotics long term is not a good option, but the parents found 7 days of therapy resulted in 5 months of relief. That is a good trade off, but why does the effect last so long? I think this rules out some possible modes of action, which would be only short term (e.g. increasing glutamate transporter expression). For the benefit of others:-

      “According to his parents’ reports, the patient took cefixime 200mg/day to control diarrhea about 2 years ago. The seizure episodes were dramatically decreased 3 days after starting the medication while the there was no change in his anti-epileptic medication regime. The seizure episodes were controlled for about 5 months, after which the number of seizure episodes again increased. His highly educated parents administered cefixime 200mg/day to control seizure again. They reported that seizure attacks were controlled markedly after taking cefixime for three days. The patient was not febrile while the medication trials were administered. Both parents reported that they repeated this trial for several times to control the seizure episodes in the recent years”

      We should be thankful for his highly educated parents !!

      I think that there are likely multiple reasons why certain people with autism benefit from specific antibiotics. This all gets lost in trials, that are not sub-group specific.
      By trying different antibiotics you could figure out what the mechanism might be. As you suggest with cefixime, it may be nothing to do with the effect on bacteria.

      Minocycline has the well-known effect on microglia.

      Perhaps in some people though the problem is bacterial; by trying different antibiotics you could narrow down where it is. If oral vancomycin works, you know the bacteria is intestinal.

      Most people seem to notice that any benefit from antibiotics is short term. Increasing glutamate transporter expression might explain some of this, but I expect in other cases the explanation is different. So it remains a case of parents having to notice when autism improves, or gets worse, and connect this with what has changed be it some medication, toothache, fever, allergy or something else. Then they can start to narrow things down.

      Studies have shown that nicergoline increases nerve growth factor in the brain. So it should be good for girls with Rett Syndrome and most old people, but might be unhelpful for those with classic autism, who have high NGF to start with.

      It does get complicated and you do need to limit the total number of interventions, by dropping the least effective old one, when you add a new one.

      The fact that lasting improvements can be made at all has not ceased to amaze me. Informed trial and error and some experimentation is unavoidable.

      Delete
    2. Tyler9 February 2016 at 07:42

      Sorry to hear about Picamilon (at least you can still legally get it if you choose to, unlike here in the USA). Also, you may or may not know that there was an important study last year that showed that it is likely GABA itself crosses the blood brain barrier much better than past research has suggested:

      http://www.nature.com/articles/srep12770

      So this is probably an alternative to Picamilon for raising extracellular GABA in the brain.

      But as you well know there are many paradoxical studies that have shown that GABA is either reduced or overexpressed in the autistic brain. Adding Picanilon or GABA or any other GABAergic analog that directly stimulates the GABA subunit of the GABA receptor won't do a lot of good if there is excessive GABA in the brain already or else if there is too much chloride in interneurons (leading them to a depolarized state).

      Perhaps you can try straight GABA and see if you get the same response as Picamilon?

      Another thing to consider which is especially important and that you may or may not be aware of is that in the superchiasmatic nucleus, bumetanide type interventions may modify circadian rhythms:

      http://www.pnas.org/content/112/29/E3920.full.pdf

      This means giving Bumetanide too close to bedtime may modify the day night cycle to favor a short day cycle (winter) versus a long day cycle (summer). Of course if the day night cycle is already extended via the GABA interneurons being excitatory, Bumetanide could help autistic individuals stay asleep if timed correctly. The other thing about Picamilon is that I coadministered it with Bumetanide, but many people do Picamilon at bedtime (which if you did meant that the Bumetanide may have been largely flushed out of his system by then).

      Also, if your child had a paradoxical response to Picamilon (which is typically sedating) and has a paradoxical response to GABA, then maybe more Bumetanide would help (dosage for Bumetanide for neurological purposes as I understand the literature is still an open ended question). If on the other hand, your child has a bad reaction to Picamilon, but had a positive or at least sedating response to GABA, then maybe the Niacin component of Picamilon is what is causing him problems (some people respond very poorly to niacin, especially those with histamine issues):

      http://jpet.aspetjournals.org/content/327/3/665.full

      Have you ever done a niacin flush test on your son? From memory I think it was that in an adult if you flush from 50mg niacin it means you have high histamine levels, 100mg you have balanced histamine levels, and 150mg or higher then you have low histamine levels (you will have to check yourself since I am not 100% sure on this).

      Delete
    3. Peter Lloyd-Thomas9 February 2016 at 10:23

      Thanks Tyler, I think you could well be right that niacin is the problem. Increasing GABA using a tiny dose of Valproate, produced a good effect, but Valproate is not a good choice for long term use, even at a tiny dose.

      A more potent centrally acting selective NKCC1 blocker would be ideal. Ben-Ari is fully aware of this. There would be no diuresis since there would be no effect on NKCC2.

      A higher dose of bumetanide did not have a further effect.

      It would be good to know how much GABA does cross the BBB. Many people, without autism, taking GABA pills seem to find an effect, or is it all placebo effect?

      Delete
    4. Agnieszka Wroczyńska9 February 2016 at 13:38

      Hi Peter and thanks for answers.

      I know too little about epilepsy to understand fully this response to cefixime. There are also too few details in this case report about how and for how long this treatment affected the child in other ways although they mentioned the reduction in aggresive behaviors very briefly.

      I just thought that it might be possibly an important information to parents, that when a child's autism improves unexpectedly on beta-lactam then one should explore the glutmate issues (or: E/I treatments) along with infections impact on autism.

      What I remeber is that my son experienced very clear, but short-term improvement on cefuroxime and I thought it's about controlling the infection related inflammation. But I have just checked my boring daily notes to see that he got cefuroxime twice for aphtous stomatitis which occurred in the middle of his "migraine episodes" and on both occasions such "episode" quit in day then, while it took longer to treat stomatitis. Behavioral improvement did not last five months however...

      I am sure I saw niacin on the lists of mast cell degranulation triggers published by some mastocystosis society.

      The question from another parent was about her son who improved on Picamilon and she thinks now about Bumetanide. One could expect paradoxical reaction to Picamilon if there is NKCC1 dysfunction, but maybe this is too simple way of thinking.

      Delete
    5. Peter Lloyd-Thomas9 February 2016 at 14:37

      This comment has been removed by the author.

      Delete
    6. Peter Lloyd-Thomas9 February 2016 at 14:46


      Hi Agnieszka, I think there is more to be discovered about those mast cells. It appears that 50% of histamine in the brain is from mast cells in the brain, so H3 receptors only modulate 50% of central histamine.

      I am pretty sure Verapamil's good effect in my son is related to mast cells and allergy. I could never explain though how it could be that I still need an H1 antihistamine to control hay fever symptoms, if Verapamil was such a good mast cell stabilizer. Perhaps Verapamil's benefit in my son is stabilizing mast cells in the brain.

      Mast cells are known to cross the BBB and so they should be able to communicate.

      Did you consider trying a small dose of Remeron/Mirtazapine to see if the central histamine effects are beneficial? The reader who found it very helpful gave only 7.5mg at bedtime.

      Delete
    7. Tyler10 February 2016 at 01:30

      Pretty much all of the research I have read constantly reiterates that GABA crosses the blood brain barrier very poorly in animals and presumably humans. The nature paper I cited suggested things might not be so simple and there was another paper I read recently dealing with nitric oxide and vasodilation/vasoconstriction that suggested the blood brain barrier is a lot more flexible than previously thought. The study done suggested oral GABA increased inhibition in the striatum in a group of adults, but they didn't exactly take brain samples or anything like that. It could be that this might be a situation where things work differently in other animals versus in humans or it could be GABA is having some other inhibitory effect via an indirect pathway, perhaps the vagus nerve or the immune system.

      As to Agnieszka's question, yah you have it pretty much correct in terms of my line of thinking here as Picamilon seemed to cause anxiety BEFORE I started with bumetanide. About two weeks in, I had read another recent study on GABA levels in the brain of autistics being too low (there are many studies to the contrary I must hadd) so I thought trying Picamilon again would be worth a shot and there seemed to be an immediate positive effect this time until I went to order some more and realized an idiot politician Senator from Missouri named Claire McCaskill single handedly got Picamilon banned from the United States, likely to test the waters in banning many more supplements (Express Scripts is one of her biggest campaign contributors).

      My experience with Picamilon and Bumetanide is a sample size of 1, but the reason I mentioned it was that I had a bad experience with it initially in my son and then it seemed to give an acute cognitive boost on top of the benefits of Bumetanide. I don't give it to him anymore (I have a small amount saved up still) because it is banned from production or import due to corrupt politicians.

      Delete
    8. Agnieszka Wroczyńska10 February 2016 at 17:32

      Tyler, thanks for explanation and sorry to heart about Picamilon problem. So many things do not make sense in autism, just as Peter pointed in the new blog entry.

      Peter, do you think that low dose Remeron/Mirtazapine would differ than old generation H1 blockers? I occasionally used Benadryl/Diphenhydramine as a "rescue" drug during flares with good effects. It was Fenistil/Dimetindene behavioral effects given instead of Risperidone prescribed to my son that made me found your blog. Some other old H1 antihistamines however made him irritable.

      Now I think that perhaps with the correct (low) dose you can expect central antihistamine action while avoid other unwanted effects for example anticholinergic. I once saw a message board where people discussed low dose Benadryl/Diphenhydramine for mitochondrial issues/autoimmune CNS conditions. I am sure that I saw Roger Kulp's comments there. I always wanted to ask Roger about that.

      I remember papers by dr L. Afrin, who treats mast cell disorders in the US, in which he discuss a lot of treatments, inlcuding Doxepin as antihistamine.

      Delete
    9. Peter Lloyd-Thomas12 February 2016 at 14:51

      Agnieszka, I think the first generation H1 antihistamines have widely varying effects and also work slightly differently in different people. Most people would never try Mirtazapine by accident. In the US very many kids use Benadryl/Diphenhydramine, in the UK they do not (UK Benadryl contains cetirizine or acrivastine). The comments about histamine effects on autism that I receive have been about 2nd generation drugs, not Benadryl.

      There is a trial showing Mirtazapine effective in 36% of subjects with autism and we have the reader who found 7.5mg at night has a good effect throughout the day.

      So I think trying 7.5mg of Mirtazapine in someone with autism, plus mast cell issues, is well worthwhile.

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    10. Agnieszka Wroczyńska12 February 2016 at 23:48

      You are right.

      I stumbled upon a case report about 5yo in whom severe autism core symptoms improved with 5 mg mirtazapine. He went down on CARS from 41 to 28 in six months.

      "A 5-year-old male child was admitted to our Pediatric Unit for a severe impairment in attention level, poor response to environmental stimuli, almost absent affective interaction with his mother, stereotyped and repetitive motor and verbal mannerisms (undulatory movements of the head associated with flapping of the right hand, tricotillomania, echolalia), irritability, aggressiveness, significant food selectivity, and inappropriate hypersexual behavior consisting of compulsive public masturbation."

      "After 6 months of treatment there was a considerable
      improvement with respect to all the autistic features: (1) strong improvement in attention deficits; (2) reduction and final disappearance of motor and verbal stereotypies; (3) lack of irritability and aggressiveness; (4) improvement in social and communicative behavior (adequacy of response to environmental stimuli, appropriate response to separation from parents, initiation of symbolic play, appearance of the pragmatic use of language)".

      The authors suggested serotonine as target of this treatment, did not mention anithistamine mechanism of action and wrote that the effects were "in some ways unexpected".

      Now for me it's the title of this paper in some ways unexpected:

      "Compulsive masturbation in infantile autism treated by mirtazapine."

      Have you seen it?

      http://www.ncbi.nlm.nih.gov/pubmed/16648008

      That in next 10 years no one attempted to replicate this result in the science is not unexpected for me anymore.

      Mirtazapine is said to interact with benzodiazepines, but it's about sedation so I guess low dose clonazepam is not a problem. It is recommended to use it with caution with CYP34A inhibitors. Acetazolamide/Diamox is one of them so maybe mirtazapine dose will have to be lowered when used together.

      Delete
    11. Nat13 February 2016 at 10:50

      I am wondering if a combination of h1 and h2 antihistamines would be worth a trial in autism, at least in cases with suspected or confirmed mast cell disorders and allergic/sensitivity reactions and mysterious ‘gut’ pain. Besides the fact that h2 blocker famotidine was one of those things that showed great promise for autism (and later schizophrenia, if I remember correctly) in that small trial that was never followed up, the combination of these different types of antihistamines often has superior effects compared to h1 ones by themselves. Btw the case of h2 antihistamines there are indications that they should not be administered for longer than few days or weeks without h1 ones on board, as they can actually increase IgE and susceptibility to allergies.

      “It has been suggested that the H 1 antagonist-H 2 antagonist combination inhibits the release of allergic mediators, whether IgE dependent or otherwise…”
      http://www.bioline.org.br/request?dv08203

      “increasing reports of beneficial effects of H2-antagonists, mostly in combination with H1-antagonists, in a variety of allergic and pseudoallergic conditions such as chronic urticaria, anaphylactoid reactions due to colloid volume substitutes, opioid analgesics and radiographic contrast media. The combined use of H1- and H2-antagonists might not only act as specific histamine antagonism but exert a mast cell stabilizing effect, as demonstrated in animal experiments and some clinical studies.” http://www.ncbi.nlm.nih.gov/pubmed/1977507

      this could be relevant to some ‘autism’ http://www.ncbi.nlm.nih.gov/pubmed/16528434

      also for example http://www.ncbi.nlm.nih.gov/pubmed/1977785

      and discussed in this book on mast cell disorders http://tinyurl.com/gucj2jj

      Delete
    12. Peter Lloyd-Thomas14 February 2016 at 22:21

      Agnieszka, yes I saw that study with the strange tittle. I think it likely that the effect of a small dose would be noticeable within a day or two.

      Delete
    13. Peter Lloyd-Thomas14 February 2016 at 22:37

      Nat, Famotadine (Pepsid in the US) was trialled at 2mg/kg by a Dr Linday. He has his own website (www.DrLinday.com), but strangely the autism part is unavailable due to technical difficulties (rather odd). Maybe he got into trouble.
      Lots of kids with ASD have GERD/reflux and so they might take a lower dose for that condition.
      I have given it for reflux but at the lower dose.
      If you lower stomach acid for a long period, you create other problems like low vitamin B12 levels.

      Delete
    14. Agnieszka Wroczyńska15 February 2016 at 12:22

      Nat,

      A quote from dr Afrin paper on MCAS: "Antihistamines typically are first-line therapies for chronić control of MCAS and often highly useful in the emergency management of the disease, too. To minimize histamine-mediated mast cell activation, most MCAS patients should try a histamine H1 receptor blocker in combination with an H2 receptor blocker.". Apart from histamine-mediated symptoms control it is suggested that H1+H2 block mast cells further degranulation induced by histamine reacting with H1 and possibly H2 receptors on mast cells themselves. I think that it's good idea to try all treatments used in MCAS in people with autism and suspected mast cell activation. As dr Afrin pointed in this paper, there are few studies on MCAS treatment, so a trial and error is the way to manage it.

      https://www.novapublishers.com/catalog/product_info.php?products_id=42603

      In my son however it was Verapamil which had the best and immediate effect on GI and other symptoms, that were presumed to be mast cell related. Ranitidine (in addition to H1 blocker) had no obvious effects and Montelukast made him very angry while Sodium cromoglicate is still indispensable for control of perpiheral mast cell activation symptoms. All are used in MCAS or mastocytosis. So I agree it's a trial and error.

      One of the first papers on MCAS reported that "67% of the patients in the cohort had either a complete or major regression in symptoms while taking medications targeting MC mediators" and first line treatment in these patients was H1+H2 blockade.

      http://www.ncbi.nlm.nih.gov/pubmed/21621255

      I don't know if you can expect the same in people with autism+mast cell activation, but 67% was high enough for me to search for MCAS confirmation in my son - in case first line treatment fails it's easier to use more risky drugs with the diagnosis confirmed.

      Delete
    15. Agnieszka Wroczyńska15 February 2016 at 13:19

      Peter, I couldn't believe when I saw this case report about Mirtazapine use. What they reported was in fact a very succesful treatment of severe autism to be highlighted and explored asap. They knew what they saw having written in conclusions section: "daily treatment of 5 mg was sufficient to control the core of autism symptoms". If you found a drug for surviving Ebola would you title your paper: "Succesful treatment of Ebola induced fatigue" for example? I saw this case report later inculded into the review on autism treatments, which authors seem to read titles only (PMID: 23226952). In this way the paper which shows that at least some autism is treatable is then used to prove it's opposite.

      Just wanted to make sure if I understand it correctly: it is H1 central blockade that might be associated with mirtazapine effects (not serotonine receptors), so it's low dose what is needed, according to this receptor selectivity chart:

      http://thelastpsychiatrist.com/images/remeron.JPG

      I am cautious about drugs that block serotonin receptors in my son.

      Delete
    16. Peter Lloyd-Thomas15 February 2016 at 21:16

      Agnieszka, in my opinion it is the central H1 blockade that is likely to give the autism benefit, but it may be more a case of mirtazapine by chance has a more potent effect in the areas of the brain that matter most. I think you can only tell for sure by trying the small 5mg dose. If you give it before bedtime, I think you will know the next day if your son is a good responder.

      Delete
    17. Nat15 February 2016 at 23:01

      Mirtazapine action on opioid receptors could also be behind the observed effects in that boy, i.e. reducing core symptoms of autism (think LDN!)

      https://www.ncbi.nlm.nih.gov/pubmed/12372565

      https://www.ncbi.nlm.nih.gov/pubmed/11931344
      … Summing up the various interactions of venlafaxine and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that … the antinociceptive effect of mirtazapine mainly involves mu- and kappa3-opioid mechanisms. This opioid profile of the two drugs may be one of the explanations to their efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity.

      Delete
    18. Nat16 February 2016 at 02:47

      PS mu opioid receptors have been observed to play a key role in 'social behaviours' of 'autistic mice' in this study, published in Nature:

      "... our data provide first evidence that disrupted mu opioid receptor signaling is sufficient to trigger a comprehensive autistic syndrome, maybe through blunted social reward processes ..."
      http://www.nature.com/npp/journal/v39/n9/full/npp201459a.html


      This paper hypothesises autism and fibromyalgia as Disorders of the Endogenous Opioid Hormonal System

      http://www.discoverymedicine.com/Brian-Johnson-2/2014/10/fibromyalgia-autism-and-opioid-addiction-as-natural-and-induced-disorders-of-the-endogenous-opioid-hormonal-system/

      Delete
    19. Agnieszka Wroczyńska18 February 2016 at 20:34

      Thanks for all information. I think Mirtazapine is worth trying. I have recently started Mefenamic acid during infection to prevent inflammatory triggers for migraine and it seems to work for that. So I will wait with another intervention until the infection is over and in the meantime I will have to answer the question if it makes sense and is safe to give both Mirtazapine (as H1 blocker) and Rupatadine (H1 blocker which I use).

      I wish we knew more medical details about this Italian boy who improved on Mirtazapine, not only his behavioral description.

      Delete
    20. Nat20 February 2016 at 17:55

      Peter and Agnieszka, I forgot to include the title of the paper referenced above:

      "Autistic-Like Syndrome in Mu Opioid Receptor Null Mice is Relieved by Facilitated mGluR4 Activity"


      It sounds like mGluR4 can be approached from more than one direction...

      Delete
    21. Nat20 February 2016 at 18:23

      Peter, I posted on another thread about mitrazipine's effect on mu opiod receptors, which may well be behind its observed effects in autism (in addition to or instead of its effects on histamine or serotonin receptos).

      That small naltrexone trial for autism, as well as numerous reports from parents who have tried Low Dose Naltrexone reported improvements in those very same areas, notably irritability, aggression, low moods. Naltrexone acts primarily on mu opioid receptors.

      Now what is REALLY interesting about this study on ‘autistic' mice who lacked mu opioid receptors is that these mice had lowered activity of quite a few genes implicated in autism. Although the genes themselves were intact, something something linked to the lack of mu receptor activity made all these genes go quiet.

      "Inactivation of the mu opioid receptor gene, therefore, alters expression of several candidate genes for ASD"

      Look at the list of the things they found (my bolding and spacing):

      "We detected changes in the expression of genes coding for the adhesion and scaffold proteins
      ------ neuroligins (Nlgn1 and Nlgn2) and SHANK3 (Shank3).

      Transcriptional levels were also modified for the genes coding transporters of
      ------ norepinephrine (NE, Slc6a2)
      ------ dopamine (DA, slc6a3)
      ------ and serotonin (5HT, slc6a4),
      ------ as well as several receptors, including beta3 subunit of GABAA receptors (Gababrb3)
      ------ and 5HT2a serotonin
      ------ and D2 dopamine receptors.

      The most dramatic changes in expression were observed for the genes coding the
      ------ neuropeptides CRH and OXYTOCIN.

      Expression of Grm5, coding these receptors, was not modified in Oprm1−/− mice; HOWEVER expression of
      Homer3, coding a key molecular interactor of mGluR5 receptors, was significantly downregulated…"

      They conclude that "Stereotyped and perseverative behaviors detected in Oprm1−/− mice further complete autistic-like core symptoms in these animals. In addition, mutant mice show multiple comorbid symptoms of ASD, including aggressiveness, exacerbated anxiety, motor clumsiness, and increased susceptibility to seizures. …”

      The researchers then go on to test treating two of the affected pathways simultaneously, with some really interesting results, concluding that "facilitation of mGluR4 signaling was able to restore social reward in these animals."


      Apart from mirtazapine and obviously naltrexone, are there any other agents capable of modulating mu receptors that you think could/should be trialed for autism?



      (that mice study can be accessed in full via
      http://www.nature.com/npp/journal/v39/n9/full/npp201459a.html

      Delete
    22. Tyler21 February 2016 at 11:49

      There are many agents actually, just you need to do a lot of research about drug addiction. I have read so many papers lately on the matter I will probably have the DEA at my doorstep any moment. I have a couple big wins lately in addressing this very issue with novel treatments independent of naltrexone and related compounds.

      Delete
    23. Anonymous31 May 2016 at 17:59

      Apart from mitrazapine and naltrexone, another agent that is capable of modulating /upregulating mu opioid receptors is NICOTINE.

      There are several reports out there of good effects of (low dose, chronic) administration of nicotine patches as well as other nicotin-acting agents in autism. The late Dr Bradstreet was recommending 1/4 patch per every 24-hour cycle.

      Delete
    24. Anonymous3 September 2024 at 20:23

      Agnieszka, here is the study you requested 10 years later. :)

      A randomized double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in children and adolescents with autism spectrum disorder

      https://www.nature.com/articles/s41386-022-01295-4

      -stephen

      Delete
  14. Anonymous9 February 2016 at 00:31

    Hi Peter,
    our son (4.5yo) is mild autist. Now the behaviour is going worse...
    We would like to try Diamox along with bumex (bumex we already tried). As you wrote you tried already. Can you please suggest some dosage for 16kg 4.5year old boy?

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas9 February 2016 at 10:34

      Did you try bumex for long enough? It can take a month to show effect. I used 125mg diamox, in a 12 year old.

      Mild autism may be very different to the classic autism I have experience of. Many people with Asperger's seem to benefit from Baclofen, which did nothing for us.

      Delete
  15. Anonymous9 February 2016 at 12:05

    Hi Peter,

    Edging closer to approval for a trial of Bumetinide. For the hoops we've jumped through to date to garner support in trialling, it'd bloody better work. Just kidding, we've been in this game long enough to know that guarantees are null and void once you open the bottle.

    Sure we could circumvent the system but a layer of comfort is added when the trial has the blessing of the establishment. This brings me to my next point on predetermining prospective candidates for Bumetinide.

    You've commented that the best way to establish response to Bumetinide is to trial it - and I would agree. However, the article in the link below suggests to test for paradoxical responses to GABA-enforcing drugs (benzos etc.) as a means of establishing the likelihood of a significant clinical response.

    How accurate could such a test be in establishing this likelihood? Testing for this effect even post-trial could give candidates that derived no positive response a basis why.


    http://pediatrics.aappublications.org/content/136/2/e539

    Regards,
    D&G

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas9 February 2016 at 13:15

      Hi D&G, it was this very paradoxical response that suggested to Ben-Ari that Bumetanide might help some autism. He was told by a psychiatrist (Lemmonier) that in some of his patients with autism, valium has the opposite effect to the expected calming one.

      It is much better to try Bumetanide for a month. In your case, with higher functioning autism, I think you should also be trying Baclofen. I think it >50% likely that one would work in your case.

      Delete
  16. SarahMR21 March 2016 at 23:27

    Hi Peter, Thank you for creating this website, I do not have the science knowledge like you do but I recently came across this copper supplement Mitosynergy which crosses the BBB unlike normal copper supplements, It supports poorly firing neurons. Please could you add your thoughts/opinions on this notion and whether it holds validity? thank you. kind regards Sarah https://www.mitosynergy.com/product/mitolipo/

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas22 March 2016 at 11:11

      Sarah, Dr Richard Frye who knows a lot about both autism and mitochondrial disease was paid by the producer to test Cunermuspir. Why not send him an email and ask him? I could not find any published outcome.

      It is very expensive.

      In previous studies of some expensive drugs for mitochondria, they found melatonin was even better. Melatonin is very cheap.

      Richard E. Frye, M.D., Ph.D.
      http://www.arpediatrics.org/index.php?Itemid=275&option=com_uams&view=faculty&sap=00038645

      Effect of Cunermuspir on In-Vitro Mitochondrial Respiration in Normal and Autistic Cell Lines, MitoSynergy, 2014-10-01 00:00:00-2016-05-15 00:00:00

      Delete
  17. Anonymous31 May 2016 at 15:52

    Hi Peter,

    I have read your blog with immense interest as I am now moving on from standard OTC biomed to more intensive intervention with my son, who presents with classic, rather energetic autism.

    My working theory is that GABA receptor disfunction may be the main culprit based on genetic sensitivity and augmented by environmental factors such as the absence of oxytocin or introduction of certain other chemicals.

    GABA enhancing interventions such as NAC and curcumin seem to make my son even more hyper, so I am thinking maybe the GABA is excitatory at the moment for his system.

    I happen to have some Diamox about and was thinking of starting him on 40mg to see how that goes. I should be able to get bumetanide in a month and clonazepam in the next few weeks, so it will be interesting to see if GABA increasing therapies have a pronounced effect after these, although theortically shouldn't we see some effect after Diamox alone?

    I'm a bit wary of bumetanide due to potassium drainage - his main behaviour is heavy, almost constant flicking of his lips and legs and he frequently suffers from sensory overload. His potassium blood levels look fine, but I feel he may be lacking and am about to start him on some supplements as I'm not sure what else can stop the flicking (can you name the French brand you use?) as magnesium isn't effective.

    Any other ideas on how to stop constant flicking?

    Thanks

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas31 May 2016 at 17:31

      Diamox should have an effect alone. 40mg is a small dose, but no harm in starting low. In my son it produced reflux as a side effect, but many people have no side effects.

      Bumetanide is well tolerated and many people do not even need extra potassium. I give BIOFAR potassium+magnesium, it is 500mg K and 150mg Mg and I give half in the morning and half in the evening.

      Your son may have a tic disorder rather than stimming/stereotypy, which would explain why NAC does not help. Tourettes is the well known tic disorder but there is a whole spectrum. I suggest you look into these disorders.

      Delete
    2. Anonymous8 June 2016 at 23:33

      Thanks Peter, we are starting him on 1/4 tablet twice a day, which is 60mg or so. Think I may drop the NAC and give it a few weeks, only other thing we are giving him is Pro-EFA for apraxia.

      Next on the list probably Curcumin (Meriva blend) and Supersprouts should arrive in a few days.

      Looking at the treatments for tics/tourettes is extremely interesting: http://www.nhs.uk/conditions/Tourette-syndrome/Pages/Treatment.aspx

      NHS recommends baclofen, clonazepam, clonidine.. I think inositol is worth a try in this case.

      Delete
    3. Anonymous9 June 2016 at 22:05

      Just to note looking up the full range of indications for diamox it is also potentially potassium leaking and a folic acid antagonist potentiator, which could disrupt the methylation pathways unless folate is supplemented (https://www.medicines.org.uk/emc/medicine/22217). Probably exacerbates GERD too given acidity increase?

      Delete
  18. Kolin28 July 2016 at 23:21

    I was wondering if you had looked into the validity and future of TMS therapy. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295436/
    I don't see any mention of this on your site. It seems to be getting a good bit of media attention and wondered if you had any thoughts.

    ReplyDelete
  19. Anonymous7 April 2017 at 08:53

    Hi Peter,
    Thanks for an extremely interesting blog.
    I actually started out thinking this was just another pseudo-scientifical blog stuffed with random links to more scientific texts... I mean, the idea that autism, asthma/allergy and gastrointestinal problems would have common causes (and cures) just sounded too far-fetched. Somehow in my own research I just happened to get her time and time again while googling on different interventions. And slowly I've been starting to see that the patterns you are describing aren't crazy, but brilliant.
    What I have appreciated a lot with your blogs is the hierarchy of easier/more complex texts. There are the links to different studies for those who want to read all the details. Then you have the cut-and-pasted texts with the most interesting parts that sometimes are highlighted i yellow or green. And finally, often at the end and the best of all, your own summary/conclusions on how this information could be used or tested in real life.
    Once again, thank you for enlightening me though I was resistant at first!
    I'll be back with my own questions and comments.
    /Ling

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas7 April 2017 at 09:41

      Ling, thanks for the comments. I also find myself often getting referred back to my own blog by google.

      It was hard for me to believe that there could be so much in the research that has not been applied in medicine. You have to discover this for yourself. We all assume medicine is science, but it is the science of 30 years ago.

      Delete
  20. Anonymous19 April 2017 at 22:08

    Peter I refer to this quote Dr Kelley also uses Ibuprofen as a short term therapy to counter the effects of increased cytokine production. Montelukast is more potent and has different side effects, meaning it might be a better choice than ibuprofen for some people.

    Do you think Montelukast is still a good choice as we found out by chance after giving a high dosage of ibuprofen that there were positives.
    The side effects seem quite worrying with regards to Montelukast

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas20 April 2017 at 08:22

      Montelukast is widely used in children with asthma as a long term therapy, as an alternative to a steroid inhaler. Ibuprofen is not a good choice for long term use. All drugs can have side effects. I think it is worthwhile to see if Montelukast has a positive effect.

      Delete
  21. Anonymous11 August 2019 at 16:35

    This is probably for Tyler. I would very much like to try the niagen as recommended by Tyler, I can't seem to find the HPN product that lists nicotinimide Riboside as the ingredient, instead it is listed as as nicotinimide riboside alternative. Can you steer me toward the exact HPN product? Thanks.
    Nancy

    ReplyDelete
    Replies
    1. Tyler11 August 2019 at 20:44

      https://www.truniagen.com/

      Nicotanimide Riboside is not patented (it is found in trace amounts in milk) but there are patents still in effect for the efficient manufacturing of NR. The company that owns these patents is called Chromadex. My understanding when I looked into the same confusion you have right now is that Chromadex decided it would be better to sever all their ties as a supplier to other products that included NR and then just sell it exclusively themselves.

      Part of this was because they got into a legal dispute from a company from a famous MIT scientist that had a product called Elysium which was basically NR plus Pterostilbene and then it was sold as a monthly anti-aging subscription for a marked up price.

      Elysium I think is now using Nicotanomide Monoamide (NMN) which is similar in function to NR though of course since many of the science studies on NR and NMN are a bit biased due to being funded by companies such as Chromadex.

      Also, I think Chromadex was forced to relabel their NR product which they called simply "Niagen" because the form of NR which they were marketing was actually Nicotanimide Riboside Chloride after testing from the FDA.

      So the TruNiagen product and all the marketing fluff behind it is what you want now even though it is the same stuff you might of previously found in other sports enhancement or anti-aging products in a vitamin store, just now it is exclusively sold by Chromadex (because of the patents) even though it is about as expensive as it has always been (maybe even cheaper due to the competition from NMN and hopefully will be even cheaper in the future).

      In spite of all the negatives I have pointed out, if I was President of the United States, I would give everyone a yearly supply of the stuff to keep healthcare bills down (among other things but NR/NMN in my opinion lives up to the hype), because low NAD+ levels from excessive stress and aging itself cause so many other downstream problems.

      Delete
  22. Unknown12 August 2019 at 23:07

    Tyler,
    So in the TruNiagen product, it is 125 mg nicotinamide riboside chloride, but provides 110 mg nicotinamide riboside.
    This dose of NR per capsule appears less than the original product you were recommdending. What would the # capsules be for an adult?
    Thanks for your help.
    Nancy

    ReplyDelete
  23. Anonymous12 August 2019 at 23:11

    Tyler, so the Tru Niagen product has 125 mg nicotinamide riboside chloride with 110 mg of actual nicotinamide riboside.
    Does this change the dosage of capsules? How much would an adult take? My son is full grown.
    Thanks for your help.
    Nancy

    ReplyDelete
  24. Tyler13 August 2019 at 19:53

    I give the standard dose of two capsules per day to my son. NR is really just a different form of Vitamin B3, as are Niacin and Nicotanimide. You are not going to overdose on it, because you will likely run out of money before then. There is one study I am aware of where they were testing it for obesity where the dosage was 2000mg per day. 20 dollars a day is still cheaper than a lot of overpriced medicines people take here in the states, but it is still a lot of money (and not covered by insurance obviously). Since there have been no studies looking at NR and autism or autistic symptoms, the best answer for what the optimum dose would be would depend on the amount of cellular stress depleting NAD+ levels in the body. Most young people produce plenty of NAD+, but levels start dropping by your mid-20's. If your cells are constantly challenged by oxidative stress (such as in some autisms), NR may help because NAD+ levels deplete faster than the body can replenish and recycle NADH to NAD+. You also produce NAD+ through the tryptophan -> kynurenine -> quinolinic acid pathway, but most of it is recycled and you only have so much of the enzyme that converts NADH to NAD+ available in different amounts and in different cells.

    So to answer your question, the answer is how much money do you want to spend and are you willing to increase the dosage to see if it has any benefit over the standard dosage of two capsules per day. Also, the answer depends on what kind of cellular stress is involved. One particular study I posted here a while ago showed NR being beneficial when it comes to lactation and boosting levels of BDNF in the brains of offspring from female rats giving NR. When it came to the temporary negative health aspects of pregnancy for the mother and nursing, it was found that the liver was sacrificing its NAD+ stores to help with lactation and that NR supplementation both normalized the livers of the lactating dames, as well as made them "super lactaters" (i.e. producing a lot of milk) and that the offspring were cognitively more fit as measured by the various tests given to rats we may associate with rat intelligence.

    ReplyDelete
  25. Anonymous5 January 2023 at 02:50

    hi Peter, how much the dose of Diamox you used for your kid

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas8 January 2023 at 15:08

      I do not recall, but the pediatric dose as a diuretic is normally 5mg/kg once a day. It caused reflux and so I stopped.

      Delete
    2. Anonymous8 January 2023 at 20:06

      diamox's hafl life is short. do you think once per day is enough ?

      Delete
  26. stephen3 September 2024 at 14:17

    I've been finding positive results with high dose Biotin (10mg/daily) for FRAA (both). As well as scn9a gene and adrm1 gene abnormalities.

    Biotin can calm overactive mtor in the brain.

    Astroglial biotin deprivation under endoplasmic reticulum stress uncouples BCAA-mTORC1 role in lipid synthesis to prolong autophagy inhibition in the aging brain.

    https://pubmed.ncbi.nlm.nih.gov/32030764/

    My current polypill formula is-

    Xolair 75mg/monthly
    Leucovorin 25mg/daily
    Biotin 10mg/daily

    -Stephen

    ReplyDelete
    Replies
    1. Peter Lloyd-Thomas3 September 2024 at 21:27

      Stephen, I was contacted by a parent whose son has a mutation in Nav1.7, which is encoded your gene SCN9A.

      There are several existing Nav1.7 blockers, such as

      Carbamazepine
      Oxcarbazepine
      Lamotrigine
      Phenytoin

      She picked Oxcarbazepine I believe and the child did well on it and continues to take it.

      B vitamins seem to have various interactions with each other. It looks like biotin may be helping folate. In other people there can be unhelpful interactions.

      Delete
    2. Unknown4 September 2024 at 12:34

      Thank you Peter. If you run across Adrm1 gene abnormalities please keep me informed. It interrupts ubiquitylation so I was thinking of adding transcranial photobiomodulation to help remove the midfolded proteins(trash) from the brain.

      Delete
    3. Peter Lloyd-Thomas5 September 2024 at 12:51

      For Adrm1 you could try and compensate by increasing autophagy.

      I think you tried rapamycin or something similar, if I am not mistaken.

      I like the idea of spermidine from Wheatgerm that is being developed to treat dementia. They have trialed it by adding it to bread in Germany. I think there are now commercialized products. It looks a good non-drug option.

      Delete
    4. Stephen5 September 2024 at 14:54

      I like the idea of spermidine; I will pick up a bottle.

      Just for reference if I do use rapamycin again, I will have to micro dose it. I have 0.5 mg tabs and 1 mg tabs just curious of what would be the best way. Probably sterile water, a dropper, and refrigerated?

      Delete
    5. Peter Lloyd-Thomas5 September 2024 at 19:32

      Stephen, check what it is soluble in. Propylene glycol, water and ethanol are common. For example it is propylene glycol for clonazepam and ethanol for Roflumilast/Daxas.

      Delete
    6. Unknown6 September 2024 at 11:43

      Thank you. Looks like it's insoluble in water.

      Also, I just read this in an article about rapamycin and it peaked my interest.

      Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced amyloid-β pathology and cognitive deficits, could also reverse elevations of the NKCC1/KCC2 ratio in these mice.

      https://academic.oup.com/brain/article-abstract/147/6/2169/7658323?redirectedFrom=fulltext&login=false

      Probably could pair rapamycin with bumetanide for an additve effect.

      Delete
    7. Peter Lloyd-Thomas6 September 2024 at 12:10

      That is a surprise. I wonder if this effect can extend beyond treating Alzheimer’s.

      Delete

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