UA-45667900-1

Saturday, 1 August 2015

NMDAR hypo-function causing E/I imbalance in Autism and Schizophrenia – Baclofen, Sodium benzoate and Cinnamon (again)


Click on figure to enlarge

Interpretation, extrapolation and graphic - Peter  


Today’s post is not the one I intended.

It nearly got tucked into long complicated one, that most people might not read.

I should caution that I am perhaps over-simplifying something that is extremely complicated, but no one fully understands the subject.

There is much talk in autism about the imbalance between excitatory and inhibitory processes. In this blog this is normally all about the inhibitory neurotransmitter, GABA, not functioning properly.

There is of course another side to the story.  The excitatory neurotransmitter Glutamate signals via receptors including the NMDA receptors.  If signaling via these receptors is either up or downregulated, the delicate balance between excitatory and inhibitory can again be lost.

What caught my interest was an experiment on mice that caused downregulation of (excitatory) NMDA signaling. This caused the famous E/I imbalance and resulting autistic behavior.

The interesting part is that the researchers normalized the imbalance and the autism not by targeting NMDA but by targeting GABA.  They used baclofen that acts on GABAB receptors.  So they made the mouse autistic by adjusting NMDA (Glutamate) signaling, but recovered the mouse by adjusting the GABA signaling.  This is really quite compelling and made me look into the E/I imbalance again.

It also neatly explains why anti-epileptics, like valproate, when given during pregnancy can result in autistic off spring.  The Valproate increases GABA signaling, i.e. it inhibits neurons from firing too easily.  This reduced the tendency towards seizures.  It will unfortunately also enter the blood stream of the unborn child.  Here again it will shift the E/I balance towards inhibitory, but unlike in the mother, the E/I balance in the child was perfectly fine.  The valproate shifts the E/I balance out of the “safe zone” into the inhibitory danger zone.  This then can affects critical processes in the developing brain leading to autism.
   


NMDA hyper/hypo function

In earlier posts we have already seen that in autism NMDA activity be hyper (too much), hypo (too little) or normal.  There are drugs that can increase NMDA activity and others that reduce it.

In this post the research shows that reduced NMDAR signaling has been associated with schizophrenia, (some) autism and intellectual disability. 

A person with autism might be in this group, but as we saw in earlier posts on NMDA they might be in the opposite group and so have excessive NMDAR signaling.  A bit of trial and error would reveal whether the person was hyper, hypo or just right.  All three are possible in autism.   


GABA/Glutamate imbalance in Autism

The neurotransmitter GABA is supposed to be inhibitory and it is kept in balance by the excitatory neurotransmitter Glutamate. Glutamate binds to NMDA receptors and AMPA receptors.  GABA binds to GABAA and GABAB receptors.

In 2003 John Rubenstein and Michael Merzenich published a paper suggesting that autism might be the result of an E/I imbalance that disrupted both the development of the brain at critical periods and also was the underlying cause of some on-going autistic symptoms, including epilepsy (found in 30% of “old” autism) and what I refer to as pre-epilepsy (odd epileptiform activity without seizures – another 40% of “old” autism).  Plenty of subsequent research has supported their hypothesis.


Once well-established theory for the development of autism is that the balance of various neurotransmitters is out of balance.  GABA, the key inhibitory neurotransmitter in the brain, ceases to inhibit the firing of neurons as it should.  The result is chaos in the brain.

In this blog we have concentrated one cause of this so called E/I (excitatory/Inhibitory) imbalance.  That cause is the presence of the NKCC1 transporter in the brain beyond the first few weeks of life.  This transporter leads to an excess of chloride inside the cells and this shifts GABA away from inhibitory to excitatory.  This then results in a GABA/Glutamate imbalance.  This impairs cognitive function and logically may be a cause of some seizures.

As Rubenstein and Merzenich observed, the hypothesis of E/I imbalance gives hope that drugs correcting this balance may treat autism. This has already been proved to be the case.

But there are other possible causes of E/I imbalance.  Today’s post is about one of those.  People who respond to the prescription drug Baclofen and the experimental drug Arbaclofen most likely are affected by this kind of E/I imbalance.

This blog has extensively covered the GABAA-related cause of E/I imbalance, for which the prescription drug Bumetanide is effective.

Baclofen affects the GABAB receptor.  One reader of this blog did tell us that in her patients with Asperger’s and anxiety did respond well to Baclofen.  They quite possibly have an E/I imbalance of the type covered in this post.  If so the underlying cause may well be NMDAR-hypofunction.

Reduced NMDAR signaling has been associated with schizophrenia, autism and intellectual disability.  By definition people with Asperger’s do not have and intellectual disability, but the Reduced NMDAR signaling may still be holding back their ever higher potential cognitive function.

As we will see, there may be a simple way to treat the NMDAR-hypofunction.

We have already covered this in an earlier post, when I talked about sodium benzoate and schizophrenia.

Sodium benzoate has multiple effects.

Sodium benzoate is a D-amino acid oxidase inhibitor. It will raise the levels of D-amino acids by blocking their metabolism and in doing so enhance NMDA function.  In doing so the E/I balance is shifted towards excitatory.


Sodium benzoate also increases the expression of a protein called DJ-1.  This is well known gene/protein because of its role in Parkinson’s disease.  The DJ-1 protein plays a supporting role to a key anti-oxidative stress defense called Nrf-1.

At times of oxidative stress, the body activated Nrf-1 which in then turns on key genes that need to respond to the stress.  In the absence of enough DJ-1, Nrf-1 is unable to sound the alarm and turn on those genes.

Sodium Benzoate is a common food additive (people with histamine intolerance “should be” allergic to it) but it is also a byproduct of eating cinnamon.  This is why cinnamon was shown to have therapeutic value in Parkinson’s disease.  Rather surprising it has also been shown to be beneficial in early Alzheimer’s disease.

In the earlier post we also saw that cinnamon had other useful effects like lowing cholesterol and improving insulin sensitivity.

We saw in the earlier post that it is important to use the “purer” cinnamon that come from Sri Lanka, since the related species from China that is commonly used by bakers does actually have side effects in large doses.

The Sri Lankan cinnamon may cost a bit more, but a one year supply is only about $15.






            Abstract

Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory–inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1neo−/− mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABAB-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.





IMPORTANCE In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition.
Another method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor.

OBJECTIVE To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia.

DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.

INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo.

MAIN OUTCOMES AND MEASURES The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.

RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes
(range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms–20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health’s Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects.

CONCLUSIONS AND RELEVANCE Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.



Abstract 
This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA – CREB pathway, which may be of benefit for various neurodegenerative disorders.

There are several advantages of NaB and cinnamon over other proposed anti-neurodegenerative therapies. First, both NaB and cinnamon are fairly nontoxic. Cinnamon has been widely used as flavoring material and spice throughout the world for centuries. Cinnamon is metabolized to NaB. NaB is excreted through the urine, if in excess.

Second, cinnamon and NaB can be taken orally, the least painful route.

Third, cinnamon and NaB are very economical compared to other existing anti-neurodegenerative therapies.

Fourth, after oral administration, NaB rapidly diffuses through the BBB. Similarly, after oral administration of cinnamon, we also detected NaB in the brain

Fifth, glycine toxicity is a problem in different neurological diseases because for movement disorders, glycine is one of the factors for inhibiting motor neurons. When impaired, glycinergic inhibition leads to spastic and hypertonic disorders such as featured in PD, multiple sclerosis (MS) and spinal cord trauma. NaB is known to combine with glycine to produce hippurate, a compound that is readily excreted in the urine. Because PD and MS patients exhibit significant elevation in plasma level of glycine, NaB and cinnamon may have added benefits for MS and PD.




Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.

Abstract 

BACKGROUND: 
N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD.

METHODS:
We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint.

RESULTS:
Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects.

CONCLUSIONS:
Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes.


The implications

There are numerous implications, since cinnamon is very cheap and Sri Lanka Cinnamon is seen as very safe.

·        Take cinnamon to lower the risk of Parkinson’s and Alzheimer’s
·        Take cinnamon if you have got Parkinson’s or Alzheimer’s
·        Take cinnamon if you are type 1 or 2 diabetic to improve insulin sensitivity
·        Take cinnamon if you have high cholesterol (perhaps you do not like Statins)
·        Rather unexpectedly, it is suggested that cinnamon should also help multiple sclerosis (MS) because it reduces glycine toxicity which otherwise leads to spastic and hypertonic disorders
·        Trial cinnamon if you have Asperger’s, Schizophrenia, Autism, MR/ID and even COPD
·        Trial cinnamon if (ar)baclofen positively affects your cognitive or emotional function.


Note that some people diagnosed with “autism” have the opposite NMDA dysfunction, they have too much signaling rather than too little.

One method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor. Cinnamon is metabolized in the body to sodium benzoate.

Giving cinnamon to someone with hyperfunction of NMDA, should make their symptoms worse.

Sodium Benzoate/Cinnamon also increases the level of BDNF



It is thought that BDNF  increases excitatory synaptic signaling partly



“BDNF increases spontaneous network activity by suppressing GABAergic inhibition, the site of action of BDNF is predominantly postsynaptic, BDNF-induced suppression of GABAergic synaptic transmission is caused by acute downregulation of GABAA receptors, and BDNF effects are mediated by its TrkB receptor and require PKC activation in the postsynaptic cell.”


BDNF is commonly elevated in autism.


So you would then expect that some people with autism/schizophrenia would benefit while others would not.


Since some people are allergic to sodium benzoate it would wise to start with a tiny amount of cinnamon.


Cinnamon has been used medicinally for centuries.

Cassia cinnamon from China, Vietnam or Indonesia contains coumarin.  Courmarin is not good for you.  Cassia cinnamon is what is normally used in food products, to save money.


In an earlier post:



we saw that Clioquinol and  D-Cycloserine should help those with those with reduced NMDAR function.

Those with elevated NMDAR function would benefit from Memantine and Ketamine.

So logically Clioquinol and  D-Cycloserine should help schizophrenia:-



Nobody seems to have tried Clioquinol on schizophrenia.



Baclofen for Schizophrenia

It is would also be logical that if some people with schizophrenia do have reduced NMDAR signaling then Baclofen should also help them, just as Sodium Benzoate has been shown to do and therefore cinnamon should.

Going back to 1977 Baclofen was indeed found to be effective in some types of schizophrenia





Conclusion


I think that Cinnamon is a better bet than Sodium Benzoate, because you actually may have other substances involved, not just NaB.

The dose at which cinnamon shows tangible biological effects in humans (lowing cholesterol etc.) is around 3g a day.  For those who can swallow capsules, that would be 3 large (size 000) gelatin capsules a day, otherwise you have to find a way of eating a teaspoonful of cinnamon a day.

According to the research “cinnamon has been widely used as flavoring material and spice throughout the world for centuries. Cinnamon is metabolized to NaB. NaB is excreted through the urine, if in excess.”  So it looks a safe therapy, whether it helps autism will depend on the specific biology of that individual.










45 comments:

  1. If NMDA signalling is downregulated, doesnt a possible treatment look for suprassing GABA signalling in order to maintain the synaptic homoestasis by keeping the E/I ratio in the safe zone?

    How come Baclofen is a right choice in this scenario, being a GABA agonist doesnt it favour more inhibitory action?

    Sorry if this is a silly question, all these ara new to me and i am just trying to make a sense of it all. My simple logic says, if E/I balance is distrupted because of more E or less E, then to keep the balance we need to move the I in the very same direction of E.


    ReplyDelete
    Replies
    1. Hi Baris, I did caution in my post that I am perhaps over-simplifying things.

      If you read the full paper I gave the link to you will see:-

      "To determine the effect of NMDAR-hypofunction on excitatory signaling, we next examined membrane properties and synaptic events in hippocampal pyramidal cells using patch clamp. Despite genetic reduction in a major excitatory signaling pathway, the major effect of constitutive NMDA-receptor downregulation was an increase in intrinsic excitability, as measured by the slope of the spike frequency (I–F) curve in current clamp (WT: 0.023±0.002 Hz pA−1, NR1neo−/−: 0.085±0.002 Hz pA−1; F1,27=272.4, P<0.0001; see Figure 3). This neuronal hyperexcitability is consistent with reports of increased blood flow in limbic regions of patients with schizophrenia and autism.56, 57 Spontaneous and evoked excitatory postsynaptic currents (EPSCs) did not differ between groups. Together, these results demonstrate that constitutive NMDAR-hypofunction is sufficient to impair E/I balance, favoring excitation."

      It was the increase in intrinsic excitability (that you did not expect) that was reversed by the pacifying action of Baclofen.

      My conclusion from this post was that for my son, Cinnamon will either make things better or worse. I really cannot say which it will be, because I can make a case for both. So I think it is best to keep a slightly superficial view of what is going on and just identify interventions that should make a change, be it negative or positive. The alternative is to become more expert than the experts, which is very time-consuming.

      Delete
    2. Thanks Peter, now it makes sense, so NMDAR hypofunction may well mean MORE excitatory signalling (to my surprise).

      For a struggling father like myself, your last comments are true guidelines. RESPECT to you for what you are doing for your son, and for sharing it with us all...

      Delete
  2. Hi Peter, how are you? do you think that cinnamon could help a boy with asperger and a movment disorder? after my visit to the neuroligist he is taking l carnitine for increasing white cells and addressing the cord, and tiapride for diskinesias, what do you think? regards, Valentina

    ReplyDelete
    Replies
    1. Cinnamon is worth a try, it is very cheap and safe.

      If he also has anxiety, he might well benefit from baclofen which might also affect his movement disorder. I think this might have a bigger effect than cinnamon. There is no way to know for sure.

      Delete
    2. Here the amount of baclofen for each tablet is 10 mg or 25 mg, which amount should i give him, morning and afternoon?Valentina

      Delete
    3. Best to use 10mg. Dosage is based on the person's weight and is usually split over the day. It can take two weeks to achieve maximum effect. It would be prudent to use a small dosage like 10mg twice a day. The doctor using it in Aspergers said there were no side effects, but did not give the dosage. For large doses you gradually increase over time and then gradually decrease if you want to stop.

      Delete
  3. Hi Peter!! Yesterday i read an article about autism and coconut oil. Searching the net i found a big number of articles claiming that coconut oil does help in autism and specifically with regard to cognitive functions. I would be very interested in your opinion on that. Moreover, i found many articles about nootropics. Are they safe?

    ReplyDelete
  4. Coconut oil is very high in a type of saturated fat that is very suitable for a ketogenic diet. Studies at Johns Hopkins have shown that this diet and the modified Atkins diet, both of which produce ketosis, have a dramatic preventative effect against epilepsy. Nobody really knows why this is the case. It would not be a surprise if some people with autism also benefit from ketosis. You would have to eat a lot of coconut oil and almost no carbohydrate to achieve ketosis.

    Just google ketogenic diet.

    Some people benefit greatly from nootropics and others not at all. The original one, that is claimed to be extremely safe, is Piracetam. This is a drug in some countries and a supplement in others. Often people take nootropics with choline.

    I just had somebody leave a comment that choline by itself had a profound effect on a mother and her daughter, both with Asperger's. She found this out by lots of trial and error.

    I did try Piracetem and I think it did have an effect, but not dramatic. Choline had a bad effect. You will find out pretty quick if it helps. It would be a lot simpler to trial than a ketogenic diet.

    ReplyDelete
  5. My son has been a great responder to NAC and flavenoids (and takes other things as well), with his rages about 90% reduced. I have added in Super Sprouts on several different days and it seems that his rages and general edginess always come back on those days. I could be wrong but I don't think so. What could be the possible reason for that? He has known acetylcholine, mitochondrial and methylation issues.

    ReplyDelete
    Replies
    1. The sulforaphane from broccoli has multiple effects. One is to turn on the body's antioxidant response, which should be very helpful; but there are other effects. It may be in your son the overall effect is negative, it seems in most people the effect is either very good or zero. If it does not help then best not use it.

      Delete
  6. Since I have had great success with baclofen for my Asperger's, implying NMDA hypofunction, would that concur that I should avoid the Bumetanide/low-dose-clozapam route in favor of going with cinnamon/d-cycloserine? Should the Bumetanide theoretically produce a negative effect on me? Or would you recommend both?

    ReplyDelete
    Replies
    1. As I commented to Baris above, things are not so simple and sometimes the effect is reversed. This means you have identified that you likely have an E/I imbalance, I would not conclude more. I would think it well worthwhile to trial the other substances you mention and see what helps. In the end you may find that all you need is baclofen?

      Delete
  7. hello Peter,
    my son with Asd has temporal lobe epilepsy.it has been published on pubmed that this kind of epilepsy may be caused by imbalance of E/I gaba status more exactly GABA b receptor.
    my son is not a responder for bumetanide and AEd low dose .
    with NAC or broccoli even behaviour is worse
    do you think maybe it is because they work more closely on gaba A receptors and my son needs an agonist of gaba B, so maybe cinnamon or baclofen is worth a tray for him?
    dou you know the dose of baclofen for a boy 8 y.o 26kg of weight?
    thanks
    Olga

    ReplyDelete
    Replies
    1. Hello Olga. Did your son develop his epilepsy before or after his autism? It seems that in this kind of epilepsy it often is associated with behavioral similar to autism. If that was the case, it might be best to find a solution to the seizures. Have you looked at modified Atkins diet and ketogenic diet?

      Baclofen is worth a try, as is old dose clonazepam. I do not have any knowledge of baclofen dosage, I tried 10mg once a day, but that is too low.

      If nothing seems to help, the underlying problem must be different. Was the autism regressive? How severe is it?

      Delete
  8. Yes,epilepsy started at 7 years (one year ago)so after his autism
    He never could comunicate .it is mild autism .
    He has a very high cognitive level like a boy of same age but he cant speak and express his feelings.he has not stimming or OCD behaviour.
    We are trying some AED without succes.
    Now we are trying Keppra
    I think his epilepsy is a result of any problem non treated
    Thanks

    ReplyDelete
    Replies
    1. I think his autism may be just a side issue.

      Most drugs/supplements mentioned in this blog will not be appropriate since he has no loss of cognitive function or significant core autism problems. He has no oxidative stress, in fact he has the opposite.

      There are a small number of people who report NAC makes things worse, your son is in that group.

      In effect he has Asperger's + epilepsy + nonverbal. There are other people in this group and you sometimes read about highly intelligent people who are non-verbal.

      If he has anxiety, then that would indicate Baclofen, is well worth a try.

      If he has no anxiety and good cognitive function, there may be no E/I imbalance. The epilepsy may be caused by a channelopathy.

      In the unrelated condition, mitochondrial disease, it was found at Johns Hopkins that L-methionine has a marked effect on speech. They do not know why this is, so it might be relevant to some non-verbal people without mitochondrial disease. You can check methionine levels in a 4 hour fasting blood test. It is simple to raise it and it is suggested that it is best to be in the high normal range. They suggest 50mg/kg/day and wait two weeks to test again.

      Of the substances I have looked at, it would be easy to do a quick trial of low dose clonazepam (relevant due to the fact that sodium channels may be causing his epilepsy) , verapamil (calcium channels are the mode of action of Keppra), baclofen. As an outside chance, I would try atorvastatin 10mg just for a few day and see if it prompts increased desire to communicate.

      I would suggest you look for any case reports on treating non-verbal people with high IQ with/without epilepsy.

      The vast majority of people with autism + nonverbal have cognitive dysfunctions. So if you look at what helps them, you will be looking in the wrong place. Better to look at "nonverbal with high IQ".

      Also maybe look for rare known dysfunctions, metabolic or genetic, that have these signs.

      Good luck.

      Delete
    2. Olga, I have another idea for you.

      Some people with unusual types of autism and other conditions have problems with the cholinergic system. Here is the science post:-

      http://epiphanyasd.blogspot.rs/2013/10/biomarkers-in-autism-cholinergic-system.html

      What is interesting is a small number of people confirmed to me that smoking (ie nicotine) has a dramatic effect, like the lady who left a comment in the post below who did not speak for seven years. When she started to smoke she started to speak.

      http://epiphanyasd.blogspot.rs/2013/10/nicotine-patches-autism-alzheimers-and.html

      There are drugs being developed that stimulate the same receptors, but likely just as effective in those people would be a nicotine patch or nicotine gum (the patch is delayed release, while the gum is not)




      http://epiphanyasd.blogspot.rs/2013/10/nicotine-patches-autism-alzheimers-and.html

      Delete
    3. Peter,do you know if nicotine can be given with epilpsy and/or AED like keppra?and about dose, I have read one 1/ 4 patch a day and remove it at evening for not disturbe sleep
      thanks
      Olga

      Delete
    4. Olga, the patches vary in strength from 7 to 25mg, so best use the weakest one. They say not to cut them, but it works fine to cut them. You need to wrap up the remaining section so it does not dry out.
      Some people think that nicotine reduces seizures. It all depends on what is triggering the seizure.
      Do a short trial, and start on a day when you can observe your son the entire time. The most likely effect is that nothing happens, if you are in luck there may be a good effect.

      Delete
    5. Hi peter,what do you mean when you said.
      he has not oxidative stres,in fact he has the opposite??
      why do you think so?because of any symptom?
      if it is true,antioxidatve substances may be bad for him?
      olga

      Delete
    6. You said with NAC his behavior is worse. That would suggest there is no oxidative stress, since you would expect an antioxidant to makes thing better or have no effect. There are other people with autism like this, but it is a minority. This is why I think you have something less common.

      Delete
    7. yes you are right
      when he was 4 y.o he was non verbal, i hadn´t listened a Word from his mouth.I did a trial with a substance called MMS that is an oxidant.
      after third dose he started speaking and his mind was very clear.
      I stopped because it is not a known substance for me like a drug or herb or supplement ..i was not sure about i was doing..
      do you know if there is any drug or supplement that Works for people like this?i mean, any thing that does the opposite effect than an antioxidant?
      olga

      Delete
    8. Paracetamol/acetaminophen is an oxidant. It depletes glutathione (GSH) the body's main antioxidant.

      MMS is Sodium chlorite, NaClO2 and is used as a bleach/sanitizer. It should be a potent oxidant. It is not wise to swallow it.

      Delete
  9. Thank you very muchos Peter.
    I have made a genetic test of CNV
    He has some duplications por deletions related todo autism like 15p11.2 or 16p11.2 or 7q 11.23
    For example in 15p11.2 there is the UBE3A gen .deletion is know un Angelman disease and dupliction for ASD.
    i think maybe UBE3A is overregulated ,in this case ,do you know any drug for treating this upregulation?
    i have read there are phosphodiesterese 4 inhibitors that help with this..dou you know any case?
    In 16p11.2 I think is MAPK3 gen also related with autism
    The problem here is to find any doctor ...I have not enough medicin knowledge
    Do you think I can try with nicotine un a child?with drugs I can calcular e the do se bit with patch por gums..
    i will study this about nicotine it is ver y interesting
    Olga


    ReplyDelete
    Replies
    1. I will look into those genes.

      You can buy the weakest nicotine patch and cut into 4 or 8 and then stick it on his back where he will not remove it. It is easy to do and plenty of people have tried it on children with autism, it can only help those with this specific dysfunction. You will see very quickly if he is a responder. Probably you only need one quarter or eigth of a patch for a week. If nothing changes then stop. No harm will be done and you will then know whether to go further.

      Delete
    2. Dear Olga

      I think you have to be very careful about interpreting the CNVs.
      The same is true of whole exome sequencing, but this does give you exactly which genes may have a dysfunction, but it may not be the cause of the autism. The exome is only a small part of the genome.

      I have not done whole exome sequencing, but is it can be done by sending a blood sample to lab specialized in this. It may be cheapest to send the sample to a US lab. They want the test to be requested a doctor (any doctor). This used to be extremely expensive, but prices are coming down fast.

      So I would not start looking at specific genes unless you have whole exome sequencing, otherwise you may be looking in totally the wrong direction. Even with whole exome sequencing you may not get the answer you want.

      Individual genetic dysfunctions can cause a cascade of changes and the one affecting the autism may be far downstream. Much of this is beyond today’s science.

      Even the specialist labs do not seem to have doctors that really understand how to interpret the results, but once you have the results you can look up the genes yourself on google. You may get about 10 suspect genes. There is a chance that none of them are the "cause" of the autism.

      Delete
  10. We are trying a trial of Pantogam Active. Over about 5 days, my 21 yr old son has increased his dose to 600 mg/day (each capsule is 300 mg).
    There is a definite difference in my son's overall calm and mood. He has always been "wired' and his body almost buzzing like fluorescent lighting and it seemed like he was completely uncomfortable in his own body. Since the pantogam active, he has slept better and, though vocal stereotypy, he has been much more typical in his body calmness.
    I don't really know what this means. I would like to try D-cycloserine for the stereotypy and the bumex is on order. Is there a sequence that makes more sense given that he seems, so far, to be a responder to a GABA-b agonist? Can I do more than one in the long term?
    Thanks so much,
    Nancy

    ReplyDelete
    Replies
    1. It is a good idea to try one therapy at a time and leave a week in between the next trial so that you go back to "normal", also the best way of seeing if something is ereally ffective is to see what happens when you stop taking it.

      For stereotypy I find NAC a near complete solution. It also works for the majority of other people. People us 600/900 mg 3 or 4 times a day. It is is effective you will see a big change within a couple of days.

      It does not really matter what sequence you use. It is not good to use a very large number of therapies in the long term, just use the ones that really have an impact.

      Delete
  11. Hellow Peter I,m giving my son NAC and his steriotip has reduced a lot.Now I have introduced broccoli powder 1/2 tea spoon a day....it seems more calmed,alert....only three days until today...we'll see in a few weeks.

    ReplyDelete
  12. Hi Peter, Okay, apologies if you have addressed this -- just read more about cinnamon in your great posts. Are you trialing cinnamon while it seems your son is benefitting from the NMDA hyperfunction balance with low dose clonazepam, bumet, etc. So on both sides? Did I get that right? Thanks, MH

    ReplyDelete
  13. MH, as I pointed out to Baris in a comment above, this post is a simplification. In some instances things can work in reverse.

    I think my son's main issues relate to GABAa dysfunctions. Both bumetanide and clonazepam address GABAa receptors.

    Cinnamon has numerous effects and I do not know which one(s) are having an effect in my son.

    It is also important to consider the magnitude of the effect. Bumetanide has a major effect in my son and in many other people. Adding low dose clonazepam, I see a further effect but it is much less than I saw with bumetanide. I think though the mechanism is different, the effect is very similar.

    Cinnamon has a positive effect, but it is small, similar in scale to what is produced by 10mg of Biotin.

    If cinnamon was an expensive drug with some side effects I would not use it. But, it is extremely cheap and many people already take it for other conditions, like diabetes. So it is cheap and safe.

    ReplyDelete
  14. Hey Peter, I've had great success with baclofen so after reading this article purchased cyleon cinnamon and d-cycloserine. I know the recommended dosage for the cinnamon is 3g but what dosage would you recommend for the d-cyclosrine? I've read that 50mg a day is an effective dosage, but I've also read that 50mg once a week provides the same benefits. I just wanted your take on this

    Thanks,
    Ned

    ReplyDelete
    Replies
    1. Hi Ned, I would start at the dose most people say works and see if you are a responder. Then you can reduce the dosage and see if you keep the benefits. I have no practical experience of d-cycloserine.

      Delete
  15. Peter, I read this article twice and do not seem to understand - is it a good idea for autistic kids to take GABA as an amino acid? A lot of biomedical treatments suggest taking GABA as calming substance. I used to give my son GABA, 500 mg a day, for several months, then stopped for months, started again, etc. I never saw any difference either way. The same is with L-glutamine. Some people reported increased speech on glutamine, but 2 gr a day at the age of two did not help us at all and my son is still non-verbal at 3.5 yo.
    Would that suggest that he would not be a responder to bumetanide or pantogam? I ordered both of those, and will try one at a time. Should I add GABA to Pantogam?

    Thank you and sorry if I sound amaturistic, but all these medical stuff is really fuzzy for me.

    Polly

    ReplyDelete
    Replies
    1. GABA should not cross the blood brain barrier in a healthy person, so it should have no effect. If your son has classic autism, there is good chance that bumetanide will have a big impact. It takes at least two weeks to take effect and could be four weeks. It should have very noticeable effects.

      I would not use things that do not have a clear effect and only try one thing at a time.

      Your son is very young and I would just use the key drugs which are bumetanide, NAC and based on the recent post, the NSAID Ponstan possibly. Later on he may develop other issues that can be treated with the other drugs.

      Delete
  16. Also, Peter, you mentioned that high intelligence could indicate that bumetanide would not work (for Olga), if I understood correctly? My son is very smart, he had taught himself all letters, numbers, colors, animals etc on his iPad at the age of 18 month, but he is still completely non-verbal now, two years later. He just recently started "answering" my questions "where is a letter/number/toy by pointing to the correct physical card. Before he only answered questions asked by iPad and did not react to my words at all. He does not follow instructions and does not seem to understand majority of what I am saying. So, his social cognitive function is greatly impaired, in spite of being intelligent and answering iPad questions. He does not understand yes/no questions though, even on iPad. That's why it's hard to judge his cognitive function. Would that make him a good responder to Bumetanide?
    NAC seems to help, he has less rituals and less teeth grinding. Broccoli and cocoa also seem to be more positive than negative. MB12 shots helped at first, but not lately. Other than that, I have tried all of the natural remedies, it seems, and he has no reaction to any of them, positive or negative. He is just as autistic as he was 2 years ago, before we started biomedical treatments.
    Should I try cinnamon on him? What else would you suggest to a non-responder like him? Is this a cognitive problem or something else?

    Thank you for your help,

    Polly

    ReplyDelete
    Replies
    1. Give Bumetanide a try.

      Children actually seem to get more autistic as the condition progresses. The idea of the NSAID Ponstan is that it could halt the damage if used at an early enough age.

      Your son is at an age where you can still potentialy halt the process rather than treat the consequences.

      Delete
  17. I subscribed and shared your posts buddy!
    Please also look at mine, and share ! ;)
    We have a lot in common, btw.
    http://area1255.blogspot.com/2014/06/signs-and-symptoms-of-low-nmda-receptor.html
    http://area1255.blogspot.com/2015/10/natural-herbal-treatments-for.html

    Keep in mind, a lot of other factors influence NMDAR's..histamine H1/H2/H3, neurosteroids, 5-ht1a/1b and 5-ht6 as well as serotonin transporters...also the net dopamine function..pH state..acidity, hydration level, stress level etc..tons of Factors ENVIRONMENTAL (lead and copper antagonize NMDA)..

    http://area1255.blogspot.com/2014/08/histamine-receptors-h1h2h3-and.html

    ReplyDelete
  18. Schizophrenia has a cure,My son is cured from the problem of Schizophrenia,He can now live a normal life.Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality. Although schizophrenia is not as common as other mental disorders, the symptoms can be very disabling.I got the cure from Dr Ben now am the happiest Mother on earth.
    Contact Dr Ben on benardleo13@gmail.com

    ReplyDelete
  19. Hi Peter, I used baclofen for 3 days (15mg/3times a day) and I really had very interesting results regarding motivation, cognition (he maybe a savant autistic but something holds him back) and stereotypy.
    Baclofen didn't work as a sedative, on the contrary, it seemed that it made him a little more anxious and I stopped for a while. As for anxiety, I can't be sure if anxiety itself raised or he found the means to express it clearly.
    My sister also trialled it and went to sleep at once, which means it had a relaxing, sedative effect on her.
    So I switched to cinnamon capsules (Solgar cinnamomum cassia, cinnamon extract 300mg, raw cinnamon powder 200mg/capsule) to see if they have a similar effect. I started low, just a capsule per day. I think it has a good effect on him. I'll raise it to 1gr today. I know that it's not the best quality but it is the most convenient for my trial.
    As for sodium benzoate, I have evidence that he craves it. He never misses the chance to consume wine vinegar from supermarkets, lemon juice, salad dressings, curry powder, hot spices and I also suspect that the gelatin cover of the capsules is the thing he needs most of the times and may not be its content.
    I think the hypothesis mentioned in your relevat articles somehow stands for my son and seems a promising approach which I have to see to it very carefully.
    Petra

    ReplyDelete
  20. I would also like to add, looking up sodium bezoate, led me to gelatin and then to glycine and finally to schizophrenia trials. Peter, I am not allowed to get into science, you are the researcher, I am sure you it crossed your mind, do you have any preliminary conclusions?
    Petra

    ReplyDelete
    Replies
    1. Petra, it really is a case of personalized medicine. What works for your son may be different to what works for your sister, some things may help both. It seem that Baclofen helps most people with Asperger's, so it is a good one to trial. Many of these substances may interact, so cinnamon alone will not necessarily be the same as adding cinnamon to baclofen. The target should be the safest, simplest therapy that best achieves your goals.

      Delete
  21. Hi Peter, I think baclofen (15mg/d) plus cinnamon (500mg/d) have eased my son's blinking eye tic disorder and he rarely flaps his fingers anymore. He seems more "down to earth" and emotionally responds in a "normal" way.
    Still he is very much affraid to "take part in real life" and doesn't want to be exposed to his obsessional fears, which makes him dysfunctional in many ways.
    There is a case study which really caught up my interest, as it resembles my son's course of disorder, regarding the hypo NMDAR hypothesis and treating it with high dose glycine.
    It is from Columbia University USA and here is the link in case you might want to have a look at it:
    http://dx.doi.org/10.1155/2009/768398
    Not being able yet to find high dose of glycine I started with 10gr gelatin powder in his frut jelly dessert and I can see responsiveness. Gelatin has 20-30% of glycine together with several other amino acids that might also help.I somehow started seeing autism as a body building issue. Of course I don't know if I am dopping him or really help.
    Peter, would extra protein and amino acids be a problem with the protein folding issue or may possibly help? Do you have any ideas/advice on that?
    Thank you

    ReplyDelete
  22. Petra, glycine (and other glycine agonists, like D-Serine) are used in Schizophrenia.

    Somebody (the author of your paper, in fact) even has a patent for glycine in OCD

    http://www.google.com/patents/US20140011878

    When I looked at this subject, I thought D-serine was interesting.

    Here is a very recent paper:-

    D-Serine in Neuropsychiatric Disorders: New Advances
    http://www.hindawi.com/journals/apsy/2014/859735/

    ReplyDelete

Post a comment