Low Dose Clonazepam for Autism - SFARI Webinar with William Catterall

Click this link  http://sfari.org/sfari-community/community-blog/webinar-series/2015/webinar-william-catterall-examines-anxiety-drugs-for-autism/

This post will be mainly of interest to the small number of people using low-dose clonazepam for autism and those considering doing so.

This therapy modifies the excitatory/inhibitory (im)balance between the GABA and Glutamate neurotransmitters.  The big advantage is that it should be very safe, is extremely inexpensive and, unlike Bumetanide, does not cause diuresis.   The disadvantage is that the effective dose is only in a narrow window, and you have to find it by trial and error.

Does it work?

It certainly does work in some children with autism.

It also appears to have an additional effect over Bumetanide alone, at least my son.

Questions remain:

·        Does it work with everyone who responds to bumetanide?

·        Does it only work in people with a Nav1.1 dysfunction?

·        Will bumetanide work in everyone who responds to Clonazepam?

One of my earlier, detailed, posts on this subject is this one:-

Channelopathies in Autism - Treating Nav1.1 with Clonazepam

Just google “clonazepam epiphany” or use the site index, for the other posts.

Professor Catterall

I have already covered the science behind low-dose Clonazepam and Professor Catterall’s trials in two mouse models.  It is quite a complex subject and in the end most people just want to know does it work in humans with autism or not.

Catterall’s research was funded by the Simons Foundation, so no surprise really that he made a Webinar for SFARI.  It covers the ground of those two papers and indicates the next steps for his research.

It is a bit lighter going than his papers, but it is a full hour of science.

Catterall plans to trial it in humans with autism, starting with those known to have sodium channel dysfunction. So he is following the same pattern he used with his mice.

The first mouse model he used was Dravet syndrome, a rare condition leading to epilepsy and autism which is caused by a sodium ion channel (Nav1.1) dysfunction.  The second experiment used a standard mouse model of autism called the BTBR mouse model, so no connection with sodium channels.

My question to Catterall was whether this therapy would only work in people with a Nav1.1 dysfunction.  He did respond via the comments on the post, but did not really answer the question.  The fact that he plans to trial his idea on humans with autism with a known sodium ion channel dysfunction, does suggest something at least.

I think that since the actual mechanism of the drug is on a sub-unit of the GABA_A receptor, sodium channels may actually be more of a coincidence, meaning that while autism Nav1.1 dysfunction may indeed indicate this therapy, it may be applicable in other autism where GABA is dysfunctional.

Bumetanide Use

The downside of bumetanide use to correct the E/I imbalance often found in autism is the diuresis and excessive loss of potassium in about 20% of people.

If you revisit the original paper suggesting an  E/I imbalance might be fundamental to many kinds of autism, you will see that this E/I imbalance is not just an ongoing issue, it is potentially an avoidable cause of disruption at key points in the brain’s development prior to maturation. In simpler terms, an E/I imbalance during development may cause the physical brain abnormalities often observed in autism.

That would suggest you should try and reverse E/I imbalance as soon as possible, well before maturation of the brain. 

One day an analog of bumetanide may be developed, that avoids the diuresis;  it is already being discussed.

Bumetanide (or low dose Clonazepam) use, even before autism has become established ?

In something like 30% of cases of classic autism there is macrocephaly (a big head), which even shows up on ultrasound scans of the pregnant mother.  A big head does not necessarily mean autism, but specific types of autism are clearly associated with big heads.

There are many other well known risk factors, like siblings with autism, siblings with other disabilities, older parents, family history (schizophrenia, bipolar, auto-immune conditions, COPD, Nobel Laureates, math prodigies) etc.

Since we also know that an indicator of this kind of E/I imbalance is that benzodiazepine drugs can show paradoxical effects (they work in reverse), it should be possible to make some kind of predictive diagnostic test.

So it would not be rocket science to identify many babies at elevated risk of autism and then treatment could be started very early and well before brain maturation.

This is rather like the Japanese researchers in the previous post suggesting that sulforaphane consumption in childhood might prevent susceptible people developing schizophrenia in adulthood.

Sulforaphane Research in Japan – Cognitive Deficits and Schizophrenia

Kagome is a very large Japanese food company that you have never heard of, with an R&D team capable of producing standardized stable Sulforaphane- glucosinolate.   

I recently received some papers about Sulforaphane from a reader of this blog and also comments from people with schizophrenia looking for therapies

Sulforaphane is already a valued part of my autism Polypill for Monty, aged 12 with ASD.  Just google "Sulforaphane Epiphany", or use the site index tab on this blog.

Sulforaphane has been patented for various purposes by John Hopkins, however even after twenty years they have not brought to market a standardized product.  The Sulforaphane (SFN) used in their research is made in the lab and then has to be kept deep frozen.

Sulforaphane is not a stable substance and so you are wasting your money buying most supplements.  Even most types of broccoli powder, which should be a precursor to Sulforaphane (SFN), were shown to be ineffective in independent lab tests.

In Japan it seems they are far more advanced, they already have a standardized SFN-glucosinolate tablets, no mention of the need to keep them frozen.

Japanese Sulforaphane (SFN) research

What is interesting in the Japanese research into cognitive deficits in schizophrenia is that SFN shows has both prophylactic and therapeutic effects.  This suggests that even if there is no immediate benefit from taking SFN in some people, there may be some long term preventative/protective benefits.

Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood

Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.

  

An Open Study of Sulforaphane-rich Broccoli Sprout Extract in Patients with Schizophrenia

After giving written informed consent, participants received 3 tablets of SFN prepared by Kagome Co., Ltd. (Nagoya, Japan), totaling 30 mg of SFN-glucosinolate per day, for 8 weeks. It is known that SFN-glucosinolate is metabolized to SFN in the body.

Objective

Schizophrenia is a mental disorder characterized by severe cognitive impairment. Accumulating evidence suggests a role for oxidative stress in the pathophysiology of schizophrenia. Sulforaphane (SFN) extracted from broccoli sprout is an agent with potent anti-oxidant and anti-inflammatory activity. In this study, we attempted to evaluate the effect of SFN on cognitive impairment in medicated patients with schizophrenia.

Methods

We recruited a total of 10 outpatients with schizophrenia, all of whom gave informed consent. Participants took 3 tablets of SFN, consisting of 30 mg of SFN-glucosinolate per day, for 8 weeks. Clinical symptoms using the Positive and Negative Syndrome Scale (PANSS) and cognitive function using the Japanese version of CogState battery were evaluated at the beginning of the study and at week 8.

Results

A total of 7 patients completed the trial. The mean score in the Accuracy component of the One Card Learning Task increased significantly after the trial. However, we detected no other significant changes in participants.

Conclusion

This result suggests that SFN has the potential to improve cognitive function in patients with schizophrenia.

   

I do get comments from people with schizophrenia on this blog and there is clearly a big overlap between some schizophrenia and some autism.  More and more therapies are being shown to be effective in both; it seems to be the SFN is one of those therapies.

What would be nice would be a commercially available, standardized product that genuinely could be relied upon to produce SFN in the body.  The Japanese appear to have already mastered this.  No need for Johns Hopkins patents.

For the time being, I am happily using my Supersprouts broccoli sprout powder which does indeed seem to produce SFN.  If one day they stop making it, I have already found that you would just need to add heat stable myrosinase (in the form of daikon radish root) to otherwise ineffective broccoli sprout powder.

For those of you who tried other products claiming to contain/produce SFN, and found them ineffective, you do not know whether the child does not respond to SFN, or your product produced none.

  

Conclusion

SFN really does look worth a try, or perhaps even a second try for those who tried one of those “false” supplements.  Price does not always indicate quality.

One day I hope that the Japanese firm Kagome, chooses to sell its SFN tablets worldwide and not just their tomato ketchups and juices.  

Has anyone tried Cinnamon (or Sodium Benzoate) for Autism?

I have written several posts about Cinnamon and its metabolite Sodium Benzoate. I know that some readers are now using it for its cholesterol lowering and insulin sensitivity improving properties that were shown in the clinical trials I highlighted.

Cinnamon and DJ-1 as a general Anti-Oxidant and perhaps Much More

Is DJ-1 expression negatively associated with severity of Autism? If so, Sodium Benzoate (Cinnamon) may well be beneficial

Sodium benzoate (Cinnamon) trialed for Schizophrenia (Adult-onset Autism)

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

But has anyone tried it for autism?

The first time I wrote about it I did acquire a big bag of the correct variety (Cinnamomum verum or Ceylon Cinnamon) and also a bag of the very high flavanol (epicatechin) cocoa.  My cinnamon trial was limited to seeing what it looked/tasted like when added to the Polypill concoction Monty, aged 12 with ASD, drinks at breakfast.  It was rather like adding a teaspoonful of fine sand, so not much “testing” took place.

Now that Monty has shown an ability, and even enjoyment, for pill swallowing, things are much simpler.  The cinnamon can be put inside gelatin capsules; it’s a little messy, but no great trouble.

Having recently been researching about the gene enhancers and silencers, which are controlled by the 95% of your DNA that rarely gets studied (the exome is the part everyone studies and some people test for abnormalities), it did occur to me that I already have two safe substances, that I have both researched and acquired, which have a gene expression enhancing effect.

Cinnamon “Experiment”

Even though summer is the wrong time to test anything in Monty, aged 12 with ASD, since his pollen allergy triggers a regression, I decided to make a trial.  I have 1 kg of this special cinnamon, and so it’s not like I need to ration it.

I gave about 2.5ml of cinnamon split into three daily doses using some gelatin capsules that used to be full of another supplement (choline).

Results so far:-

Complete absence of summertime bad behaviors, which are already 90% subdued by Verapamil, but do sometimes present themselves.

Interesting behavioral developments:- 

·        Like many people with autism, Monty likes order.  So turn off lights, shut doors, wash dirty hands etc.  The latest surprise was that when I took something from the rear of my car and he shut the tail gate (boot). Given the size of my car, for someone of his small stature, this is quite an achievement, since he really has to stretch on his toes.  This is the first time he has ever done this and now he does it every time.

·        Monty can brush his teeth and get dressed, but his clothes are sitting there on his bed.  The other day when told to go upstairs and brush his teeth, he returned fully clothed, having chosen/found his clothes all by himself.

·        On awakening, sometimes Monty might say “can I have a glass of water”, to which he might be told go downstairs and get water, and usually someone would go down with him.  Recently I find him in the early morning sitting at the kitchen table playing on his iPad with the glass of water he served himself with.

·        Piano playing also seems to be going very well, indeed on Wednesday after his piano lesson the teacher started telling me that she has taught 73 children with autism and never has she had someone start at his beginning level and progress so far.  This is clearly not down to cinnamon (it was greatly helped by bumetanide, atorvastatin and NAC), but why is she telling me this now, after over three years of lessons?

·        Speech for people with Classic autism, even when it develops, is always a little odd, reading a book out loud or singing does not mean you can speak.  It is as if the mother tongue is a foreign language and needs to be translated in your head. So for me it would be like speaking German.  It is my fourth language, I know lots of words, but I cannot think in German.

Many people with autism like to know their schedule. Today Monty was going to go swimming, amongst other things, but a change of plan meant we had gone to eat.  So I said to Monty “I am too full to go swimming, we will go later”.

A few minutes later as I stopped the car, Monty says “swimming when Dad feels better”.

There is nothing super clever in that statement, but it is not the sort of unprompted comment I usually get to hear for son number two.

These are all little steps and may be coincidental, but normally with Monty things go backwards in summer.  Even effective interventions appear to lose their effectiveness. 

I still keep an open mind on cinnamon, but I did just order a big bag of empty gelatin capsules.

Anybody else tried Cinnamon?

It would be useful to know from people who found that Bumetanide or Sulforaphane were effective for autism, whether cinnamon also has a positive effect.

There are several reasons why it may help:-

·        Change in NMDA signaling, affecting the excitatory/inhibitory balance

·        Affects gene expression related to oxidative stress (why cinnamon helps reduce cholesterol and improve insulin sensitivity)

·        Increases BDNF, Brain-derived neurotrophic factor  (aka “brain fertilizer”)

·        NaB (sodium benzoate) reduces Microglial and Astroglial Inflammatory Responses

·        NaB exerts its anti-inflammatory effect through the inhibition of NF-κB

·        NaB suppresses the activation of p21^ras in microglia

·        NaB can also regulate many immune signaling pathways responsible for inflammation, glial cell activation, switching of T-helper cells, modulation of regulatory T cells

NF-κB is the master regulator of inflammation in the same way that Nrf 2 is for oxidative stress.

Incorrect regulation of NF-κB has been linked to cancer, inflammatory, and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory

In autism it seems that we want to activate Nrf2 but to inhibit NF-κB.  Safely inhibiting NF-κB is the Holy Grail for many diseases.

We covered RAS in earlier posts.  The RAS protein is abnormally active in cancer.

So called RASopathies are developmental syndromes caused by mutations in genes that alter the Ras subfamily.  RASopathies are often associated with autistic symptoms and/or intellectual disability/mental retardation.

Common inhibitors of RAS are statins and Farnesyltransferase inhibitors.  Most Farnesyltransferase inhibitors are expensive cancer research drugs, but one is gingerol.

Since statins do very clearly improve the autism of Monty, aged 12 with ASD, I did try adding gingerol as my “Statin plus” therapy.  At the dose I used there was no noticeable effect.

However, I now learn that “NaB suppressed the activation of p21^ras in microglia”.  P21, RAS, and p21^ras are different names for the same protein.  So it would seem that NaB is therefore a RAS inhibitor and perhaps a more potent one than gingerol.

   

Too much BDNF, just like too much lawn fertilizer, may not be a good thing.

BDNF is low in schizophrenia, but is thought to be elevated in “most” autism.

   

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Reduces Microglial and Astroglial Inflammatory Responses

 Abstract

Upon activation, microglia and astrocytes produce a number of proinflammatory molecules that participate in the pathophysiology of several neurodegenerative disorders. This study explores the anti-inflammatory property of cinnamon metabolite sodium benzoate (NaB) in microglia and astrocytes. NaB, but not sodium formate, was found to inhibit LPS-induced expression of inducible NO synthase (iNOS), proinflammatory cytokines (TNF-α and IL-1β) and surface markers (CD11b, CD11c, and CD68) in mouse microglia. Similarly, NaB also inhibited fibrillar amyloid β (Aβ)-, prion peptide-, double-stranded RNA (polyinosinic-polycytidylic acid)-, HIV-1 Tat-, 1-methyl-4-phenylpyridinium⁺-, IL-1β-, and IL-12 p40₂-induced microglial expression of iNOS. In addition to microglia, NaB also suppressed the expression of iNOS in mouse peritoneal macrophages and primary human astrocytes. Inhibition of NF-κB activation by NaB suggests that NaB exerts its anti-inflammatory effect through the inhibition of NF-κB. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on iNOS expression, and NF-κB activation by hydroxymethylglutaryl-CoA, mevalonate, and farnesyl pyrophosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the anti-inflammatory effect of NaB. Furthermore, we demonstrate that an inhibitor of p21^ras farnesyl protein transferase suppressed the expression of iNOS, that activation of p21^ras alone was sufficient to induce the expression of iNOS, and that NaB suppressed the activation of p21^ras in microglia. These results highlight a novel anti-inflammatory role of NaB via modulation of the mevalonate pathway and p21^ras.

  

Immunomodulation of experimental allergic encephalomyelitis by cinnamon metabolite sodium benzoate.

ABSTRACT Experimental allergic encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), the most common human demyelinating disease of the central nervous system. Sodium benzoate (NaB), a metabolite of cinnamon and a FDA-approved drug against urea cycle disorders in children, is a widely used food additive, which is long known for its microbicidal effect. However, recent studies reveal that apart from its microbicidal effects, NaB can also regulate many immune signaling pathways responsible for inflammation, glial cell activation, switching of T-helper cells, modulation of regulatory T cells, cell-to-cell contact, and migration. As a result, NaB alters the neuroimmunology of EAE and ameliorates the disease process of EAE. In this review, we have made an honest attempt to analyze these newly-discovered immunomodulatory activities of NaB and associated mechanisms that may help in considering this drug for various inflammatory human disorders including MS as primary or adjunct therapy.

Conclusion

Rather to my surprise, Cinnamon does seem to have a noticeable cognitive effect in the type of autism I am interested in.  It appears, rather like the statin, to promote improved adaptive behavior by reducing inhibition and increasing spontaneous thought and actual decision making.

Of all the many possible modes of action, I am thinking that inhibition of NF-κB and/ or RAS inhibition are most likely since the effect is very similar to that produced by the statin.

I will certainly continue with cinnamon and when my size 000 gelatin capsules arrive, I will look at different doses.  Currently the dose is about 2.5 ml split three times a day, using size 00 gelatin capsules.

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

Click on figure to enlarge

Source of text quoted:   E-I Balance and Human Diseases – from Molecules to Networking

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 GABA_B 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 GABA_A and GABA_B 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.

Model of autism: increased ratio of excitation/inhibition in key neural systems

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 GABA_A-related cause of E/I imbalance, for which the prescription drug Bumetanide is effective.

Baclofen affects the GABA_B 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.

GABA_B-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction

            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-NR1^neo−/− 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 GABA_B-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.

Add-on Treatment of Benzoate for Schizophrenia A Randomized, Double-blind, Placebo-Controlled Trial of D-Amino Acid Oxidase Inhibitor

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.

Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: Therapeutic implications for neurodegenerative disorders

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

http://jn.physiology.org/content/88/2/595.long

“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 GABA_A 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:

Altered Homeostasis in Autism: Cl-, K+, Ca2+, and quite possibly Zn2+

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:-

Trial of D-Cycloserine in 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

Baclofen in the treatment of schizophrenia: a pilot study.

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.