I am still looking for additional cognitive enhancing autism therapies. It
seems the best way to find them may actually be to reread my own blog.
A long time ago I suggested that Cinnamon could well be therapeutic in
autism, most likely (but not entirely) due to the sodium benzoate (NaB) it
produces in your body.
Sodium benzoate (NaB) is both a drug used to reduce ammonia in your
blood and a common food additive that acts as a preservative.
NaB has many biological effects.
One effect relates to a protein called DJ-1, which is produced by a Parkinson’s
gene (PARK7). I had noticed that when the body tries to turn on its anti-oxidant
genes after the switch Nrf2 is activated, the process cannot proceed without
enough DJ-1. This is why Peter Barnes,
from my Dean’s list, suggested that patients with COPD might benefit from more
DJ-1. COPD is a kind of severe asthma
which occurs with severe oxidative stress, the oxidative stress stops the
standard asthma drugs from working, which is why so many people die from COPD.
Oxidative stress is a key feature of most autism.
To make more DJ-1 you can use sodium benzoate (NaB) which is produced gradually
in the body if you eat cinnamon. So in theory cinnamon is like sustained
release NaB, it is also extremely cheap.
Independently of all this NaB has been trialled in schizophrenia and a
further larger trial is in progress.
Autism is not schizophrenia, but the hundreds of genes miss-expressed in
autism do overlap with the hundreds of genes miss-expressed in schizophrenia,
so I call schizophrenia autism’s big brother.
GABAA α5 subunit
The scientist readers of this blog may recall that there are two sub-units
of the GABAA receptor that I am seeking to modify, to improve
cognition. One is the α3 subunit and the
other is the α5 subunit. Low dose clonazepam works for α3.
The α5 subunit is the target of a new drug to improve cognition in people
with Down Syndrome (DS).
Very recent research links the same sub-unit to autism, so it is not just
me looking at this.
As is often the case, it
looks like some people might need to “turn up the volume” from α5GABAA receptors
and others might need to turn it down.
I had yet to find a practical way to affect α5GABAA. Now I have
realized that I have already stumbled upon such a way to do it.
Pahan, a researcher in Chicago, has shown that he can improve cognition in
mice using cinnamon. He noted that in poor learners GABRA5 was elevated, but that after
one month of cinnamon GABRA5 was normalized.
Cognitive loss in autism, schizophrenia and Down
Syndrome
Most people might associate MR/ID with
autism and indeed Down Syndrome; you likely do not really consider people with
schizophrenia to have MR/ID. In reality, cognitive loss is a common feature/problem
in schizophrenia and indeed bipolar, just not enough to be called MR/ID.
Those researching schizophrenia seem
to focus on NMDA receptors, whereas my blog only goes into the great depths of
science when it comes to GABAA . To the schizophrenia researchers NaB
is interesting because it is a d-amino acid oxidase
inhibitor, which means that it will enhance NMDA function. So if you are one of those people with too
little NDMA activity (NMDAR hypofunction) then sodium benzoate should make you
feel better.
The schizophrenia researchers think
NaB is helpful because of its effect on NMDA, for me it is GABRA5 that is of great
interest. The same should be true for parents of kids with Down Syndrome (DS).
We have seen that bumetanide should, and indeed does, help DS. It looks to me that NaB/Cinnamon should further
help them and no need to wait for Roche to commercialize their GABRA5 drug.
NaB and Cinnamon
I am yet to determine how much NaB is produced by say 3g of cinnamon.
The clinical trials of NaB use 1g per day in adults. People using cinnamon,
like Dr Pahan, for cognition or just lowing blood pressure and blood sugar use
around 3g.
It is quite difficult to give a teaspoonful of cinnamon to a child, whereas
NaB dissolves in water and does not taste so bad.
NaB and Cinnamon Trials
I did trial cinnamon by putting it in in large gelatin capsules and at the
time I did think it had an effect, but I doubt I got close to Dr Pahan’s
dosage.
A prudent dose of NaB would seem to be 6mg/Kg twice a day. This is similar
to what is now being trialed in schizophrenia.
A small number of people do not tolerate NaB and logically also
cinnamon. They are DAAO inhibitors, just
like Risperidone. People who are histamine intolerant need
to avoid DAAO inhibitors. If you have allergies it does not mean you are histamine
intolerant.
I did try NaB on myself and I did not notice any
effect.
Conclusion
I had already obtained some NaB to follow up on my earlier trial of
cinnamon. Having read about the effect
of NaB on GABRA5 expression, I am even more curious to see if it helps.
Any positive effect might be due to DJ-1 boosting the effect of Nrf-2, it
might be boosting NMDA or it might be reducing GABRA5 expression. In some
people all three would be useful.
Press release:-
Pahan a researcher at Rush University
and the Jesse Brown VA Medical Center in Chicago, has found that cinnamon turns
poor learners into good ones—among mice, that is. He hopes the same will hold
true for people.
His group published their latest findings
online June 24, 2016, in the Journal of Neuroimmune Pharmacology.
"The increase in learning in
poor-learning mice after cinnamon treatment was significant," says Pahan.
"For example, poor-learning mice took about 150 seconds to find the right
hole in the Barnes maze test. On the other hand, after one month of cinnamon
treatment, poor-learning mice were finding the right hole within 60
seconds."
Pahan's research shows that the
effect appears to be due mainly to sodium benzoate—a chemical produced as
cinnamon is broken down in the body.
In their study, Pahan's group first
tested mice in mazes to separate the good and poor learners. Good learners made
fewer wrong turns and took less time to find food.
In
analyzing baseline disparities between the good and poor learners, Pahan's team
found differences in two brain proteins. The
gap was all but erased when cinnamon was given.
"Little
is known about the changes that occur in the brains of poor learners,"
says Pahan. "We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor
learners.
Interestingly, these particular changes were reversed by one month of cinnamon
treatment."
The
researchers also examined brain cells taken from the mice. They found that
sodium benzoate enhanced the structural integrity of the cells—namely in the
dendrites, the tree-like extensions of neurons that enable them to communicate
with other brain cells.
As for himself, Pahan isn't waiting
for clinical trials. He takes about a teaspoonful—about 3.5 grams—of cinnamon
powder mixed with honey as a supplement every night.
Should the research on cinnamon continue to
move forward, he envisions a similar remedy being adopted by struggling
students worldwide.
The paper itself:-
This
study underlines the importance of cinnamon, a commonly used natural spice and
flavoring material, and its metabolite sodium benzoate (NaB) in converting poor
learning mice to good learning ones. NaB, but not sodium formate, was found to
upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive
calcium influx and increase of spine density in cultured hippocampal neurons.
NaB induced the activation of CREB in hippocampal neurons via protein kinase A
(PKA), which was responsible for the upregulation of plasticity-related
molecules. Finally, spatial memory consolidation-induced activation of CREB and
expression of different plasticity-related molecules were less in the
hippocampus of poor learning mice as compared to good learning ones. However,
oral treatment of cinnamon and NaB increased spatial memory
consolidation-induced activation of CREB and expression of plasticity-related
molecules in the hippocampus of poor-learning mice and converted poor learners
into good learners. These results describe a novel property of cinnamon in
switching poor learners to good learners via stimulating hippocampal plasticity.
We
have seen that cinnamon and NaB modify T cells and protect mice from
experimental allergic encephalomyelitis, an animal model of multiple sclerosis.
Cinnamon and NaB also upregulate neuroprotective molecules (Parkin and DJ-1)
and protect dopaminergic neurons in MPTP mouse model of Parkinson’s disease. Recently, we have seen that cinnamon and NaB attenuate
the activation of p21ras, reduce the formation of reactive oxygen species and
protect memory and learning in 5XFAD model of AD. Here we delineate that NaB is
also capable of improving plasticity in cultured hippocampal neurons. Our
conclusion is based on the following: First, NaB upregulated the expression of
a number of plasticity-associated molecules (NR2A, GluR1, Arc, and PSD95) in
hippocampal neurons. Second, Gabra5 is known to support long-term depression.
It is interesting to see that NaB did not stimulate the expression of Gabra5 in
hippocampal neurons. Third, NaB increased the number, size and maturation of
dendritic spines in cultured hippocampal neurons, suggesting a beneficial role
of NaB in regulating the synaptic efficacy of neurons. Fourth, we observed that
NaB did not alter the calcium dependent excitability of hippocampal neurons,
but rather stimulated inbound calcium currents in these neurons through
ionotropic glutamate receptor. Together, these results clearly demonstrate that
NaB is capable of increasing neuronal plasticity.
These results suggest that NaB and
cinnamon should not cause health problems and that these compounds may have
prospects in boosting plasticity in poor learners and in dementia patients. In summary, we have demonstrated that
cinnamon metabolite NaB upregulates plasticity-associated molecules and calcium
influx in cultured hippocampal neurons via activation of CREB. While spatial
memory consolidation-induced activation of CREB and expression of
plasticity-related molecules were less in the hippocampus of poor learning mice
as compared to good learning ones, oral administration of cinnamon and NaB
increased memory consolidation-induced activation of CREB and expression of
plasticity-related molecules in vivo in the hippocampus of poor learning mice
and improved their memory and learning almost to the level that observed in
untreated good learning ones. These results highlight a novel plasticity-boosting property of
cinnamon and its metabolite NaB and suggest that this widely-used spice and/or
NaB may be explored for stimulating synaptic plasticity and performance in poor
learners.
The
schizophrenia trials:-
Plenty of people with schizophrenia
now self-treat with NaB; just look on google.
P.S.
There is now is a small trial in autism:-
A Pilot Trial of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added on Augmentative and Alternative Communication Intervention for Non-Communicative Children with Autism Spectrum Disorders
https://www.omicsonline.org/open-access/a-pilot-trial-of-sodium-benzoate-a-damino-acid-oxidase-inhibitor-added-on-augmentative-and-alternative-communication-intervention-2161-1025-1000192.php?aid=83472&view=mobile
Results: We noted improvement of communication in half of the children on benzoate. An activation effect was reported by caregivers in three of the six children, and was corroborated by clinician’s observation. Conclusion: Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with more children participated for clarification of its efficacy.
https://www.omicsonline.org/open-access/a-pilot-trial-of-sodium-benzoate-a-damino-acid-oxidase-inhibitor-added-on-augmentative-and-alternative-communication-intervention-2161-1025-1000192.php?aid=83472&view=mobile
Results: We noted improvement of communication in half of the children on benzoate. An activation effect was reported by caregivers in three of the six children, and was corroborated by clinician’s observation. Conclusion: Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with more children participated for clarification of its efficacy.