Sunday, 24 September 2017

Hypoperfusion in Autism Revisited

One old post from this blog has been going viral recently (3,000 views in one day, via Facebook) and it is quite relevant to a debate that has been going on in the comments about the potential merits and mechanisms of Hyperbaric Oxygen Therapy (HBOT). Two commenters are big fans of HBOT.
Hypoperfusion is reduced blood flow, which is found in some people with autism and also in people with some types of dementia  
Having reread my old post I would recommend it to those who are looking into the treatment of brain damage caused by ischemia. 

While much in neuroscience is extremely complicated, there are some pretty basic things to consider that are not. Adequate blood supply is one of the basic issues and is something that can be improved.
You can increase blood flow by reducing vascular resistance, which means reducing the work the heart has to do to circulate blood around the body. As you reduce this resistance, blood pressure will fall, but that does not mean the flow rate of blood has reduced, it just means it is circulating more freely.
You can measure cerebral blood flow and this is how researchers know that it can be abnormal in autism.
As I noted in the old post above, HBOT is one therapy proposed by some. Using an MRI you could establish with certainty if HBOT was effective in any particular individual, in regard to increasing cerebral blood flow.
I think there will be many ways to improve perfusion in an affected individual. Without a particular type of MRI you cannot really know for sure if your case of autism is one of these.
The dementia research pointed me towards cocoa flavanols, which seem to affect nitric oxide (NO), but do not directly produce it.
Nitric oxide (NO) is very important in the body and one of its roles is vasodilation (widening of blood vessels).
Some people believe that nootropic drugs work by vasodilation, i.e. more blood flow increases cognitive function.  I think that this is one of many possible ways to improve cognition, which will work in some people, but not others. 
To understand Nitric oxide (NO) you have to go a little deeper and look at eNOS (endothelial nitric oxide synthase), iNOS (inducible NO synthase) and nNOS (neuronal NO synthase). Nitric oxide can be very good for you, but it can also be very bad for you.  The short version is that Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) plays a protective role in maintaining vascular permeability, whereas NO derived from neuronal and inducible NOS is neurotoxic and can participate in neuronal damage occurring in ischemia.,
For a thorough explanation here is a highly cited paper:-

Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins. 

Statins are already in my Polypill. Telmisartan seemed to be the most likely ACE inhibitor or ARB (angiotensin receptor blocker) to help some autism, when I reviewed them in a previous post. Telmisartan produced more singing, as does Agmatine (see below).

Now look at how NO is produced by eNOS:-


“In the vascular endothelium, NO is synthesized by eNOS from L-arginine and molecular oxygen, which binds to the heme group of eNOS, is reduced and finally incorporated into L- arginine to form NO and L-citrulline. The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO. In the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled. In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system.

BH4 (Tetrahydrobiopterin/Kuvan) is one of substances that comes up in autism research from time to time.  You would not want to be deficient in BH4 and if you have autism and BH4 deficiency you have a very obvious therapy.   

A good article, surprisingly from the UK Financial Times, which they ask not to be cut and paste, so I have not. Take a look.

If Kuvan lights up the brain, as Dr Frye suggested in the above FT article, I wonder what else can, in those people.  L-arginine might help, or perhaps its metabolite Agmatine, as used by our reader Tyler.
If you read the quite complicated paper below you will see that, in rats at least, Agmatine increases eNOS, while reducing  iNOS. 
You compare EC6 (experimental control after 6 hours) with Agm6 (Agmatine after 6 hours) and then EC24 with Agm24. 

Effects of eNOS and iNOS expression by agmatine treatment following transient global ischemia in rat hippocampus. Representative expressional levels of eNOS (A) and iNOS (C) at 6 h after agmatine treatment (100 mg/kg, i.p), and densitometric data (B, D). Data represent means±SD for n=5/NC, n=3/EC and Agm group per each time point. *


BH4/Kuvan/Sapropterin is rather expensive, but people do use it off-label in autism.  It is the only FDA-approved medication for Phenylketonuria (PKU) to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin (BH4-) responsive PKU.

PKU is one of those rare inborn errors of metabolism that lead to intellectual disability/MR and, not surprisingly, also autism. It is included in my Treatable ID tab at the top of every page.  The link will take you here

Agmatine is cheap and does have an almost immediate positive effect in some people with autism.

Do people who respond to BH4 respond to Agmatine and vice versa?
Agmatine does have many other modes of action, other than increasing eNOS and reducing iNOS.
I have been experimenting with Agmatine, and while Dr Frye suggests Kuvan can “light up the brain”, my impression of Agmatine brings the Energizer(US)/Duracell (Europe) Bunny to mind.

A daily dose of Agmatine is like having better battery in your toy bunny, at least in my house.  It is also associated with more singing.
Judging from Tyler’s comments perhaps he is seeing the same magnitude of effects that Dr Frye attributes to Kuvan.   


  1. How do you deal with hypo and hyper perfusion in that the brain may be not getting enough to one area but too much to another so strengthening areas of the brain that are overdeveloped? Isn't that the case in many autistic brains? Would one of these treatments better deal with it than others?

    1. The problem is that you do not have any detailed knowledge of the specific brain you are interested in, so it all becomes guesswork.

      In theory an MRI could be used to see exactly what is going on in a particular person and then you could have a tailor made treatment.

  2. How would Clonidine factor into this -- like having some of the benefits like lowering blood pressure. Would it have some of the same benefits as Telmisarta?

    1. Clonidine does reduce vascular resistance but it also increases norepinephrine which is thought to be why it helps in ADHD.

      Most drugs like clonidine have multiple modes of action and that is often why they have side effects in some people.

      Telmisartan's other effects are on PPAR receptors, which could be good for people with metabolic disorders.

      So while many drugs do lower blood pressure their other effects are completely different.

  3. Everyone, who has used Cocoavia (or something similar) for your autism or children's autism and what have you seen? I would love to hear feedback. Peter have you used for your son? Tyler? What would be the downside-- other than the cost? Others?

    1. When I first wrote about Cocoavia it was only sold in North America, so I used ACTICOA, which is a cocoa powder.

      I found ACTICOA had an effect, I bought more of it, but it is not so easy to give it. In adults worried about dementia you just add a teaspoon of cocoa to your coffee and get used to the taste.

      So it ended up with the big bag of cinnamon at the back of the shelf; cinnamon also has some effect.

      Agmatine dissolves in water, you need a small amount and it is not expensive.

    2. I have used Cocoavia for several months in my son but not consistently throughout the day because of school and stuff like that interfering, plus it does not taste great and my son won't swallow pills. The best I could do was mix it with milk and sucrose and that could of compromised it's efficacy. On top of that it has caffeine which means he had to get it right after school or else before then or else there could be some sleep issues.

      It is something may try again, especially since I wonder if it has a synergistic effect with agmatine and my son is a bit older and more compliant now in the mornings. He already gets his bcaa drink in the morning so we only have so much time before make everything work. It is also not the cheapest supplement either.

  4. Peter, what dose of agmatine are you using to get the positive effect for your son?

    1. Tanya, I am giving 1.4g once a day. My son about 50kg.

  5. Thanks Peter. btw I couldn't open the paper from the Financial Times.. I may give the agmatine a shot. My son is homozygous for mthfr a1298c which means less bh4 available. Just curious if you or Tyler use the NO saliva test strips?

    1. Access is now blocked, the article said that Dr Frye thinks Kuvan is great but others are skeptical. Kuvan is very expensive. I have not used NO saliva test strips. Another NO therapy is beetroot juice, which endurance cyclists use. Having read all about it, I now use it myself; you do get used to the taste, you only need about 150ml. I have not given it to my son on a regular basis.

  6. I've used NADH (enada) in the past with great great greatly improved energy levels (10-20mg sublingual), allthough 20mg seemed to cause me to be overenergetic, considering NADH is a huge factor in BH4 production, along with vitamin c (im also a good responder to higher doses of vitamin c) for BH4 recycling.

    Would it be somewhat save to assume im bh4 deficient?
    In general, nearly all energy/mitochondria boosters seems to positively influence me (NAC has a strong anti-fatigue effect on me aswell, but i suspect this is due to increasing my glutathione levels that are genetically low by default).

  7. Peter- Reading about the comment and needing a specific MRI to determine HBOT need, exactly what type of MRI are you referring too? I know there is fMRI and SPECT and other types of imaging studies.

    1. Quantitative Cerebral Blood Flow Measurements Using MRI

      This relates to a neurologist, I recall reading about in the US who had a patient who responded to HBOT, but the insurance company did not want to pay for it. The doctor then used MRI to show the patient had impaired cerebral blood flow and after MRI blood flow was improved. I think this is a specific type of autism, otherwise everyone would improve on HBOT and clinical trials are not so positive.

  8. Hi Peter, being Agmatine an arginine metabolite, do you know if it could feed measles virus as arginine does ? Thanks.


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