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Thursday, 4 May 2017

Angiotensin II in the Brain & Therapeutic Considerations





In a previous post I suggested that another cheap generic drug (an ACE inhibitor) could potentially be repurposed to treat schizophrenia and some autism. The original idea was related more to modifying the immune/inflammatory response in the body, rather than the brain.  There is however plenty of research regarding Angiotensin within the brain and the numerous roles it plays.

Juggling - maximizing effects, while minimizing
drug interventions



You may recall in the earlier post that in both schizophrenia and autism there is elevated angiotensin II.

In the brain there are two types of angiotensin receptor, AT1 and AT2.  Their actions are opposing each other.

In many kinds of disease we would want to stimulate AT2, but inhibit AT1.

AT2 is thought to be important for cognitive function and is now a target for Alzheimer’s research.

Using an ACE inhibitor you reduce the amount of angiotensin II and so in effect inhibit both AT1 and AT2.

In theory angiotensin II should not cross the blood brain barrier (BBB), so we should be dealing with centrally produced (i.e. inside the brain) angiotensin II.  In practical terms it seems that people with high levels of angiotensin II may have a permeable BBB.

This is relevant because most ACE inhibitors do not cross the BBB, but the original ACE inhibitor called Captopril does cross the BBB.  So if a centrally acting ACE inhibitor were found to be required, it was discovered 40 years ago.

A therapy would ideally be targeted selectively at AT1 or AT2 receptors.  An AT1 blocker might treat for stress-induced disorders.  An experimental AT2 receptor agonist, called compound 21, is now available and is expected to reduce inflammation and oxidative stress.


Angiotensin II receptor AT1 antagonists are widely used drugs indicated for hypertension, diabetic nephropathy and congestive heart failure. They block effect of Angiotensin on AT1 and might be good in the brain.

We would like to increase the effect on AT2, we could do that with more Angiotensin II, but then we would make things worse with AT1.


                          Do nothing  ACE inhibitor    AT1 antagonist      AT2 agonist

Effect on AT1               none                            good                                     good                          none

Effect on AT2               none                            bad                                       none                          good



AT1 antagonists are widely available and seen as well tolerated.

AT1 antagonists appear to protect against Alzheimer’s.

The only AT2 agonist is an experimental drug called Compound 21.

The only ACE inhibitor that should affect AT2 in the brain is Captopril and so may be an unwise choice. It will reduce Angiotensin II in the brain and in the rest of the body.


Why were we interested in Angiotensin?


In the original Angiotensin post in this blog we saw that in schizophrenia and some autism, that Angiotensin II is elevated.  We also saw that:-

·        Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1, Th2 and Th17. 

·        In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.

·        It should also reduce any troubling high levels of leptin, which we saw in another post is an issue in most autism

So the idea was that many broadly anti-inflammatory effects of reducing Angiotensin II might be helpful in autism.

But what about inside the brain?


Angiotensin in the Brain

Here we do get to the science, but I will start with the conclusion. We actually want more effect from the Angiotensin AT2 receptor, which should give numerous benefits, but have no means of achieving this. What we can do is make sure we do not reduce AT2 activity, this means better to use and AT1 antagonist, rather than an ACE inhibitor.

The science supporting the use of an AT agonist follows:-

In the text you will see ARB and compound 21. Both are doing good things. The suggestion is that by doing all these good things there should be improved cognitive function; this has yet to be proved in human tests.

ARB = Angiotensin Receptor AT1 Blocker

Compound 21 = Angiotensin Receptor AT2 agonist



The brain renin-angiotensin system (RAS) has been highlighted as having a pathological role in stroke, dementia, and neurodegenerative disease. Particularly, in dementia, epidemiological studies indicate a preventive effect of RAS blockade on cognitive impairment in Alzheimer disease (AD). Moreover, basic experiments suggest a role of brain angiotensin II in neural injury, neuroinflammation, and cognitive function and that RAS blockade attenuates cognitive impairment in rodent dementia models of AD. Therefore, RAS regulation is expected to have therapeutic potential for AD. Here, we discuss the role of angiotensin II in cognitive impairment and AD. Angiotensin II binds to the type 2 receptor (AT2) and works mainly by binding with the type 1 receptor (AT1). AT2 receptor signaling plays a role in protection against multiple-organ damage. A direct AT2 receptor agonist is now available and is expected to reduce inflammation and oxidative stress and enhance cell differentiation. We and other groups reported that AT2 receptor activation enhances neuronal differentiation and neurite outgrowth in the brain. Here, we also review the effect of the AT2 receptor on cognitive function. RAS modulation may be a new therapeutic option for dementia including AD in the future.






Figure 1: Possible effect of angiotensin II on neurovascular unit. AT2: angiotensin II type 2 receptor, AchR: acetylcholine receptor, BBB: blood brain barrier, and TGF-β: transforming growth factor β.







Figure 2: Effect of angiotensin II type 2 receptor signaling on cognitive function. AT2: angiotensin II type 2 receptor, ATIP: AT2 receptor-interacting protein, Id1: inhibitor of DNA binding protein 1, MMS2: methyl methanesulfonate-sensitive 2, NO: nitric oxide, SHP-1: Src homology 2 domain-containing protein-tyrosine phosphatase 1, and Ubc-13: ubiquitin conjugating enzyme 13.








Figure 3: Effect of angiotensin II on cognitive function. ACE: angiotensin converting enzyme inhibitor, AT1: angiotensin II type 1 receptor, AT2: angiotensin II type 2 receptor, and ARB: angiotensin II type 1 receptor blocker.


Continuous stimulation with angiotensin II may damage neurons via multiple cascades through AT1 receptor stimulation. On the other hand, stimulation of the AT2 receptor is expected to prevent neural damage and cognitive impairment (Figure 3). However, it is difficult to perform clinical intervention studies to confirm the results of animal studies because of the long-term progression of cognitive impairment. Moreover, in clinical practice, it is not possible to exclude the antihypertensive effect of RAS blockade on cognition in patients with hypertension. However, RAS modulation may be a new therapeutic option for dementia including AD in the future. Therefore, the hypothesis that RAS regulation affects future cognitive function should be confirmed with carefully designed clinical studies.



Which ARB (Angiotensin Receptor Blocker) for Autism?

Very many biological markers are disturbed in autism and many of them seem to be best ignored, you cannot “correct” them all.

However, there will be an underlying reason behind each one of them being disturbed.

As we saw in the recent post on metabolic syndrome, it is not uncommon to find a cascade of downstream problems that might seem to indicate a huge list of drugs.  A different approach is required, it is necessary to treat the underlying (upstream) problems and have a much shorter list of therapies.

We saw in the post on leptin that the elevated levels in autism are treatable, but is there any point?

We have a long list of other things that might be useful in autism and it would be nice to have a single therapy that might address many of them.

It appears that selecting the optimal ARB might give the opportunity to address numerous issues at once.

Telmisartan seems to have numerous potentially useful additional effects:


·        Acts as a PPAR gamma agonist, like the glitazone drugs shown effective in autism trials

·        Acts as a PPAR delta agonist, which should activate the impaired PPARδ  PGC-1α signaling pathway, and enhance mitochondrial biogenesis. This should help people with mitochondrial disease and should be evident by increased exercise endurance and, in theory, improved cognitive function.

·        Telmisartan regulates the Bcl-2 cancer gene, implicated in autism


While the effect in autism is complex, Telmisartan is already seen as a potent target for prevention and treatment in human prostate cancer

·        Telmisartan and other ARBs appear to give protection from Alzheimer’s Disease (suggested to be via its effect on PPAR gamma). Perhaps useful for young adults with Down Syndrome, where early onset Alzheimer’s is expected?


·       Telmisartan and other ARBs have a tendency to increase the level of potassium in blood. Up to 10% of people would experience mild hyperkalemia.  For people with autism taking bumetanide, this effect on potassium might actually be helpful. They would need to reduce their potassium supplementation, or might need none at all.




Telmisartan in clinical trials related to autism

As is repeatedly the case, schizophrenia research is again more advanced than autism research. A quick check showed this:-



This is a 12-week, randomized, double-blinded, placebo-controlled trial of telmisartan 80 mg/day as an adjunctive to clozapine or olanzapine therapy, in 70 schizophrenia subjects to examine telmisartan's effect on glucose metabolism, weight, food intake, resting energy expenditure, and body composition. In addition, the study will examine insulin's effects on psychopathology and cognition.



Conclusion

We currently have no possibility of something like Compound 21, but Telmisartan looks very interesting and it would nice if those psychiatrists who have trialed it in schizophrenia would do the same in autism.  

It looks like the beneficial effects should come at a lower dose than that used to lower blood pressure. In the schizophrenia trial I think they used a higher dose (80mg) than necessary, I suppose they wanted to maximize their chance of success.  In order to minimize any possible negative effects, I would suggest the psychiatrists trial 20mg in youth with autism.

There will be a post on PPAR delta and mitochondrial disease, because there are at least two other ways to target mitochondrial disease in this way, if you do not like Telmisartan.  There is the cheap drug Bezafibrate and the supplement berberine.







41 comments:

  1. Hi Peter, thank you for another great post!

    I'm very curious to read your next post because as I've looked at various mechanisms of action, berberine has popped up a few times.

    Peter, further to a comment you made in a previous post about statins, I have a few questions for as you have me very intrigued:

    1. You had said the difference was noticeable after just the first dose of a statin - would you kindly expand on this? What did you see and how big was the improvement after the first dose, and then did the improvements continue after the first dose or did they plateau?

    2. You've noted Lipitor would be your first choice? Any issues or shortcoming with other statins, like Crestor?

    3. When looking at statins, what dose relative to a normal adult dose is needed? Is it a microdose relative to the normal dose (like Clonazepam) or is it the regular dose that is needed (adjusted for child's weight)?

    Thank you very much in advance Peter!

    AJ

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    1. AJ, very few people have tried a statin for autism. The effect has nothing to do with cholesterol, but statins are actually FDA approved for children. The effect in my son is that he started to do things he wanted to do but could not do. So coming downstairs in the morning by himself, or paying the piano without the need for someone to sit with him. All little things, but striking non the less. It is like an increase in initiative or self confidence. When you stop the pill behavior switches back. The effect is from the first pill and does not change much.

      The statin has to be lipophilic to enter the brain. The other good ones should be simvastatin and lovastatin.

      For atorvastatin the adult dose is from 10mg to much more. It us approved in children up to 20mg when I checked. In a very young child a quarter of a 10mg pill would seem reasonable.

      Atorvastatin seems to have the least side effects in adults. Having seen its effect, I decided to take it myself as well. The cardiovascular benefit comes from the anti inflammatory properties more than the cholesterol effect. There is a lot written about this.

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    2. Thank you Peter!

      AJ

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    3. Peter,
      As you say very few people try statin for autism. But what about policosanol? It seems Amy Yasko prescribes it in her autism protocol. Can policosanol be an alternative to statin? It has less side effects?

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    4. Salempeacock, the majority of the hundreds of millions of people taking statins have no side effects. My son and I have both taken Atorvastatin for 4 years without any side effect of any kind.

      The people that do get side effects from statins can very likely completely treat them with Co enzyme Q10, which statins can deplete.

      The mode of action in autism is likely the anti-inflammatory action of the statin, which is a "side effect" of a drug developed to lower cholesterol.

      I doubt policosanol has the same anti-inflammatory effects as Atorvastatin, but any anti-inflammatory drug has a chance of being helpful.

      You actually only need one Atorvastatin pill to determine if you have a responder, so it does not seem a risky trial. If you do not respond, you can just forget all about it.

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  2. Hi Peter, my experience with diamox has been good, speciallly in a cognitive, role play,and speech level. If I up the dose to 250 mg a day the effect should be better? He has been taking 125 mg during 6 days. The problem is that he started with a throat infection and guess what? head tics started again after many months of being without them.Histidine couldn,t prevent this from happening. Iam giving ibuprofen, vitamin C and papaya enzymes. I was thinking of adding AlA, but berberine could be a better choice? It´s incredible how viral and bacterial products affect my son´s brain. When we started talking about it so recently, was a kind of premonition.
    Valentina

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    1. Valentina, you could try giving diamox twice a day to see what works best. It is best to use the lowest effective dose, rather than keep increasing it. That way you minimize the chance of any negative effects. ALA is very different to berberine, many people find ALA effective and it is well worth a try.

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  3. Interesting post Peter, especially in light of thinking of ways of tinkering with the immune profile in the brain.

    Some research on schizophrenia came out today that involves an indirect approach to interacting with receptors via astrocyte activation:

    Press Release:

    https://www.sciencedaily.com/releases/2017/05/170504131902.htm

    Paper:

    http://www.cell.com/neuron/fulltext/S0896-6273(17)30347-1?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627317303471%3Fshowall%3Dtrue

    Basically what the researchers found was that a7nAChRs (alpha 7 nicotinic acetylcholine receptors) activation on astrocytes causes them to dump D-Serine into the synaptic space of NMDA receptors, thereby impacting behavioral and cognitive functions governed by NMDA receptors such as wakefulness and memory. This may or may not relate to some autisms, but the idea of thinking about using the support cells in the brain (astrocytes, micoglia, oligodendrocytes, etc.) to impact neuron to neuron synapses (sometimes called the tripartite synapse) is a relatively new idea in neuroscience.

    Unfortunately, I know very little about how astrocytes directly modulate the activity of neurons aside from them uptaking glutamate and converting it back into glutamine, so I have no real good ideas or rather any ideas period on this front, but since astrocytes in theory have limited reserves of certain neurotransmitters, trying to target them for indirect synaptic modulation might be an approach with less side effects than bathing the brain in powerful drugs that work on neuron synapses directly.

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  4. Hi everyone,

    Just wanted to share this really interesting finding that blocking opioid receptors significantly improves oxytocin's ability to enhance social interaction:

    https://medicalxpress.com/news/2017-05-combination-approach-boost-social-interactions.html

    I know there are several trials out there right now using intranasal oxytocin to improve social interaction.

    I don't know if / when this new insight will make its way into the trials, but it sure is interesting.

    Have a wonderful day!

    AJ

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    1. Very interesting. Unfortunately, naloxone as old as it is happens to be more or less a controlled substance due to its use by heroin addicts in managing their habit, so the only way you can get as far as I know is ironically at a rehab center. I think small amounts can be prescribed to addicts and their family members for an emergency dose in case of an overdose, but short of that it is sadly out of reach for most people here in the USA.

      The L-Aspartic acid therapy I have mentioned before is supposed to more or less do the same thing as nalaxone or naltrexone. Intranasal oxytocin can be readily purchased but is quite expensive and its effects seem to taper off a bit from chronic use. Maybe this combination therapy might deal with that problem (who knows).

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    2. Hi Tyler,

      Thanks for your insights! I didn't know that L-Aspartic Acid could be an alternative to Naloxone for this purpose. It is very easy to get.

      In terms of Intranasal oxytocin, you've noted it can be readily purchased. When I looked for this in the past, it seemed that when the product of some manufacturers was tested (independently), some products had little to no oxytocin available.

      Do you know of a reliable product? If you would kindly provide a link, it would be much appreciated!

      Also Tyler I would love your insights (and Peter's) on the other paper I posted. In that paper, they took the sera of ASD and normal kids, injected it into rats, and the sera of ASD kids basically gave the rats ASD. The researches think it's the mix of neurotrophic factors, and in fact note that there are high levels of proBDNF, FGF2, and LIF, and low levels of BDNF and CNTF.

      I've read conflicting articles about BDNF, whereby sometimes it is said that BDNF is high in ASD. It could be that it is high in some and low in others (i.e. the balance is off and that's the issue), but here it seems that the issue is that the proBDNF is not being turned into BDNF (via Furin or Plasmin based on another article I looked at).

      Would you kindly provide your insights into what this paper is saying, and what it may mean for us in terms of potential treatments? They are using P6 as a pretreatment in cells / rats, but do we have anything we can access to bring the neurotrophic factors noted into balance?

      Thanks very much Tyler!

      AJ

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    3. For some time I was wondering why Cerebrolysin was never mentioned on this blog (or comments). Any reason? One polish blogger believes in it as much as Peter believes in bumetanide (he described fantastic effects in his younger son with down syndrome).

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    4. Thanks for the comment.

      I do think there is merit in exploring the various growth factors (BDNF, NGF, IGF-1 etc) as therapies for autism. We should also note, as highlighted recently by AJ, they were likely also a cause of some people’s autism.

      Cerebrolysin is a mixture of growth factors (BDNF, NGF etc) made from pigs’ brains and given by injection.

      It is used to aid recovery after stroke and to treat vascular dementia.

      Most interesting is an old Russian study showing its effect in autism.

      The effect of cerebrolysin on cognitive functions in childhood autism and in Asperger syndrome
      https://www.ncbi.nlm.nih.gov/pubmed/12872620

      Based on the outcome of that study it is quite possible that some people with autism, or Down syndrome might benefit.

      One complication is that people with autism can be hypo and hyper in each growth factor, so a drug that increases the production of growth factors would be helpful for some, but unhelpful for others.

      Down syndrome is very specific and results in the over-expression of 300 to 500 genes. Autism results in both over expression and under expression of hundreds of genes and not always the same ones.

      The Polish blogger may well have found a therapy that should indeed be trialed in a larger group with Down syndrome (DS). It is known that there are strange things going on with both NGF and BDNF in DS. This is thought to protect them from atherosclerosis.

      It looks like the Russian study in autism was not followed up, or perhaps only in Russian literature.

      If anyone decides to trial cerebrolysin for autism, I would be very interested in the results.

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    5. To BDNF or not to BDNF, that is the question and this paper you cited AJ seems to suggest that a lack of BDNF may be the issue here. Now the P6 compound does not appear to be anything that is you can take orally or even inject into the blood, rather they injected it directly into the brains of the rats (I only skimmed the paper so I could be wrong, but that is what I gathered).

      Now, coincidentally I was reading some other stuff and came across a very long thread and old thread (52 pages) on a discussion forum discussing a compound called Dihexa which is claimed to be an Angiotensin IV analogue:

      http://www.longecity.org/forum/topic/59312-dihexa-it-would-take-10-million-times-as-much-bdnf-to-get-as-much-new-synapse-formation-as-dihexa/

      It is a very long thread of people discussing theoretical pros and cons and some people even ordering small but very expensive quantities of the peptide and using it for personal use with the hope of becoming smarter or healing some past brain injury (one user has ALS) via its purported effects on increasing BDNF. In the thread, I also came across this paper posted by one of the commenters:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261279/

      It is thought that the main mechanism of action for Dihexa is on Met receptor tyrosine kinase, hence why one commenter brought it up. Peter has discussed TrkB signalling extensively on this blog as I am sure you already know.

      There were also several other comments discussing whether this substance would be a pro-autism inducing compound or not or whether it would help with schizophrenia under the theory there are too many synapses in autism and too little in schizophrenia (I don't currently subscribe to this one way or the other as there is a lot of research going both ways for autism).

      There was also a posting about a small trial of Dihexa for Parkinsons disease by the Michael J. Fox foundation (for international readers he is a famous actor who is almost as famous for developing Parkinsons at an early age):

      https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=993

      Here is an old press release concerning the original study on Dihexa for Alzheimers disease (link to the paper is in the press release):

      https://www.sciencedaily.com/releases/2012/10/121011090653.htm

      Also, the only supplier I could find for Dihexa is here:

      https://nootropicsource.com/

      One last thing is that many of the anecdotal reports of its use suggest increased sensory perception (more vivid colors, etc.) which would be interpreted as sensory overload (bad) or else interpreted as an increased signal to noise ratio in sensory processing (good).

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    6. AJ, read the comment about Cerebrolysin, above/below.

      https://epiphanyasd.blogspot.com/2017/05/angiotensin-ii-in-brain-therapeutic.html?showComment=1494228976053#c9144759879525097734

      It is clear that in some people growth factors can be a therapy, just as disturbances in the same growth factors, at the wrong time, may cause/worsen autism.

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    7. Hi Peter and Tyler,

      Thank you both for your responses!

      With respect to Cerebrolysin, I have found the following, which is basically supposed to be an oral (but less effective as its oral) version of Cerebrolysin:

      http://www.memoprovememory.com/healthcare-professionals.html

      As Tyler noted, injecting something into the brain versus taking it orally are two very different things, and clearly much will happen to any substance taken orally before it gets to the brain, assuming it makes it past the BBB. Having said that, could this MemoProve have any potential for us in your opinions? It is N-PEP-12

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392105/


      Tyler - thanks very much for your detailed response, and the info on Dihexa! I had never heard of it before you noted it. I'm going to look into it. I was also thinking about D-Cycloserine as I had read somewhere it improves verbal capabilities. As I had never head of L-Aspartic Acid as an alternative to D-Cycloserine, I'm adding it to my list of next things to try.

      As always thanks for your insights Peter and Tyler!

      AJ

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    8. Hi Peter and Tyler,

      Just found something very interesting!

      Tyler, I took a look at the site you had identified as offering Dihexa and looked around, and saw something called P21. I was curious, so I looked it up and it looks like P21 is a version of P6 with better BBB permeability.

      http://www.longecity.org/forum/topic/65066-cntf-based-peptide-p21/

      Assuming that the paper I had noted earlier about neurotrophic imbalance being corrected by P6, could a P21 nasal spray be worth trialing?

      Would really appreciate your insights on this.

      Thanks much in advance!

      AJ

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    9. AJ, MemoProve is made by the same Austrian company that makes Cerebrolysin. You would think that the people injecting Cerebrolysin every day would have thought to give MemoProve a try; like the Polish parent with a Down Syndrome child.

      Very many things can marginally improve memory in older people - all those herbs like Rosemary and Sage in the Mediterranean diet, the cocoa flavanols, almost any antioxidant. There are scores of studies and trials.

      It is very easy to spend a fortune on supplements.

      I would guess that Cerebrolysin is 1000 times more potent than Memoprove.

      If you do try Memoprove, let us know the result.

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    10. The Cerebrolysin trial you linked to was actually followed up (though in combination with neuroleptics) a couple of years later:
      https://www.ncbi.nlm.nih.gov/pubmed/16548370

      /Ling

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  5. Hi everyone,

    I was about to post an FYI on the approval of a new drug for ALS, that may be of interest based on its mechanism of action, and as I looked for something related to post, found a study that blew my mind:

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118627

    I'm going to dig through it, and post any specific findings of interest, and ask that the community kindly provide your insights as well.

    To give you a sense of the study, the following 2 quotes sum it up, but the key will be in the details of the full paper which is linked above:

    "One of the most remarkable findings of the current study is the development of several features of autism in young rats whose brains were exposed to sera from autistic children via i.c.v. injections. This single finding strongly suggests the important role brain environment plays during early development in the pathophysiology of autism. Early postnatal exposure of brain tissue to sera from autistic children which had abnormalities in neurotrophic factor levels led to developmental delay and social communication, interaction, and memory deficits in young rats. Several of these deficits such as developmental delay and social memory deficits were rescued by P6 treatment."

    "In summary, this study provides evidence regarding the neurotrophic abnormalities in autism and the potential role they play in the pathophysiology of the disease."

    Thanks very much to all for your insights!

    AJ

    P.S. Tonya - my daughter has been getting a full dose of P5P for a week or so now, not a single complaint and I really believe we're seeing some improvements. Your identification of a riboflavin deficiency looks to have been 100% accurate. Thanks again!!!

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  6. P.S.S. Sorry Tanya, meant to say Tanya, not Tonya - I have a client named Tonya so I'm used to typing the name that way.

    AJ

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    1. It's ok AJ, It happens all the time. ;) I am so glad you are seeing improvements! It can be tricky figuring out the Bs, but once you do, nice to see a simple nutirent making a difference. Gosh there are so many variables to consider with our kids, aren't there?

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  7. Peter, what do you think about neurotensin from mast cell activation, the product neuroprotek, and the fact that the word neuroinflammation is so freely used to describe and simplify the autism´s problem.
    Valentina

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    1. Valentia, neurotensin and the hormone CRH can activate mast cells, this is why emotional stress activates mast cells. So someone who gets very upset, for example after a funeral, may exhibit an allergic reaction.

      Neuroprotek is very expensive and I am not sure it has a comparable effect.

      Neuroinflammation = chronic inflammation of the central nervous system (CNS)

      It is an over-used term because it can mean very different things, so there is no single "cure" for neuroinflammation.

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    2. Ok Peter, I will try ALA, it seems that 125 mg diamox is better than 250mg. This is for Tyler also, today my son got up at 4 in the morning and when no one saw him he began to flood almost the hole house again,he also emptied a bag of xylitol on the floor and throw water inside the oven. Also he is super obsessive with door and windows, he feels that he must close all of them. He is out of risperidone and recently of valproate. Continue with bcaas 8 gr and diamox 125mg. Also Lserine, carnitine and histidine with zinc and of course NR. I don´t know what to do, it seems that nothing can stabilize him. In addition,he has a terrible caugh and sore throat.
      Valentina

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    3. I have had those situations when my son was younger. The door and windows stuff are classic OCD symptoms and they likely relate to striatum problems. The bizarre behaviors you can never intuitively make sense of are also likely related to a striatal prefrontal cortex circuit for cognitive functions being imbalanced in favor of the direct pathway. In short your son is still getting too much d1 receptor gain and not enough gain in the d2 recptors. I am simplifying things here but what you want is to do what you are doing now in limiting excess dopamine which tends to activate the direct pathway more strongly than the indirect pathway while also targeting brain regions/receptors that add gain to the indirect pathway. Other indirect methods of dealing with dopamine signaling would include the various opioid receptors. Again to simplify things here you would probably want to antagonize mu-opioid receptors and agonize kappa opiod receptors. You are looking at nalaxone/naltrextone here if you can get it, otherwise the only other idea is the l-aspartic acid of 4-8 grams a day and see if that helps at all.

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    4. Tyler and Valentina, jumping in here if I may because my son has COMT snps, some behaviors similar to Valentina's son (not constant, comes in cycles) and I am interested in all things dopamine - Tyler, what about lithium for d2? How would dosing extra niacin affect this? Looking at other options in case a no-go on naltrexone (couldn't get it last time I asked). I do give him aspartate forms of magnesium and potassium but not high amounts....
      Thanks

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    5. Valentina, does treating with any type of antimicrobial help at all with these behaviors?

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    6. Tyler, ok one more question for you - because I am not fully understanding micro dose clonazepam yet : when in these cycles would micro dose clonazepam help? I know Peter says it takes about 3 days to get to effectivenss wity it, so could it be used in a pulsed fashion, for when these issus creep up??

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    7. Hi Tanya, about lithium for d2, of course always refering to orotate, for my son was always positive, i used it in combination with valproate and was certainly a good much,was something that did on my own with good results, can say you that it helps, but my experiencie was valproate plus lithium orotate. I don´t use valproate any more, it was of huge help for many years but now I let it go, thanks to Peter and Tyler that gave me the last push.The problem with lithium is that you have many interactions. Now giving diamox but think there is an interaction there. About antimicrobial support, use a wormwood combination wth clove and blackwalnut, but I dont know, in this case I can´t tell you nothing clear. I wanted to ask you about the home school experience in your son, sometimes I think that would be the best for him,he would be calmer, with less presure and better form the academic point of view. The problem is that he loves being with his neurotipical classmates, doesn´t matter how.
      Valentina

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    8. Tyler,
      Regarding Nalaxone what is the dosage? Regular or low dose like 1 mg to 4 mg? Thank you.

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    9. Tanya I have never trialed low-dose clonazepam as it is a controlled substance and I would need to doctor shop for a very liberal doctor to prescribe it. The low-dose clonazepam also is intended to address a totally separate issue from dopamine, and that is dysfuntional GABAA receptor subunits. It is one of those interventions I would like to try because it is safe, but can't because of politics here in the United States that allows people to purchase and drink any amount of alcohol, but if you have a small amount of a drug that could help your child that $300 an hour (or more) doctors won't prescribe you without many prior "consultations", you go to jail for a long time. In the United States, 20% of our economy is devoted to health care and it does not take a whole lot of investigation to see which people in the "health care system" drive the best cars and live in the best houses and never have to worry about job security due to how the various medical guild systems operate so as to keep costs extremely high for patients and taxpayers and salaries and other reimbursements extremely high for doctors willing to play the game. I don't have the money to "doctor shop", as doing so would cost more money than all of the other costly interventions I employ combined.

      Doctor politics aside, I don't know a lot about lithium's specific uses though I believe Peter covered it in a blog post several years back.

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    10. It is relatively easy to get Clonazepam prescribed for i) anxiety if your child is older or ii) management of seizures (or a short course to stabilise them), which are quite common for parents with ASD.

      The 0.5-1mg tablets last a very long time, just one is needed to see if it works or not.

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    11. Tyler, Oh - I was thinking in some way it would affect dopamine due to at high doses people can become addicted. I just didn't know if it would help d2 indirectly when you need that boost there - since you explained to Valentina in her situation sounded like she needs more d2 boost and less d1 (I need to educate myself more on this, sorry).
      I am in the US, and my son's pediatrican rx'd low dose clon with no hassle. And sent the rx to a compounding pharmacy so we could get the dose right. I briefly tried it before the tree pollens got high - the .5 dose the first day made him sleepy - maybe a coincidence? waited a few days to try again at the lower dose of .25 and couldn't really see any difference. Still considering trying again when pollens are down.

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    12. Valentina, thanks so much for sharing... About the homeschooling - I had the same concerns as you did about my son missing out on the social opportunities because he liked it - but the other factors just stressed him out so badly. And then I realized, the relationships and activities he really likes, the natural and not contrived way, he was never going to get from that particular school, so it became an easy choice. In other words, that setting just created more health problems and made his "autism" worse. It isn't ideal, but he is doing much better.

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    13. Hi Tanya,

      The low dose clonazepam is in micrograms, i.e., .025mg. Is that what you meant? .25mg is closer to a regular dose with the ensuing side effects including drowsiness.

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    14. Hi RG, yes, sorry, that is what I meant .025 and .05. Such a small amount and I saw drowsiness with the .05 dose! Just did that dose once - so possibly a coincidence, but knowing my kid, I doubt it.

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    15. RG - another question: I know the Catteral study the dose was not used for anxiety but for cognitive issues, am I correct? Since the study was with mice, obviosuly couldn't tell if those cognitive improvements would include language - did you happen to see any language boosts? I was hoping it could help with situational anxiety/ptsd type reactions.

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    16. Hi Tanya,

      It did not directly boost language. It helped my daughter sing loudly and on demand, where before she used to be inaudible in public. It did help her speech become more clear, audible and she was more confident in using speech.

      My daughter had the habit of taking a stressful situation and layering it with other connected events and places, and making it all into one big anxiety loop. For instance, my cousin's death was connected to aunt and uncle's place and refusing to go there, then connected to a flight from Heathrow, and then refusing to get on a flight and then getting anxious just driving by an airport. There were many such loops. Within a month of starting low dose clonazepam, she planned a long holiday which included several flights and had fun the entire time. Anxiety is almost non existent now.

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    17. Thanks RG - I am no pyschiatrist but what you describe does sound like a ptsd type reaction - and very promising that you can connect the improvement in those symptoms to micro dose clonazepam! thanks so much for sharing the details and Happy Mother's Day to you!

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  8. off topic: Support for neurofeedback in mainstream media.
    http://www.bbc.com/future/story/20170507-the-most-promising-route-to-mental-superpowers

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