UA-45667900-1

Monday 7 December 2015

One of Thousands Autism




Some occasional visitors of this blog ask why if one drug helps their case of autism, another can be ineffective.

Perhaps it would be much more helpful right at the start to diagnose people with “one of thousands autism”, then people might better understand their situation,  and plan their way forward.

Autism is not a biological diagnosis, it is just an observational diagnosis.

Some readers have suggested “sorry, we don’t know” would be the honest diagnosis.



Several hundred autism genes and still counting

Some of these 740 genes linked to autism are shown here:-



There are existing mouse models covering 192 individual genes that can cause “autism”.

There are 18 known individual chemicals that can induce ‘autism” in mice



You may wonder how come there is a thimerosal-induced mouse model, but it exists.



There are dozens of rescue models, where scientists can make a mouse have “autism” and then reverse it.




Autism as an Adaptive Response

Any combination of what will likely become at least a thousand genetic and environmental factors can lead to what gets termed “autism”.  Autism is just the result of the brain’s adaptive response to those factors.

Certainly there are common pathways and downstream nexuses, where unrelated dysfunctions converge.

So in the end there will be a manageable number of clusters where most people’s autism can be located.

The thousand autisms will not require a thousand different therapies.

Sooner or later it will be necessary to stop calling it autism and start diagnosing each person’s biological dysfunction.  Only then can you treat it properly.

The efforts of the late Lorna Wing (autism as a “spectrum disorder”, ASD) and Barons Cohen (autism is not a disorder, it’s a friendly “autistic spectrum condition”, ASC) have certainly served to dramatically widen the number of people diagnosed, and even now wanting to be diagnosed, but have made actually treating it, very much harder.

We should start with what Knut Wittkowski, from the previous post, called Strict Definition Autism.  Apply what doctors call triage, start with those where you can make the biggest impact;  minimize cognitive dysfunction (mental retardation), self-injury, aggression and epilepsy.

   
Your one in thousands Autism

If you took a representative sample of 2015 diagnosed children with “autism”, who would it contain?

The following is based on what appears in previous posts and is not supposed to be definitive.


·        The largest category is probably misdiagnosed autism 

This would include people who are naturally late at developing speech, some people better diagnosed as ADHD, some people with Mental Retardation / Intellectual Disability, people who were deaf during key developmental periods and even people brought up in a cold, stimulus free environment like a 1980/90s orphanage in Romania.  Recall Leo Kanner's refrigerator mother ideas.

Quasi-autistic patterns following severe early global privation. English and Romanian Adoptees (ERA)Study Team.



·        Metabolic disorders that are likely not caused by a single gene

The big one here is mitochondrial disease, often triggered by some environmental event, like oxidative stress or an inflammatory response.  This includes the group that had a viral infection and then regress into autism, usually before the age of five.

There are other metabolic disorders like, cerebral folate deficiency, that are substantially reversible.


·        Then comes the large number of single gene dysfunctions that lead to symptoms that often include autistic behaviors

These vary from reversible to treatable.  Some well-known and not so well known, examples are:-

·        Smith–Lemli–Opitz syndrome (also SLOS, or 7-dehydrocholesterol reductase deficiency) which is in effect low cholesterol

·        Biotinidase deficiency

·        X-linked creatine deficiency

·        Pitt Hopkins

·        Rett Syndrome

·        Fragile X

All the above can be identified by genetic testing, but often are not.

·        Then comes “Dysmaturational Syndrome” which is Tourette’s Syndrome with autism “recovery” by 6 years old


This group accounted for about 5% of diagnoses in a large Italian study.   They do maintain their tics, but the autism features just fade away.


Now we are heading to what the “experts” call “Idiopathic autism”, which is the “we really don’t know”, catch-all category.

This group I will split into hypo/hyperactive pro-growth signaling pathways, based on the clever recent suggestion of Subramanian et al, from Johns Hopkins, we saw in an earlier post.









·        Hyperactive pro-growth signaling pathways

This group includes the textbook classic autism, with accelerated (brain) growth.  They can be identified by some of the following:-

·        Noticeably big head (and brain), maybe just at birth and maybe even Chiari 1 brain hernia (caused by no space for the growing brain)

·        High birth weight and muscular tone as a one year year old

·        Subsequent large drop down the percentiles on growth charts.


·        Hypoactive pro-growth signaling pathways

This group is smaller than the Hyperactive pro-growth category, but is sufficiently large to make most autism clinical trial pretty useless.

In many ways this hypo group are the entire opposite the hyper group, and what is good for them, may well be the opposite of what is good for the others.

This group will have small brains and I presume will have low birth weight. 

This does not mean they will be small as adults.

The hypo/hyper active growth refers to what is happening as the fetus develops and in the first year or two after birth. 



Implications for Clinical Trials and Therapies

It really is not good enough to carry out clinical trials on people, based solely on a DSM behavioral diagnosis of autism.  They are almost doomed to fail and indeed they almost always have failed.

Identify sub-types of autism, based on biological markers and then make trials on one sub-type vs another sub-type.  Then we might actually learn much more.

Some interventions that work in one sub-group should actually aggravate the autism of other sub-groups.  This should be entirely expected.

Autism researchers need to wake up, read other people's research and properly plan their trials based on the entirety of what we already know.  It is not rocket science; that is actually far more complex.  Planning trips to Mars is far more complex than what most autism researchers get up to. 

If you are going to compare therapies with other autism Mums/Moms and Dads, first check that your sub-type of autism is vaguely similar to their sub-type.  Otherwise you may be wasting your time/money and possibly doing more harm than good.




Conclusion

After receiving a diagnosis of autism, ASD or PDD-NOS, I suggest you ask the specialist to be more specific and help find you a biological diagnosis, rather than the observational/behavioral one.

If they cannot give you, at least pointers towards, a biological diagnosis, perhaps they should not be diagnosing  autism? Or just admit “I do not read the autism literature and so I know little more than you; but I get well paid as an autism expert, regardless”.








52 comments:

  1. Well the only specialists I know of in my area seem to be sticking to their guns when it comes to decades old debunked ideas, usually based on quack research. These are primarily moms who are only superficially involved in treating their child's condition and after enough doctors they typically give up on the idea of treatment and focus more on accommodations and acceptance.

    None of them would ever dare prescribe Bumetanide or anything else off-label but they would be happy to write scripts for antipsychotics and antidepressants, for children no less.

    On a sidenote, one of our speech therapists (not a specialist of course) demanded I try a special form of fish oil with the right balance of EFA's because it had cured autism and aphraxia in some families of clients she knew in another state. I tried to explain to her that I already give my kids fish oil and she said that the fish oil was not working because the ratios were out of balance. I then asked her what EFA's are (I knew but was just curious) and she didn't understand. She of course also does not understand that perfectly formulated ratios of fatty acids are pointless because everyone's body digests and metabolizes them a bit differently. The link she demanded I read (which I did out of curiousity) also did not have any link to a direct study about this fatty acid profile claim, yet had research citation spam a mile long of research papers which may have only the most tangential relevance to the fatty acid miracle cure.

    She was only trying to be helpful but whenever I try and explain to people that there could be thousands of different genes involved, a myriad of environmental insults too long for any human being to remember them all (and I know a lot of them), plus the fact that the only thing researchers seem to agree on is that they don't agree on anything other than the core definition of autism, they just think I am being ridiculous because a lot of people can't deal with uncertainty.

    ReplyDelete
    Replies
    1. Thanks Tyler. Most people cannot deal with complex issues and so get by on sound bites. They will never understand autism, the Palestine/Israel question, nor anything else that cannot be explained in thirty seconds in words of few syllables. More worrying we have a generation of doctors unwilling to explore and innovate for fear of falling foul of the rules. Off label prescribing used to be very common, because older doctors, who knew little about genes, knew that their patients were all slightly different. So a little bit of trial and error was accepted.

      Delete
  2. I also had an IEP meeting recently, where one of the school staff (this is a public school BTW) told me that because some of the other children in my son's class would willingly eat whatever was thrown in front of them, that my son should be able to do the same, implying that his food sensitivities were somehow my fault. This was after I raised a concern about my son at times not consistently eating the lunch I pack for him and then they wonder why he has bad days. I even raised an issue about sleep issues with autism and one of the teachers countered that she knew of a study where autistic children do better if they have earlier school times (obviously she was lying to save face) as my son sometimes was late to school because I would let him sleep in on nights he would finally fall asleep very late (sending an autistic kid to school hungry and on 4 hours of sleep I guess is a great idea according to these people).

    And as for general practitioners who do understand autism's heterogeneity, they also understand there is no money to be made treating 1000 different nebulous disorders. You would have to be a jack of all autisms and master of none. People go to specialists to get results from an expert, not an answer of "well science is not sure yet, but lets do our best here".

    In the case of my children, I feel I now have a pretty good idea how to SAFELY deal with some of the most common symptoms reported in the autism literature, though that is just my gut feeling personally. I have no idea if the various interventions I am employing would help anyone else, though I suspect most of them might. But unless you wear a white coat (in the USA at least), nobody will take you seriously. Unfortunately, nobody serious with a white coat actually treats autism in the United States in a comprehensive manner.

    Nonetheless, I do believe unsupervised machine learning algorithms could do a lot with all of this potential data from parent led interventions in figuring out what may work and for what subset of those with autism and with what symptoms. There are researchers trying to do this with analyzing the nexus of genes with other environmental variables with their own research data, but while laudable this is very expensive and slow. If there was a place where parents could openly share everything they do or have done without fear of ridicule or invasions of privacy, then I think you would rapidly start understanding what interventions, no matter how strange they might seem, actually have a useful effect in a given subgroup of those diagnosed with autism. And even the most seemingly broken interventions could even bear fruit as a broken clock is still right twice a day. The fact is we just don't know what may be working and what may not be working because what may end up working may not make logical sense, hence why machine learning could make big inroads in this department.

    ReplyDelete
    Replies
    1. Tyler, if you can help your own kids, that is great. No parent can really hope for more.

      There is sadly no point trying to convince others, save those very few who have opted to inform themselves by delving into the scientific literature, or just Wikipedia.

      Delete
  3. I can only speak from my experience but in Australia a paediatrician refers you to a developmental psychologist who gives the ASD diagnoses. As I recall psychology falls under the category of the arts, it's pretty far removed from science. If my son's psychologist is anything to go by, his profession won't be giving up "ownership" of ASD anytime soon. Classifying autism as a mental disorder and entirely pyschological causes unnecessary heartbreak and helplessness. Amazing strides can be made with a scientific approach. Peter has helped so many by sharing his knowledge and research findings.
    Nina

    ReplyDelete
  4. Thanks Roger. It is human nature to want to blame something/somebody, and better something you feel you understand and can see. So people blame vaccines, Lyme disease, parasites, candida etc. They do not blame genes, because that might imply parents blaming themselves.

    Much better to skip the blame game.

    It is only recently that autism research has really picked up any momentum. It was a no go area for years, following all the Wakefield saga. Even today, almost no mainstream physicians wants to even try to treat it, or bother to read the research.

    ReplyDelete
  5. Very good Peter!, i am also convinced like Roger that my son´s autism is a genetic primary immune deficency, that is something that no physician or neuropsichiatrist will investigate for your son, nowhere in the world. Valentina

    ReplyDelete
  6. Another year is almost over without a single trial of calcium channel blockers for autism, while it had been suggested even before my son was born. If I hadn’t stumbled upon your blog Peter, I wouldn’t think about giving my son Verapamil although I had read many papers before - in the same way which was usually enough for patients under my care. If you are involved in tropical medicine at 54°N you are used to read PubMed at work (but you don’t know how to distinguish tic from stereotypies unfortunately). But in autism on the one hand there’s a lot of research, on the other - little is really helpful and practical for doctors.

    Yes NAC and Bumetanide studies are underused. But it’s not all about off-label prescribing, see what happened to people repatriated to Europe with Ebola from Africa last year - they all were treated with off-label or experimental drugs. No one said: the books say Ebola is untreatable. I remember the first article about Bumetanide I found was from SFARI and was titled “Controversial study touts blood pressure drug for autism” - instead of calling it “Life-changing study...” Why? I imagine that doctors may feel puzzled if such experts say it’s controversial. I think there is a need of big change in the way of thinking about it.

    I tried Acetazolamide in my son intermittently in last few weeks. What I can tell now it is the only drug I know which can stop his headache episode when given in the middle of it and after a few days bumetanide-like effects can bee seen: improvements with learning and socializing. This happens when it is used in combination with Bumetanide rather than alone and disappears with Acetazolamide withdrawal. Seems like you can’t give it with normal Clonazepam dose as it probably increases its concentration (via CYP3A4 inhibition). We are about to decide whether to give it long-term.

    Thanks for highlighting Knut's paper, it's really impressive.

    ReplyDelete
    Replies
    1. I am glad you tried Acetazolamide (Diamox).

      What dosage have you found to be effective? How long does it take to show an effect? Do you give it at the same as Bumetanide? Does it increase diuresis? Does it further effect K+ levels?

      I thought the science pointed towards Acetazolamide being useful, but it is not available where we live, so I have not tried it.

      At some point you might consider writing up a case study on your treatment experience with your son. I would be very happy to post it on this blog; then whoever is interested can potentially benefit from it.

      It is sad that specialists are not open minded. Dr Lemmonier was forced to leave his hospital in France, because his fellow Psychiatrists did not like what he was doing. They prefer not to change there view of autism being treatable. My brother in law is a Professor of Psychiatry and he show not the slightest interest in what I am doing to his nephew. But several years ago, when a small boy we knew developed a fatal cancer, inoperable where we live, I only had to make a couple of phone calls to my UK doctor relatives. Within a few days he was on plane to Great Ormond Street Hospital, diagnosis was confirmed. The parents were told to deposit 300,000 euros, the maximum cost of the full treatment. Various people donated the money and treatment began. The boy made a full recovery and he remains cancer free.

      I thought the Ebola response was eventually great. There are lots of innovations in some areas of medicine; there is a smell test for early Parkinsons. A lady who husband died from Parkinsons told the Consultant that his smell changed when before the onset of Parkinsons. She successfully identified other people in a test the Consultant organized. Now they are figuring out what underlies this and hope to identify Parkinsons even before its symptoms appear.

      Delete
    2. I started with 2x60 mg (a bit more: it’s 1/4 tablet 250mg) at the beginning of migraine-like episode. It then resolved in 3 days instead of at least a week. Then I reduced to 2 x 30 mg. The "autism-effects" can be seen after about 5 days. It increases diuresis, that's nuisance: I think in my son it’s impossible to use Diamox 2x60mg with Bumetanide 2x0,5 mg together because of this. But it was the same with 2x1mg Bumetanide. The higher dose of Diamox with Bumetanide lowers K+ level, but it is said that Diamox influences K+ level mostly during the first days of using it. So it’s better to check this. Diamox has been associated with adverse effects in some adults and there are only few reports of long-term safety in children - they are reassuring. There is very cheap acetazolamide generic in my country.

      This is also interesting with regard to Diamox:
      http://www.ncbi.nlm.nih.gov/pubmed/22855057

      Christmas time for a child with gluten allergy is perhaps the same what is summer for pollen allergy affected. It is difficult to introduce new treatment when I know there is gingerbread to steal anywhere and he always has flares this part of the year including now.

      Thanks for invitation to write about my son in blog, it would be really an honor to me as you know it is your research that helped my son. I wish I could manage effectively Mateusz headaches, it is difficult and bad for him.

      You are right with what you say, this is somehow about autism perception and also there is a big confusion starting with wrong disease definition. I see autism as a serious medical condition associated with at least poor quality of life, significant co-morbidity and the risk of premature death. This is all shown by research, do I read different articles than those who say that it’s just an alternative way of brain wiring?

      I understand what you say about cancer treatment and Professor of Psychiatry in your family. A researcher, being both a psychiatrist and a special education teacher, who knows my family well, followed the story of my son for a while. She is an autism expert here and happens to collaborate with Baron-Cohen also. When I sent her a kind of summary of my son medical findings with references etc she promised to discuss it seriously when back from presenting her research results abroad. The research is a multinational EU funded study promoting social inclusion of children with Autism Spectrum Conditions. They make nice web-based tools for such kids. I have respect for that kind of work as it for sure helps many. Unfortunately my son is definitely not ASC but ASD or SDA and does not understand them. And this was the last message from her and it will be soon a year since then.

      Ebola story also tells me about great health inequalities, unfortunately this also refers to autism. It’s a neglected disease, but in the other way than the african ones are. That’s why I think there is a need to change minds.

      Delete
  7. Peter, is there a post or posts that would be good primers on helping parents understand the markers of the various sub-types? Based on what supplements/drugs recommended here that have made any kind of noticeable difference in my son's presentation, I can then link that back to what dysfunction your blog associates with that drug or supplement. Is this how I start to build a profile of my son's sub-type?
    Thanks very much,
    Nancy

    ReplyDelete
    Replies
    1. Nancy, you told me in an earlier comment that your 22 year old son has blistered-looking skin and the skin responded to quercetin, but the stimming/sleep got worse.

      This is pointing to some kind of auto-immune problem. Think of it like an allergy. The drugs used by people with autism and allergy/mast cell problems would be a good place to start. One of those is quercetin, but some people get side effects, it gave me side effects.

      Your son might respond to mast-cell stabilizers that include chromolyn sodium (Intal) and potentially to Verapamil.

      If you tell me his other behavioral features, health issues and what drugs you have tried, I will try and highlight the therapies that I have reviewed that could potentially be helpful. In the end there will some trial and error.

      Delete
  8. Peter – you have succinctly expressed my vague musings on the causes of and potential treatments for ASD better than I ever could. It constantly amazes me here in Australia that we are encouraged (with the help of government payments) to put our kids into early intervention, but have to struggle to get brain scans or relevant blood tests. For how many other conditions would we acknowledge there is something wrong with the functioning of the organ (in our instance the brain), but not clinically investigate the organ itself to find out if we can cure the dysfunction?

    I believe that deep thinking about, and research around, our own families’ physiological and psychological histories is one way to organise that mess of a thousand causes. For example, in my son Morgan’s case, I think his ASD is partially a malfunction of the serotogenic system. But the fact he has such an amazing positive response to N-acetylcysteine also shows some kind of neurological inflammatory condition: potentially, something like Huntingdon’s disease, or perhaps anti-NMDA receptor encephalitis (my very deep depression during pregnancy causes me to wonder whether I also was experiencing something like the latter condition). Morgan also benefits hugely from a ketogenic diet, in a way he never did with gluten- or casein-free diets: maybe he simply can’t use glucose as a brain food, or perhaps he has an underlying epileptic condition – and yet Furosemide did nothing for him, while Diamox did. Additionally, ever since he was a baby, Morgan has rarely fallen sick: given the various common immune disorders of his relatives, does this indicate an over-enthusiastic immune system, whilst simultaneously excluding a condition similar to Hunter syndrome? And so forth.

    As for finding an ASD expert: well even in Melbourne, with all our wealth of great researchers and fabulous medical practitioners, I have not heard of anybody who is really across all the different possibilities for triumphantly treating childhood developmental disorders or intellectual disability. Such practitioners will arise, very very soon. But until then, we are left with our own research, assisted by Peter and others like him, such as Doctors Clara van Karnebeek and Sylvia Stockler (see their website http://www.treatable-id.org/. As an aside, has anybody used http://autism360.org/? Was it any help?)

    Finally, I hope all here don’t mind if I address Roger Kulp directly. Roger, I have been reading your posts on various ASD sites for a couple of years now. I think you have a great deal of useful, maybe vital biomedical information to offer the world, as well as your personal insights. Have you considered establishing a blog, as well as continuing to contribute in various other online forums?

    Best wishes to all for a happy and peaceful end to the year. Ciao for now, Alexandria.

    ReplyDelete
    Replies
    1. Thanks Alexandria.

      Can you share with us your experience with Diamox? How old is Morgan? what does hos autism look like? What effect did Diamox have and what dose are you giving. Any side effects?

      Delete
    2. On the serotonin side of things, I spent the better part of half a year trying to come up with a solution to solve my son's aggressiveness issues that pop up whenever winter comes around. Discussing serotonin autism issues is a complex subject, since generally most of the evidence suggests that a large percentage of autistic individuals (especially low-functioning ones) have hyperserotonemia peripherally, but low brain serotonin signaling either from less serotonin flowing around, serotonin receptor issues, as well as SERT transporter problems (SSRI's target inhibiting this protein).

      Another factor to consider is that inflammation upregulates the kynurenine pathway which shunts tryptophan from the serotonin pathway and the cocktail I use to address these serotonin issues on an acute basis has worked well for me (I say acute because the half-lives of many of the ingredients are on the order of 4 hours or so).

      (1) 1 Scoop of BCAA Xtend Powder (Watermelon is best tasting I think)
      (2) 1/16 ounce Hydrolyzed Collagen

      Note: 1 and 2 consist of proteins that produce a state called Acute Tryptophan Depletion. The best way to achieve this is through free form aminos, but they taste bad, are expensive, and all around impractical. The most important ingredients are protein that lacks tryptophan and the dopamine precursors L-Tyrosine and L-Phenylalanine, plus BCAA's which help plug up the Large Amino Acid Transporter that moves tryptophan into the brain (BCAA's compete with this transporter which is why sugar gives you a serotonin rush since the insulin spike causes blood BCAA levels to drop as they are dumped into skeletal muscle, thereby decreasing the ratio of BCAA's to other large amino acids such as tyrosine, tryptophan, and phenylalanine. The collagen with the BCAA's are best in the morning when the liver is most sensitive to protein synthesis (i.e. taking existing tryptophan out of the blood to make other proteins).

      Since Acute Tryptophan Depletion is extremely effective at reducing tryptophan levels (and therefore serotonin levels in the brain, as well as kynurenine levels which can cause inflammation problems in the brain), we add in

      Delete
    3. (3) 2x Niagen (once a day) - This is a special form of B3 that raises NAD+ levels in the body and brain (unfortunately patent protected and expensive, but necessary with this treatment). When the body is under attack from a virus, allergy, or some other immune activator, cells use a lot of NAD+ and when a cell runs out of NAD+ it undergoes apoptosis. So as a compensatory mechanism, the body upregulates the kynurenine pathway and produces more quinolinic acid which is used for the synthesis of NAD+ endogenously (besides it being recycled which is a different process). In most neurodegenerative diseases (including depression), kynurenine upregulation occurs and more specifically high levels of quinolinic acid (which is also a neurotoxin by the way, especially if it gets produced faster than it is consumed as NAD+). Now kynurenine can be produced anywhere in the body and brain via different enzymes (TDO in the liver, IDO in the brain and elsewhere), but kynurenine also uses the same Large Amino Acid Transporter that Trytophan uses, so the BCAA+Collagen blocks kynurenine from getting into the brain (and causing lots of problems if it gets out of control like I believe it does in autism). So this is why Niagen is critical here (unless you want NAD+ levels to get super low which causes mitochondrial stress which is bad for a lot of other reasons).

      (4) 50-200 milligrams 5-HTP

      SSRI's are still not very well understood, but 5-HTP is safe and gets the job done with respect to serotonin replacement with this therapy. Nevertheless, a recent study I read last week suggested Lexapro downregulates kynurenines in the brain somehow (the hypothesis provided by the research team was not terribly convincing to me though).

      (5) Green Tea Extract or ECGC (helps suppress 5-HTP conversion to serotonin in the gut).
      (6) Mucuna Pruriens (unless you think keeping dopamine levels low is desirable since excess dopamine in the brain pops up in several autism studies, though there is much ambiguity here).
      (7) Apigenin - Potent IDO inhibitor and helps boost NAD+ levels.

      (8) Sucralose as needed for taste - Real sugar will spike insulin and cause the BCAA's to go into muscle tissue and as a consequence allow a lot of tryptophan and more importantly kynurenine to enter the brain, causing neurological issues especially if the person is seizure prone. The main point is not to spike insulin anymore than you have to. Having a ketogenic breakfast or some MCT Oil is fine. Also, mixing in NAC (not great tasting when crushed and put in liquid) is fine as well, or any other drugs if your kid wont do capsules/pills.

      Anyways, hope this helps. You can try it and see what happens, though this is a 3x a day regimen for severe serotonin/kynurenine issues which can be reduced to 2 or even 1 a day if the other systemic inflammation issues are somehow addressed (which is hard to ascertain, but inflammation is the cause of the low brain serotonin in the first place so none of this is necessary if you can address the root cause somehow).

      Delete
    4. Tyler,

      have you tried or looked into trialling Valtrex/valacycolvir or acyclovir to correct tryptophan pathway issues?

      For some reason these medicines affect IDO inflammatory pathway, which as you note is upstream of tryptophan/serotonin one.

      IMO this is the most likely reason these meds are often reported to work so well for our kids, and not their inhibition of herpes viruses (although who knows ... and btw these also for some inexplicable reason appear to lower HIV expression and activity … so many mysteries still to be uncovered there…).

      Dr Goldberg's NIDS autism protocol often combines these very antivirals with SSRIs, so another reason to think their combined activity and action on serotonin pathways is behind their reported positive effects in ‘some’ autism.

      There are several studies out there showing that both these meds activate inteferon-gamma (which, if you are familiar with Saxena study is one of the major genetic risk factors in autism, the other being chemokine receptor polymorphisms), which then affects IDO.

      Two more interesting things to throw in here for further musings on all things serotonin and IFN-gamma: many parents report worsening of symptoms when first starting valtrex, especially in the areas of irritability and aggression, followed by various improvements (ranging from speech/social, to improved motor skills, to better sleep regulation). Another reason to suspect this IFN-gamma/IDO action in those cases? The other thing to keep on the radar is the recent mice study showing IFN-gamma presence or absence to be a crucial factor determining animals' social engagement. Nat x

      Delete
    5. I have not looked into Valtrex and am unaware of its effects with respect to tryptophan. An initial search turned up nothing so perhaps you can forward a link for me.

      As to the topic at hand, lots of things block IDO and of natural compounds, Apigenin seemed to be the best according to a study I found on the subject (topic was most relevant to cancer). Apigenin is high in celery and parsley to name a few plants, but good luck getting my kid to eat a lot of celery every day.

      Also, blocking IDO is just one way of lowering kynurenine levels, but you don't want to be too aggressive with it because of various side effects. Kynurenine also is not a big deal really in the brain except when it comes into contact with activated microglia (hello autism), and that is where quinolinic acid is created, whereas kynurenic acid which is a neuroprotective metabolite of kynurenine (provided it is not in excess) is produced via astrocytes.

      The protein PGC1-alpha also through an indirect mechanism reduces kynurenine levels by increasing production of kynurenic acid in skeletal muscle and kynurenic acid does not cross the blood brain barrier while L-Kynurenine does (using the LNAA Transporter). There was a lot of press about this phenomenon under the premise that excercise (which produces PGC1-alpha in the muscle) helps combat depression via this very mechanism of having skeletal muscle act as a sink for L-Kynurenine. The supplement alpha lipoic acid also increases levels of PGC1-alpha, as does cold exposure.

      Dealing with the serotonin pathway is just one of many many many biological symptoms with respect to autism and certainly not all autisms, just that this protocol I have come up with has anecdotally helped my kid, especially in the winter in addition to the usual serotonin boosting interventions such as using a SAD light, and getting him as much exercise on the treadmill as is practical.

      Another thing to keep in mind is I believe the quinolinic acid buildup (the research specific to autism is mixed but it shows up in just about every other neurodegenerative disorder that has so many parallels to autism), I believe directly contributes to worsening symptoms over time and eventually seizures as high levels of persistent quinolinic acid is a form of low-level brain damage as it is not only an excitotoxin, but a very potent oxidant as well that can trigger an inflammatory response on its own.

      Delete
    6. Tyler & Natasa

      Another group of substances that down-regulate IDO (indoleamine 2,3-dioxygenase) are COX-2 inhibitors, like ibuprofen.

      For those of you treating with autism + allergy:-

      The indoleamine 2,3-dioxygenase (IDO) pathway controls allergy

      http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2012.02830.x/epdf

      Delete
    7. Tyler

      Why do you think your son has winter-time autism flare-ups? If you can figure that out, you will likely better understand his underlying biology.

      Our son has has allergy driven summertime flare-ups. that are treatable/preventable.

      Our winter-time flare-ups (one now in progress) are linked to the slow reabsorption of the roots of milk teeth. It sounds very odd, but if you read up on it is the likely source of our winter-time IL-6 driven regression. I have pulled out two teeth in the last month and the final three are wobbly. The same thing happened last December.

      Behavior got worse and then one tooth came out and then later another, then behavior came back to normal. It is not pain from the tooth, it is the IL-6 increase that he body uses to signal the root to be reabsorbed. This problem does respond to things that reduce IL-6, like COX-2 inhibitors.

      Why does he lose his milk teeth only in winter? That I do not worry about.

      Delete
    8. Hi Tyler,

      I don't have those papers saved and cannot trace them myself now, but have found these and http://link.springer.com/article/10.1007/s11011-008-9095-4

      and
      'Mechanisms by which acyclovir reduces the oxidative neurotoxicity and biosynthesis of quinolinic acid':

      http://www.sciencedirect.com/science/article/pii/S002432050600909X

      Delete
    9. Peter, where we live in the midwest United States, there is less daylight in the winter and consistently cloudy days. It is certainly serotonin related and this treatment I mentioned helps a lot (SAD light helps too). The milk teeth hypothesis is intriguing, but in this circumstance I believe it is related to tryptophan dysregulation that causes both low brain serotonin via tryptophan shunting to the kynurenine pathway, and excitotoxicity from the quinolinic acid buildup in conjunction with pervasive activated microglia (a hallmark of most autisms), not to mention that the oxidative stress of quinolinic acid likely feeds a vicious cycle causing NAD+ to be used up very fast as well as depeleting cofactors in NAD synthesis such as Vitamin B6 (which sometimes helps some people with autism). This is just my personal hypothesis here and the solution I have come up with which is unconventional in the sense that acute tryptophan depletion studies on autistic subjects caused significant increases in irritability and aggression. The way I get around this is to feed back in 5-HTP, Nicotanimide Riboside (increases the NAD+/NADH ratio), and optionally L-Dopa (Mucuna Pruriens) into the body, all of which freely cross the blood brain barrier, while Tryptophan, Tyrosine, and Phenylalanine all compete with BCAA's for access to the brain, as well as L-Kynurenine.

      Also, FYI Apigenin is a COX-2 inhibitor and also has a unique function in that it is also a general monoamine transporter (i.e. it increases the turnover of serotonin, dopamine, and norepinephrine which can be very beneficial if the dopamine transporter is dysfunctional as is often the case in various forms of mental retardation, which of course includes autism much of the time).

      Also, Nat thanks for the paper. Will read it tomorrow.

      Delete
    10. Also, on Apigenin a new study out discusses its role in neural differentiation (the frontal and temporal lobes in autism usually show immature differentiation of neural cells).

      http://www.regenerativebiology.net/index.php/arb/article/view/29244

      Estrogen is thought to be neuroprotective with respect to autism and hypothesized as to one of the reasons autism prevalence is higher in males than females as females with autism usually have more severe symptoms and need more genetic hits to receive an autism diagnosis. I have been giving my son apigenin supplements (their efficacy I cannot attest to but they are from Swansons) for several years now for a different reason cited above. Apigenin is a complex molecule to be sure, but it might be worth taking a closer look at with respect to autism as a general treatment based upon this latest research.

      Delete
    11. With reply to Peter's question above – Morgan has classic ASD, with an IQ of less than 50. I divide his condition into four components, all of which affect one another: (1) The core ASD. Under the DSM 5, he satisfies all three of the social communication criteria (he has always been completely non-verbal). However, he only satisfies the sensory criterion in the restricted and repetitive behaviours components (he is centrally hyposensitive but hypersensitive in his extremities, constantly moving, sometimes an escapologist, and annoyingly sensory-seeking). He does not have fixed or obsessive interests or behaviours, just very limited interests. (2) Intellectual disability. He finds it very difficult to concentrate for long periods of time, to understand very simple verbal instructions, or to learn … almost anything. At age 6 he is still not toilet trained. He has a processing time of a few seconds if he can even hold on to the thought that long. Most importantly, he has never made an indicative point at an object of interest, and rarely imitates others’ actions (he has only once engaged in imaginative play). (3) Physical disabilities. He does not have a dominant hand, and has some motor problems (most notably oral: cannot suck through a straw, lick lips, blow out candles, or purse his lips to kiss). (4) Other “crazy behaviour” problems. He toe walks or “bouncy” walks, has flappy hands or jazz hands, yelps, vagues out, and giggles manically while staring into space or while lying the in dark at night.

      I will also mention that Morgan does not suffer anxiety or SIB, has no skin, gut or digestive problems or asthma, has good emotional self-regulation, and is not aggressive. He has had one attack of epilepsy but that hopefully was just a febrile episode. He is also very loving, funny, happy, smiley, robust and determined.

      However, when all the treatments for Morgan are working, the “crazy behaviours” disappear almost totally, as well as the annoying sensory seeking. Moreover, he understands what people are saying to him, even if he can’t see their mouths or if there are no supporting indicative gestures. He is able to learn both through observation, direct instruction (both hand over hand and face to face), and experimentation; his processing time is almost instantaneous; he can concentrate; and he can remember. He also interacts more joyfully with known adults and children, and is more open to the approaches of stranger children, instead of completely ignoring them. In short, the treatments almost totally eliminate issue 4 and the sensory aspects of issue 1, greatly ameliorate issue 2, slightly address the social aspects of issue 1, and don’t help with issue 3. (Continued below.)

      Delete
    12. (Continuation.) So, these are the positives from the Diamox, the NAC, and the Modified Atkins (ketogenic) diet. These three treatments I have tested independently of one another, so I know they all work for Morgan. (We also rely on anti-histamines, but have not tried these independently. They put him back on track when everything else suddenly “stops working”.) Regarding the diet: the deeper the ketosis as measured using Ketostix, the greater the positives.

      However regarding the Diamox: the positive effects were not as wide or deep as with the NAC or MA diet. There remained some vagueness, slow processing times and inappropriate giggling, as well as many of the annoying behaviours, though these just did not exhibit as often. Most tellingly, people who know Morgan well, and did not know of the Diamox, did not make any “wow he’s different” comments after four weeks’ trial. In fact, the greatest positive is that it reduced Morgan’s snoring (we noticed no other side effects). The positives, in short, did not seem strong enough to warrant Diamox’s continued use, particularly as it can lose its effectiveness anyway in epilepsy treatment after a few months, and that some medical practitioners will not prescribe it to people on a ketogenic diet because of the risk of kidney stones.

      The Diamox dosage, from my notes, was 20mg twice per day, so 40mg daily in total. I think my notes are correct … though it is a very low dose. Anyway, as noted, Furosemide (actually Lasix) also produced nothing, apart from lots of urine, and worrying burping. This was administered at the rate of 40mg twice a day (Morgan is about 25kg). Is there any reason to think Bumetanide would work when Lasix does not?

      In any case Peter, I am going to think about what you posted on 23 December 2015 regarding administration of Bumetanide, Diamox and Picamilon together, and consider having another go. Also thanks to everyone for their comments on all things related to serotonin: lots of great stuff for me to think about there. Alexandria

      Delete
    13. Alexandria, I am assuming you have ruled out the known syndromes that overlap with autism. Most have some physical indicators, but I expect they get overlooked. In Angelman Syndrome, kids are very happy, frequent laughter/giggling, but often cannot suck, they do not always have characteristic facial variation. It can be tested for. There are treatments in development, since the cause is well understood.

      Having ruled those syndromes out, I would go back and try Bumetanide. It is extremely similar to Furosemide, but does it cross the blood barrier and affect NKCC1 to the same extent? There must a reason Ben-Ari choose Bumetanide over Furosemide.

      I am trialing 125mg of Diamox, which I thought was a low dose. Maybe your dose was too low?

      As one professor of medicine suggested to me, maybe Diamox and Bumetanide have a synergistic benefit.

      Since your son has ID, it is worth trying a RASopathy therapy for a few days. It may do nothing, but it will not do any harm. That would be Atorvastatin 10mg for a few days. In my son the change is visible within 24 hours.

      Also in case of ID, reducing alpha 5 GABA subunit is widely accepted as desirable. You cannot do that yet, but low dose clonazepam will upregulate alpha 3, which may also help. The dose is tiny.

      Delete
  9. This comment has been removed by a blog administrator.

    ReplyDelete
  10. Hi Peter and All,

    As a self-reply to my ranting above: I would like to write a paper, which would be - sorry for using slang - a case series about children treated with Verapamil to be jointly published in a peer reviewed medical journal. Would you agree to share some medical details about Monty’s treatment in it? I would like to ask the same question to other people who use or used Verapamil: Maja, RG, JB and perhaps others whose comments I missed. Case series is better than one case.

    I talked recently by a brilliant pediatrician who wanted to learn more about CCB in autism. What shall I reference to her? She’s quite traditional and not really research-blogging follower, nevertheless - an experienced, open-minded doctor with great respect to medical needs of autism kids. Maybe there are more doctors like her: she is not an “autism specialist” so was not told all their life that autism is untreatable and fortunately even doesn’t know what DAN means.

    I thought that I would be able to include my son’s genetic tests results, but the tertiary center in my country finally refused CACNA1A sequencing as “low probability to find anything according to existing literature”. No wonder: no one bothers to check, so there are no papers. I will do it on my own, but I wanted to pave the way. WES is offered by one university here at the cost of what state pays for 2 months of special education for a child with autism, so I can say that in this way Poland is similar to Australia… Isn't it crazy?

    ReplyDelete
    Replies
    1. Agnieszka, I am sure people will be happy to cooperate.

      If you make a questionnaire, it can be a special post on this blog, to attract some attention.

      Then people can respond to the questionnaire. If they do not want it all in public, I do not publish their responses, but forward them off-line to you. Or we can collect email addresses, off-line and unpublished.

      Maybe see if your pediatrician friend will try Verapamil on any of her patients, with classic autism plus some kind of allergy /mast cell dysfunction.

      Delete
    2. Hi Agnieszka, check this review article one for references and suggestions to pass on to that peadiatrician:

      http://autismcalciumchannelopathy.com/ (in need of updating but will hopefully give you a good starting point)

      Delete
    3. Thank you Peter for reply and Nat for the reference!

      I will make this questionnaire. I have also a question from one other very progressive doctor here: is there any biomarker which we can measure before and after Verapamil treatment? Something like Il-6 measured in recent Theoharides study? I really don't know.

      Delete
    4. You are very welcome!

      I am not sure what biomarkers would be our best bets here (hoping Peter might have a clearer idea), but how about something along the lines of Persico/Palmieri's speculation that calcium/ion dysfunction may be upstream of mito dysfunction in autism?

      see this (my caps):

      "... Substantial percentages of autistic patients display peripheral markers of mitochondrial energy metabolism dysfunction, such as (a) ELEVATED LACTATE, PYRUVATE, and ALANINE LEVELS IN BLOOD, URINE and/or cerebrospinal fluid, (b) serum CARNITINE deficiency, and/or (c) enhanced OXIDATIVE STRESS. These biochemical abnormalities are accompanied by highly heterogeneous clinical presentations, which generally (but by no means always) encompass neurological and systemic symptoms relatively unusual in idiopathic autistic disorder. In some patients, these abnormalities have been successfully explained by the presence of specific mutations or rearrangements in their mitochondrial or nuclear DNA. However, in the majority of cases, abnormal energy metabolism cannot be immediately linked to specific genetic or genomic defects. Recent evidence from post-mortem studies of autistic brains points toward abnormalities in mitochondrial function as possible downstream consequences of dysreactive immunity and altered calcium (Ca2+) signalling. ..."

      Some of these might be relatively easy to check in a mainstream clinical setting, without employment of full scale expensive research labs?

      http://www.sciencedirect.com/science/article/pii/S0005272810001519

      Also as a very long shot it might be worth writing to one or both of them asking for suggestions and opinions. Nothing to lose :)

      Delete
    5. Agnieszka,
      I'm flattered that you'll use my experience in your work. If you need more than that, just ask...
      Best regards,
      Maja

      Delete
    6. Agnieszka, I think IL-6 will be the best biomarker. But it would be very interesting to also measure IL-10, the most relevant anti-inflammatory cytokine, and indeed histamine itself.

      In my son Verapamil solves the allergy-driven autism problems, but not the common allergy problem itself. This is odd.

      "Mast cell stabilizers block a calcium channel essential for mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine"

      Delete
    7. I don't know if my previous comment reached the blog, but to make it short, Peter is SLOS treatable?

      Delete
    8. Petra, SLOS is currently treated by cholesterol supplementation.

      There is a new trial about to start, to validate its use.

      https://clinicaltrials.gov/ct2/show/NCT01773278

      Delete
  11. Thanks Maja, I will start with this questionnaire as Peter suggested. It will take some time as I am not experienced in writing about autism. I just want to live in a bit less crazy world.

    Thanks for ideas. The question from that doctor was about how to design a small study with Verapamil for autism using biomarkers. Mitochondrial dysfunction and calcium signalling are related and indeed Nat these parameters are easy to check. On the other hand I rememeber that Peter wrote about another father whose son did not respond to verapamil and later was diagnosed with AMD by dr Kelly. I

    L-6 and IL-10 are clear. Yes that doctor convinced me to do some urinary methylhistamine serial measurements, but the net effect of this "research" was that the grant given to me by me run out very soon :-)) It is very tricky, the concentration seems to change rapidly.

    Peter, your remarks about teeth are very interesting. I gave Diamox to my son in the middle of his teeth problems: peridental abscess treated at the beginning in a wrong way. I was surprised to see any cognitive effect in that situation and also saw how important was controlling inflammation until finally we found a clever dentist who removed this tooth. Other dentists did not want to remove the tooth not seeing clear signs of infection and my explanations about importance of avoiding peripheral inflammation in a child with autism and communication difficulties were not understood. After tooth removal the good effects peaked as expected.

    ReplyDelete
    Replies
    1. Hi Agnieszka,

      I would be happy to fill out your questionnaire and also supply any further information you need. I think this is a fantastic idea. Many thanks in advance.

      Delete
    2. Hi RG,

      Thanks for reply and also for your previous comment a few weeks ago about dental issues. I read it, but I coudn't find it later to answer. In case of my son it turned out to be severe dental infection, hopefully over now.

      This is interesting what you wrote about Sytrinol. When something happens in my son soon after meal I assume it's GI mast cell related. I can see such behaviors after meal regularly when he is "in the flare".

      I also thought that it might be a K+ decrease associated with insuline peak after carbohydrate meal, but you don't use carbs in modified Atkins diet, do you?

      Delete
    3. Hi Agnieszka,

      I am glad that your son is doing better with the tooth extraction. My RSS feed is not working, and if there are more than five recent comments, I don't know how to read them.

      An update on Sytrinol is that it is continuing to work, but partially. It never had the same effect as the first time where it cleaned up her distress completely.

      I am afraid that she is in the middle of another 'big hit', because there is almost constant low grade irritability throughout, very little emotional control, frequent small rages and SIB, and at least a couple of bigger meltdowns. Bumetanide is also working partially, and especially when I notice that she drinks too much water (about one liter within fifteen to twenty minutes) and then behavior breaks down. Yesterday, in the middle of a rage, I gave her 200mg ibuprofen, she calmed down in twenty minutes and then went to sleep for a couple of hours, which is very unusual for her. I am going to keep the Sytrinol in, hope it will have some cumulative effects.

      Delete
    4. Her potassium levels were normal at last testing, we are still on 1mg once a day, though now I think I will move to twice.

      We do use carbs in MAD, my daughter seems to do well between 15 to 20gms per day. Many people are closer to 10. I do think she has GI issues since she has had loose bowels since the big hit in November 2013 with worsening behaviors and seizures.

      Delete
    5. RG, also worth considering: Naproxen, a much longer acting NSAID, which people do use in autism. Also, the NSAID Ponstan which acts like Ibuprofen but also affects some ion channels relevant to autism. In some countries Ponstan syrup is used widely as a painkiller for toddlers (so it must be pretty safe). So you might be able to avoid these crises before they start.

      Delete
    6. Thank you Peter. Will try.

      Delete
  12. Hi Peter.

    I like your thorough review of our results suggesting variations in K/Cl ion channels as associated with mutism in autism and, thus, that mefenamic acid, which is known to modulate (but not unconditionally open) some of these channels, as having the potential to prevent mutism in autism. A recent review article even refers to "channelASD" as a separate type of ASD (Guglielmi 2015). The Simons Foundation actually funded the research that let to the findings you reviewed, but the want more animal studies to be conducted before testing the hypothesis that a prodrug of MFA might prevent disruption of active language development.

    Knut

    ReplyDelete
    Replies
    1. Hi Knut

      I hope you don't mind my over-simplification of the science.

      I did review that Italian paper on Channelopathies in January:-

      http://epiphanyasd.blogspot.rs/2015/01/kvxy-channelasd-navxy-channelasd-cavxy.html

      The Simons Foundation are behind most of the good research that I have taken a few steps further. (Catterall, Ben Ari etc)

      Re-purposing safe existing drugs really should be able to bypass mouse studies. It just adds a few years and hundreds of $k to the costs.

      I suspect drugs like Ponstan may be useful beyond those who are non-verbal. One reader has already commented that as a baby, her son responded to Ponstan in a totally different way than to Paracetamol.

      Delete
  13. Dear Peter, I need your advice on NAC supplement, together with some other information.
    You told me that I can raise the dose up to 3000 mg (5x600) daily which I basically do. What do you think could be done when he doesn't get 9 hours of sleep? For example yesteday he stayed up all night and then he had to get up early , with only 3 hours of sleep. In order to avoid oxidative stress I had to raise the dose by 600mg more. What would be better. to raise the dose or leave him untreated in that case?
    Also sleeping disorder could tell us that there might be something wrong with his methylation cyrcle. As far as I know methylation cyrcle is related to folate, B12, melatonin and so on. Having read one of your bloggers post about MTHFR deficiency and homocystinuria, I found out that it is a reggressive disorder and could worsen in early aduldhood. Do you think that by checking homocysteine amino acids in blood would give clues if there is something wrong there?
    One of my priorities is to check out the 4 types of treatable autism you mention in your articles.
    As for the cerebral folate deficiency, I've checked folate in blood and it's OK. We can't check folate in brain though. Do you think homocystein checking would help more in that case?
    SLOS syndrome could also be possible as he has low cholesterol and high HDL; this is also my personal profile. I should also address to that. If I don't use the cholesterol supplements for the time being, would eggs and fatty cream and meat be a good choice for a trial?
    Furthermore does creatine deficiency shows in blood-urine?
    Meanwhile I use Uridine because his uric acid remains suspiciously stable to almost 1 point higher than normal means although many other things have changed. I have only been using it for 3 days, raising the dose from 300 mg to 900 mg daily. I'm not sure about the results yet. If I have results I'll let you know.
    So far he seems a responder to Nac, broccoli, melatonin and possibly Uridine, Postan and Ibuprofen, when needed.
    I'm quite sure that we need to go further.
    There are so many life-saving things going on in your blog that at least worth a trial.
    Peter thank you so much, indeed.

    ReplyDelete
    Replies
    1. Petra, there are so many possible metabolic dysfunctions you really need to ask an expert. There are some in Greece. Look at the authors of this paper:-

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871708/

      They are mostly from the Aristotle University of Thessaloniki. Maybe get in contact ?

      Sleep disorders are very common in autism and do often respond well to melatonin. You say that you are using melatonin. At a higher dose of around 10mg, melatonin has potent anti-oxidant effects. So maybe try melatonin half an hour before bed. This will promote sleep and reduce oxidative stress.

      Remember that with so many possible dysfunctions, the chance of any one being relevant is slim, so check all the symptoms. Also, there are often physical differences, which you would have noticed, if they were present.

      http://ghr.nlm.nih.gov/condition/smith-lemli-opitz-syndrome

      So I doubt your son has SLOS.

      Delete
    2. Hi Peter,

      Thank you for putting forward this link. It might be relevant to my son's condition.

      If you say SLOS would have been obvious then I might have been misdirected by picking up selective information that matches my son's profile.

      I'll try to get in touch with these Greek experts, but I am sure it won't be easy.

      As far as I can understand from the article, they treated ASD patients with biotin and some of them responded without having a clear explanation on that.

      Purine metabolism dysfunction is also mentioned.

      My biotin trial was very short and with low dosage. I've mentioned that he looked very normal, but in the evening he became a little hostile and were afraid to continue.

      I'll have to risk another trial starting with almost 5 mg and maybe raise it to 10 mg.

      Is it Ok to add biotin together with my other supplements?

      Delete
    3. Petra, I think those people in Thessaloniki will likely have knowledge/interest in other metabolic dysfunctions not just biotin. So they might be open to your questions and be able to help with lab testing. I think biotin is very safe, so no harm in adding it.

      Delete
    4. Peter, In order to make an appointment with them, I think that I should firstly need to justify my concern about possible metabolic dysfunction.
      I only have an Asperger's diagnosis and psychiatric evaluation and treatments (antiderpessants,neuroleptics) that he did not respond to.
      Does the fact that he is a responder to antioxidants (oxidative stress just obvious) give enough evidence that he may be suffering from a metabolic disorder?

      Delete
  14. Petra, you could tell them that you have established that the Aspergers is treatable (antioxidants) and that you want to rule out mild forms of treatable metabolic disorders so that the Aspergers is kept to the absolutely minimum. You can say that you read about biotin but would like to check all the known metabolic dysfunctions that might be relevant.

    ReplyDelete
  15. Hi Peter, I recently started verapamil for my son but his histamine issues increased so much. Is there anything similar that I use for my son but doesnt cause a decrease in DAO levels? Thank you

    ReplyDelete

Post a comment