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Friday 3 February 2017

Autism + PANDAS/PANS ? - Basal ganglia circuitry mechanism underlying some repetitive behaviour



Pu-erh, a fermented tea from Yunnan province, China.  An mGluR5 inhibitor to remedy basal ganglia circuit abnormalities?


PANDAS/PANS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections/Pediatric Acute-onset Neuropsychiatric Syndrome) are recognized disorders in North America, but nowhere else.  If you take your child to Boston Children’s Hospital and ask about PANDAS they will know what you are talking about, try this at a children’s hospital in Europe and you will be directed to the local zoo.

For those new to the subject PANDAS/PANS cause sudden onset of tics and Obsessive Compulsive Disorder (OCD) accompanied by sudden cognitive regression.

I have written about PANDAS/PANS in previous posts.



I was surprised how well documented these syndromes are and that they are treated by some mainstream physicians.

The leading researcher in the field, Susan Swedo, makes a point that PANDAS/PANS is not autism.  I think that given the ever broadening definition of what counts as autism, it should be considered as a treatable sub-type of regressive autism.

To what extent can people with classic early onset autism also have PANDAS/PANS is an open question.

Can you have both?  Well based on my n=1 experience, it looks like you can.

After a brief infection just before Christmas, Monty aged 13 with classic early onset autism, suddenly developed Tourette’s-like loud verbal tics.  This behaviour had never occurred before and erupted overnight.  Even his brother declared that Monty now has Tourette’s and when would it go away.  This is the kind of behavior that many siblings, and I suppose some parents, would find extremely embarrassing.

Having a blog jam-packed with information on autism and related issues, I thought this was another problem that I should solve myself.  


On one of Harvard’s blogs it says regarding PANDAS/PANS symptoms:-


If your child suddenly shows any of these symptoms, call your doctor as soon as you can. Then contact the International OCD Foundation to find an OCD specialist in your area. Early treatment may prevent life-long mental illness.


Well none of that advice was an option for me, but I do think that early treatment is key in neurological disorders.  This also applies to people with autism developing seizures, where I think pre-treatment can lead to never developing seizures.

So I decided I would treat Monty as if he was having PANDAS flare-up.  This entails antibiotics and a short course of steroids.  The alternative was to do nothing and hope it just all went away.

Monty very rarely has antibiotics; his immune system seems very effective and quite possibly overly effective.

Having had a severe asthma attack several years ago we have prednisone on hand.  Oral prednisone is a cheap generic steroid drug that can be used as therapy for an asthma attack that does not respond to the usual inhaler treatment.  Long term use of prednisone has significant side effects and therapy longer than a few days requires you to taper the dose.

Having started the therapy, the loud random verbal tics continued for a few days and then faded away to zero over a couple of weeks.

Would this have happened without Amoxicillin and Prednisone?  I have no means of knowing, but I agree with Monty's big brother, we do not want to have Tourette’s/PANDAS/PANS in addition to autism.

Therapy started within two days of the tics.




If your child suddenly shows any of these symptoms, call your doctor as soon as you can. Then contact the International OCD Foundation to find an OCD specialist in your area. Early treatment may prevent life-long mental illness.


and an interesting comment on that same Harvard blog:-


“PANDAS and autism is very common. My son has both. When we can get his PANDAS under control, his autism is almost nonexistent. He has been diagnosed with PDD-NOS, which is atypical autism. PANDAS antibodies can also attack other areas of the brain if the infection gets out of control. People need to be aware of this. Untreated strep would result in my son regressing further into autism. If you have looked into Saving Sammy, you’ll notice he stopped responding, like many autistics, and that some of his repetitive behaviors could be considered similar to stimming.

With my son, he also gets repetitive movements and OCD, but ADHD symptoms, major defiance and extreme outbursts, threats of violence, etc.

More doctors of autistic kids need to screen them for PANDAS.”




PANDAS and Tourette’s Syndrome

There is a debate over whether PANDAS/PANDAS is just Tourette’s syndrome.

This is where you need to know the difference between the tic type of compulsive behavior and the repetitive behavior that is stimming/stereotypy.  They are not the same and do not respond to the same therapies.

In this blog I do refer to Tourette’s-type autism.  This is one type of autism that research shows can just fade away.



 



Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes isomorphic to tics and scarce knowledge about the immunological phenomena favoring the transition from natural adaptive immunity to pathological outcomes.



Basal Ganglia and SAPAP3 gene

It is suggested that PANDAS is caused by group A beta-hemolytic streptococcal (GABHS) infections. The proposed link between infection and these disorders is that an initial autoimmune reaction to a GABHS infection produces antibodies that interfere with basal ganglia function.

Many other disorders that are often comorbid with autism are also linked to the basal ganglia, such as tics, stuttering, Tourette’s and even tardive dyskinesia caused by inappropriate treatment of autism with antipsychotics.



The following is a list of disorders that have been linked to the basal ganglia




Repetitive behaviors are common in several neuropsychiatric disorders, including obsessive-compulsive disorders and autism spectrum disorders. Guoping Feng and his team are investigating the pathological mechanisms underlying repetitive behaviors, with the aim of understanding the neural mechanisms and genetic factors that cause or contribute to autism.

The team’s previous studies in mice show that deletion of the SAPAP3 gene, which is implicated in obsessive-compulsive disorders, leads to repetitive behaviors1. The gene’s deletion leads to defective neuronal communications in the basal ganglia, a brain region known to be involved in voluntary movement.

There are two circuits within the basal ganglia, known as the direct and indirect pathways. Feng’s group generated transgenic mice in which SAPAP3 expression can be selectively turned on or off in these two pathways. They found that selective re-expression of SAPAP3 in the direct pathway of the basal ganglia completely reverses the repetitive behavior seen in mice lacking SAPAP3. This effect is not seen in the indirect pathway, indicating that the two pathways play different roles in the pathogenesis of repetitive behavior.

Feng’s group also studied SHANK3, which interacts with SAPAP3 protein in the basal ganglia. SHANK3 mutations are strongly linked to an autism spectrum disorder called Phelan-McDermid syndrome2. The researchers found that deletion of the SHANK3 gene in mice leads to repetitive behaviors similar to those seen in mice lacking SAPAP33. Importantly, the researchers discovered similar neuronal communication defects in the basal ganglia of SHANK3 and SAPAP3 mutant mice. Together, these results provide strong evidence for a common basal ganglia circuitry mechanism underlying repetitive behavior4





In the new study, Calakos’s team found that overactivity of a single type of receptor for neurotransmitters -- mGluR5, found in a brain region involved in compulsive behaviors -- was the major driver for the abnormal behaviors. When researchers gave Sapap3-lacking mice a chemical that blocks mGluR5, the grooming and anxiety behaviors abated.

“The reversibility of the symptoms was immediate -- on a minute time frame,” Calakos said. In contrast, the original study describing Sapap3-lacking mice found that antidepressants could help treat symptoms but on the time scale of weeks, as is typical with these drugs in patients.

Intriguingly, by taking normal laboratory mice and giving them a drug that boosted mGluR5 activity, Calakos’s team could instantaneously recreate the same excessive grooming and anxiety behaviors they saw in the Sapap3-lacking mice.

The researchers found that without a functioning Sapap3 protein, the mGluR5 receptor is always on. That, in turn, makes the brain regions involved in compulsion overactive. In particular, a group of neurons that give the “green light” for an action, like face-washing, is working overtime. (These same neurons can promote a habit, such as eating sweets, according to a study published by Calakos’s team earlier this year.)

Calakos said that mGluR5 should be considered for the treatment of compulsive behaviors. “But which people and which compulsive behaviors? We don’t know yet,” she added. 




Conclusions

These findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.


Diagnostic Tests for PANDAS/PANS

Madeleine Cunningham, who used to work at the NIMH researching PANDAS with Susan Swedo, went off to set up a company to promote her “Cunningham Panel” of tests.

The Panel consists of 5 tests which measure circulating levels of autoantibodies directed against specific neuronal antigens in the patient including: Dopamine D1 Receptor (DRD1), Dopamine D2L Receptor (DRD2L), Lysoganglioside – GM1 and Tubulin. The 5th assay targets CaM Kinase II, a key enzyme involved in the up regulation of many neurotransmitters (dopamine, epinephrine, norepinephrine).




In the United States, 6.4 million children have received an ADHD diagnosis; 50% of all children with the disorder are diagnosed by age 6. Meanwhile, one million children have been diagnosed with Autism Spectrum Disorder ¹ and 500,000 children are living in the U.S. with OCD.
Identifying the underlying cause of these symptoms is imperative and answering the following question could change the course of treatment: ‘Could an infection be causing my child’s symptoms?’ Children may be misdiagnosed with a primary psychiatric disorder and receive psychotropic medications to treat the symptoms. But if the symptoms are due to an infection-triggered autoimmune response, the root cause of the behaviors must be addressed. Treatment must include eradicating the infection (if possible) and addressing the immune dysfunction.

                                                                                       

Treatments for PANDAS

Treatments for PANDAS are not yet well-studied as this condition has only recently been identified. Conventional treatments may include oral antibiotics to eradicate a Streptococcal infection, and prophylactic antibiotics to prevent recurrence. Oral prednisone is also used as a potent anti-inflammatory to relieve inflammation of the brain and prevent damage. Another therapy known as intravenous immunoglobulin (IVIG) is being investigated.

Intravenous glutathione, a potent antioxidant, can be used to protect the brain from being damaged from inflammation.








Time for Tea?

If you read the SAPAP3 research above, a totally different type of therapy might also improve OCD disorders stemming from the basal ganglia; you would try inhibiting metabotropic glutamate receptor 5 (mGluR5).

Given many people’s aversion to drugs, they might want to brew up some Pu-erh tea.  This type of tea is widely used for weight loss.  It should also reduce your cholesterol.





Glutamate is one of the major excitatory neurotransmitters of the CNS and is essential for numerous key neuronal functions. However, excess glutamate causes massive neuronal death and brain damage owing to excitotoxicity via the glutamate receptors. Metabotropic glutamate receptor 5 (mGluR5) is one of the glutamate receptors and represents a promising target for studying neuroprotective agents of potential application in neurodegenerative diseases. Pu-erh tea, a fermented tea, mainly produced in Yunnan province, China, has beneficial effects, including the accommodation of the CNS. In this study, pu-erh tea markedly decreased the transcription and translation of mGluR5 compared to those by black and green teas. Pu-erh tea also inhibited the expression of Homer, one of the synaptic scaffolding proteins binding to mGluR5. Pu-erh tea protected neural cells from necrosis via blocked Ca2+ influx and inhibited protein kinase C (PKC) activation induced by excess glutamate. Pu-erh tea relieved rat epilepsy induced by LiCl-pilocarpine in behavioural and physiological assays. Pu-erh tea also decreased the expression of mGluR5 in the hippocampus. These results show that the inhibition of mGluR5 plays a role in protecting neural cells from glutamate. The results also indicate that pu-erh tea contains biological compounds binding transcription factors and inhibiting the expression of mGluR5 and identify pu-erh tea as a novel natural neuroprotective agent.



Scientific studies report that consumption of pu-erh tea leaves significantly suppressed the expression of fatty acid synthase (FAS) in the livers of rats; gains in body weight, levels of triacylglycerol, and total cholesterol were also suppressed. The compositions of chemical components found to have been responsible for these effects (catechins, caffeine, and theanine) varied dramatically between pu-erh, black, oolong, and green teas.


Pu-erh tea supplementation suppresses fatty acid synthase expression in the rat liver through downregulating Akt and JNK signalings as demonstrated in human hepatoma HepG2 cells.

Fatty acid synthase (FAS) is a key enzyme of lipogenesis. Overexpression of FAS is dominant in cancer cells and proliferative tissues. The expression of FAS in the livers of rats fed pu-erh tea leaves was significantly suppressed. The gains in body weight, levels of triacylglycerol, and total cholesterol were also suppressed in the tea-treated rats. FAS expression in hepatoma HepG2 cells was suppressed by the extracts of pu-erh tea at both the protein and mRNA levels. FAS expression in HepG2 cells was strongly inhibited by PI3K inhibitor LY294002 and JNK inhibitor II and slightly inhibited by p38 inhibitor SB203580 and MEK inhibitor PD98059, separately. Based on these findings, we suggest that the suppression of FAS in the livers of rats fed pu-erh tea leaves may occur through downregulation of the PI3K/AKt and JNK signaling pathways. The major components of tea that have been demonstrated to be responsible for the antiobesity and hypolipidemic effects are catechins, caffeine, and theanine. The compositions of catechins, caffeine, and theanine varied dramatically in pu-erh, black, oolong, and green teas. The active principles and molecular mechanisms that exerted these biological effects in pu-erh tea deserve future exploration.



Conclusion

Sudden onset tic disorder associated with loss of cognitive function does seem to be a distinct dysfunction. Fortunately it is being well researched.

Whether antibodies, due to an infection, crossing the blood brain barrier and causing chronic inflammation in the basal ganglia is the cause remains unproven, but seems plausible.

Exactly what kinds of infections can trigger this response is an open question.  The people selling the PANDAS/PANS diagnostic test, the Cunningham panel, suggest that a wide range of both viral and bacterial infections can trigger this reaction.  As is often the case, there may be a case of some over diagnosis and very expensive use of IVIG therapy.  No test will be perfect because the area is highly subjective.

A recent paper reconfirmed the view that both the blood brain barrier and the intestinal barrier can be compromised in autism.





This suggests that all kinds of things might be crossing the blood brain barrier.

As we have seen, autism seems to be usually caused by multiple hits, rather than a single gene dysfunction, but we have also seen that in cases of severe autism there can be a step-change regression from earlier moderate autism to severe autism.  I called this double-tap autism, so as not to confuse with multiple hits. 

In double-tap autism things usually start out quite well, with good response to behavioral therapy, in early years, and then take a nose dive and can spiral completely out of control leading to institutionalization.

We have seen cases where the second tap/event is immune related and others where it is the onset of seizures around puberty, but usually the trigger remains unidentified.

I would imagine that PANDAS/PANS could also be such a second tap/event.  The issue is not just the tics/OCD but the associated loss of cognitive function. Given that immediate intervention has been shown to be highly effective in PANDAS/PANS, before the condition has become chronic and much less responsive, it would be wise for more people to be aware of what can be done.

Will some Chinese tea affect mGluR5 in a good way?  It remains to be seen; these receptors are present in different parts of the brain where they have opposing functions.  mGluR5 is a target of autism research at MIT and was covered in earlier posts. Here is another link:-




It may be necessary to have a brain region specific mGluR5 inhibitor.

We can add Pu-erh tea to the growing list of things that reduce cholesterol - cinnamon, pantethine (active form of vitamin B5), sytrinol etc.  Interestingly 600mg of pantethine lowers cholesterol but increases coenzyme Q10 (statins reduce coenzyme Q10).  Pu-erh tea actually has some naturally lovastatin in it, but that may not be its main mode of lowering cholesterol .






87 comments:

  1. Never even heard of Pu-erh tea before this post. I guess the English really know their tea (-:

    I also had been looking for effective natural interventions for mglur5, even if they are mild ones and could not really find much in that department even though there are several drugs in development for selective mglur5 antagonism (of course not for the purposes of autism).

    I guess I will have to read the whole study, but it sounds like rather than antagonizing mglur5 directly that Pu-erh tea decreased the number of mglur5 receptors (expression) thereby decreasing the sensitivity of the synapses. It is unclear from my reading of the highlighted text you have provided if this means they are assuming mglur5 receptor downregulation was the direct result of lowering glutamate levels or just rather a direct regulatory action by something in the Pu-erh tea. I would think that decreasing glutamate levels would generally increase the number of mglur5 receptors but maybe I am missing something here in my reading of this.

    Nevertheless, I will definitely be looking into this. Hopefully, I can make it palatable to my son (-:

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  2. Peter, thank you for this post,in some way reflects everything that happens to my son.For me,certainly is time for tea.
    Valentina

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  3. Hi Peter and community,

    Thanks for another excellent article Peter! I've actually had my daughter on Pu-Erh tea for a couple of months, and she likes it. I get it from David's Tea - the one I get has chocolate and orange in it (yeah, no wonder she likes it! plus I sweeten it with Agave nectar). I did get it for the MGluR5 inhibition, and can't say I've seen any obvious improvement from it, but I keep using it just in case - I spent $20 for a canister of the tea and its still going.

    I did spot another interesting paper to share that shows that these kids are low in MAO-A. Will do some research on this to see what agonists of MAO-A there may be:

    https://www.ncbi.nlm.nih.gov/pubmed/28151561

    Also, about the article on Endoplasmic Reticulum Stress and Calcium signaling, I did some research and the item that kepts popping up is TUDCA (Tauroursodeoxycholic Acid)

    Interesting enough, TUDCA was also noted for tamping down neuroinflammation (and of microglia) so it sounds like a good option. Someone mentioned it in the comments about a year or so ago, but given the latest papers on ER Stress, I thought I would mention TUDCA again. Anyone trial it? I think I will based on what I've reach up on it:

    https://www.ncbi.nlm.nih.gov/pubmed/27987324
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126306/
    https://www.ncbi.nlm.nih.gov/pubmed/27744574
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691030/

    Have a great evening everyone!

    AJ

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  4. People using this Pu-Erh tea to lose weight consume something like 10g or 5 tea pots a day. So as with many natural products, any possible health benefit may require dosing more like a food than a medicine. This was true with the people who drink cocoa as their main fluid and do not have heart disease and people who eat large amounts of curcumin and have low cancer rates.

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    1. Hi Peter,

      That's a good point - I don't give my daughter a whole lot of it (maybe 50ml of tea), which may be why I haven't seen an impact - it may require much more to really have an impact.

      AJ

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    2. Merhaba Peter. Oğlum 5 yaşında 21 kilo. prednizon. Dozu ne olmalı. Oğlum hiç göz teması kurmuyor. Konuşuyor ama ne dedigi belli degil. Net bir kelimesi yok.Ben Pandalardan şüpheleniyorum. Oğluma prednizon kullanmak istiyorum

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    3. "Hello Peter. My son is 5 years old and weighs 21 kilos. prednisone. What should be the dose? My son never makes eye contact. He is talking but it is not clear what he is saying. There is no clear word. I suspect Pandas. I want to use prednisone for my son"

      I suggest using the dose used for an acute asthma attack, which is 1-2 mg/kg for 5 days. This is very safe. Give the drug first thing in the morning to minimize its interaction with the body's own hormones.

      When given for more than 5 days you have to gradually reduce the dose ("taper" in English).

      When treating PANS/PANDAS that has been present for a long time, it takes longer to cure it. In these cases a longer course of Prednisone will likely be needed.

      Some people without access to Prednisone have success using Ibuprofen for a couple of weeks. In some cases a more potent therapy is needed.

      Delete
  5. Hi Peter,

    Great post as always but I was really disappointed in your use of the expression 'behaviour embarrasing for parents and siblings'. I wish you had followed it with another set of words 'which should not be so'. What if Monty can sense your embarrassment. This maligns the entire intent of treating one's child. As individuals we do get embarrased by what 'irrelevant others' think of us but this is so ordinary. We should try not to be ordinary at least when you are a blog author with a great following. I know I have picked on specific words but when I went to pick my child from school after getting a call I was a tad embarassed and then I thought this is so regressive and probably that is why I am overreacting. Those who are embarrased about their loved ones who function differently, infirm or senile parents, spouse or a child who does not confirm are a mental and physical health hazard needing spiritual evolution.

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    1. Teenage siblings are really concerned about looking good and fitting in. Having a brother or sister with autism does cause moments of embarrasment, I think this is normal behavior on the part of the sibling.

      Parents have to just take everything and most do. Some give up and pass the child to Grandparents or the State. There are entire books written to help siblings deal with autism.

      It is better to be open about these issues with siblings rather than pretend they do not exist. It really is normal to wish your brother did not have severe autism and not want to have further troubles.

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    2. Yes I have some of those issues myself (with my younger son who is diagnosed with ASD but has made enough progress that very few if any people would classify him with autism). I have never told my younger son he was diagnosed with ASD, and I don't really use the word "autism" around the home because even few adults really understand what the word really means. Nevertheless, when my younger son makes fun of his older brother (who is more severe) lets just say the situation becomes a "teachable moment" when it comes to morality and what the word "family" means and why it is important in today's world.

      Also, I have always had very thick skin throughout my life, so I take my not-so-well behaved kids into many public situations that few other parents have the stomach for and I know this because I always have the least behaved kids in any given situation (always) and the deer in the headlight stares from other people don't even bother me the slightest anymore, though fortunately with the improved behavior and functioning of my children (some of it being age of course) I am progressively getting less of that over time. And since thing have taken a turn for the better in the last year (with regards to all of their behavior) I will say that it is unlikely I would have been able to get them to this point if I had just kept them inside our home away from the world to see (which seems to be what the parents in my oldest son's class seem to do as they don't even take their kids to speech therapy anymore). To give you a frame of reference here, we were kicked out of speech therapy and occupational therapy at one place because of my kids behavior in the waiting room a little more than a year and a half ago. Getting kicked out of places and getting kicked down over and over and getting back up again for more abuse from the rest of the world is just something you have to endure as a parent of someone with moderate to severe autism if you want to actually do what is best for your child in the long run.

      So for me shame is just an emotion I shrug off, because guilt is far worse and I am happy to have none of that.

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    3. Tyler,

      I think what you shared has really inspired and emboldedned me. Its not only a question of standing up for family but that of claiming the right to a life of dignity for all...probably the apes too..and maybe dogs?

      That said, although its pretty insignificant, I would like to apologize to Peter for selectively picking out words out of context and doling out a stupid, moralistic over the top comment, probably at a feeble attempt to lessen my own confusion or guilt. Peter was gracious enough to publish it..though I wish he hadn't as its hugely embarrasing.

      Guilt is the worst emotion to have, so I render an apology to Peter shrugging of shame, and am happy to have none of that.

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    4. Kritika,

      If anything, I wish Peter didn't publish your apologetic second comment. Your initial comment was brilliant. It was from the heart and channeled all those instinctive feelings that parents of children with ASD have.

      Your second comment was overly considered, talk of guilt confusion and embarassment. If anything, it was the antithesis of everything you railed against in your brilliant initial comment - regression, spiritual evolution, embarassment ...

      I think Peter as the blog owner would appreciate comments from the heart that critique his blog posts in a tactful way. I believe that is an organic way to advance the cause. By Peter publishing your comments, he demonstrates this so.

      Regards,
      D&G

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  6. Kritika, I didn´t take badly what Peter said,in short is what we all feel,sepecially those who have children with tourette´s like movements and dyskinesias. I take it as something said in confidence, spontaneous, and it really is so difficult to ¨educate¨ others! We have to do an exhausting double job, evolutionate ourselves and make others to do it.
    Valentina

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  7. Hi everyone,

    I've made a connection between some information from recent papers that I wanted to share. So we have seen in some recent papers that ER stress in ASD affects Calcium signaling, and also have seen that ASD kids seem to be relatively low in MAO-A. In the following paper, there is a connection between these two that I wasn't aware of (many of you probably were):

    http://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-8-73

    So basically, it looks to me like there is ER Stress, which leads to Calcium signaling issues, which lead to low MAO-A (among other issues I'm sure)

    So tracing it back, if we can alleviate the ER stress, the issue of low MAO-A would be resolved versus solely trying to fix the MAO-A issue (which looks more like a symptom than a root cause). I don't know why these kids have ER stress, but the issues with Calcium signaling likely do more than just lower MAO-A, so I think I'll focus more on the ER Stress than the MAO-A, as it may help several areas.

    Also, I've been looking for ways to affect the MAO-A issue and nothing straightforward has popped up. I've ordered TUDCA, which should help with ER Stress. Will let everyone know how that goes.

    Just wanted to share my thoughts, and would appreciate any input.

    AJ

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  8. Peter, great post. PANDAS is only recently recognized disorder in US in the last 5 years or so and in many hospitals is still not fully mainstream. However, 5-10 researchers (with Swedo encouragement) along with an incredibly active parent community have brought it to the forefront. My son was one of the first at Stanford PANS center We caught it very, very late --and took a long time to improve (for us, antibiotics, IVIG and NSAIDS/steroids ) were the treatment. He is currently still on long terms NSAIDs and we monitor it at Stanford. They would prefer that he stay on antibiotics proph. but we have chosen not to. His residual is some chorea in his hands. mGluR5 is interesting; I didn't understand if you think that cinnamon, sytr etc. is a mGluR5 inhibitor or it does a lot of mechanisms of mGluR5 inhibitor would do like lower cholesterol.

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    1. Cinnamon etc are just things that have been mentioned in this blog that lower cholesterol among other interesting things. For mGluR5 the choice is very limited.

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  9. What are your thoughts about lithium for mGluR5 inhibitor? And, when researchers discuss this, are they assuming small dosages or pharmaceutical dosages (like for bipolar, etc)?

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    1. I think they are thinking about the bipolar doses. Lithium causes some people troubling side effects, so probably best avoided.

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  10. Peter, I am sure that hyperventilation crossed your mind while researching vocal tics and inflammation.

    In my son's case vocal tics arise during extreme stress. In the beginning I couldn't see the difference between stimming and vocal tics. I know from Asperger's forums that stimming feels good because it regulates dopamine or other hormones. On the other hand vocal tics come as a stress response and seem to control breathing. My son uses his diaphragm to produce some kind of singing or immitates the way some actors speak in English by completely changing his voice which seems to come only through his diaphragm.

    Maybe this post gives me another good reason to use acetazolamide.

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  11. I didn't know that having a perfect foreign accent is actually a syndrome!
    I think he also has that.

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  12. I know this post is about a totally different kind of tea, but of the many things I knew about EGCG (in green tea), I did not know its use in helping to prevent protein clumping of the alpha-synnuclein and beta-amyloid kind.

    http://sciencebulletin.org/archives/10091.html

    This is just something I came across. Parkinson's is looking more and more to have oxidative stress and breakdown of the mitochondria as being the root cause of Parkinson's even though clumping of toxic alpha-synuclein seems to be what causes the initial symptoms and the rapid spread of the disease.

    In several post-mortem studies of adults with autism, Alzheimer's like pathology has been consistently reported, so for good band aid approaches to keeping brain tissue healthy, in addition to interventions to safely minimize oxidative stress (NAC, Alpha Lipoic, etc.) perhaps it would be wise to employ interventions that help reduce the toxic clumping of amyloids as a preventative measure as well (aside from Alzheimer's drugs the only other stuff I know of that does this decently is methylene blue and perhaps now EGCG).

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    1. Hi Tyler,
      Why not curcumin?

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    2. Curcumin has a dubious record for absorbtion (even with piperine). Virtually all the studies I have read on curcumin involved injections in other animals. There is Longvida Curcumin which supposedly crosses the blood-brain-barrier, but it still has absorbability issues.

      Really my opinion on curcumin is mixed because whether you believe enough of it is absorbed (orally) depends on which research papers you believe. The only other thing I don't like about curcumin is that there is evidence its anti-cancer action is based on inflicting DNA damage which could also be where the other health benefits exist in that inducing DNA damage entails a hormetic stress response in the cells that are affected. In summary, the dose response relationship is just too much of a gray area right now for me to use it with my son.

      Delete
  13. Peter, I am looking for the right kind and brand of Pu erh tea, it seems that the caffeine content of both ripe and raw pu erh is like any other tea. Caffeine worries me about the fact that he have to drink 3 or 4 cups a day to get an effect.Also I wanted to know if the fermented ripe pu erh is better than the raw pu erh,to get the inhibitory effect on mglur5 or doesn´t matter.
    Valentina

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    Replies
    1. Valentina, the studies refer to fermented Pu-erh. The fermentation may well be very important. This aging is why it is an expensive tea.

      I think the best idea is to buy the type the Chinese drink, not a version processed by a big Western company. They sell it in blocks called "cakes" and you break small pieces off to make the tea and leave the rest to continue to age. If there are many Chinese people in Uruguay, you may find it locally. It is very widely used for weight loss.

      Delete
    2. Tyler, Peter, my son started to show challenging behaviors and began to do all kind of crazy things, iam very worried, it´s as if he had gone mad, not agressive but mad. If I go to the neurologist he will tell me, ¨I told you¨ and will start to give him risperidone again. I will suspend all.Only keep valproate and tizanidine. I am afraid he have a seizure.
      Valentina

      Delete
    3. Well you said you were doing 5-HTP. It was a Dr. Jekyll and Mr. Hyde intervention which is why I stopped it, even though other people benefit from it.

      In autism, there seems to be poor serotonergic signaling, but high levels of serotonin in the blood. Some research suggests that there are low levels in the brain, but not in the periphery but what I do know is that if you either increase levels of a neurotransmitter or else increase its efficacy (like with SSRI's) the receptors downregulate in number. There are basal levels of neurotransmitters you are supposed to have, and any more than that simply adds noise to whatever system you are perturbing. It is why stimulants are thought to increase performance in some people with ADHD (low dopaminergic tone) while in normal people they just cause anxiety and hyperactivity with increasing doses.

      The "non-aggressive" but "mad" behavior sounds exactly my experience with 5-HTP which may have to do with tolerance (not unlike the experience some people have with SSRI's). I am sorry if I confused you, but I said the NR was what you really needed, not the 5-HTP which is optional.

      Delete
    4. Ok Tyler, I knew that, and had things clear about NR. I will suspend BCAAs until I can get NR by march, unless there is a possibility of using niacine or niacinamide with bcaas that i don´t think so. Yesterday during the madness episode he emptied all the house containers on the floor:face creams, liquid soap,softener, water bottles, perfumes, and other crazy tings you could imagine.Today the storm ended but it had been threatening for 2 or 3 days before. Should I continue with bcaas and niacinamide or wait until I get NR?
      Valentina

      Delete
    5. We also had a 'Dr. Jekyll and Mr. Hyde' type reaction to 5hpt, but only when we gave 50mg or higher in one go.

      On the other side once we learned to not go over 25mg once, or occasionally twice a day, it was GREAT. Really suited ds, one of our top interventions.

      Delete
    6. I don't need to imagine those things, rather I think a good percentage of people on this blog (including myself) directly experience these behaviors at one time or another. For me personally, I had to hide my shampoo after every shower because my son would empty it all into the tub if I ever forgot (he would empty everything though to be clear the really unsafe stuff like Drano we would have in a different part of the house, inaccessible to him. All of it of course makes keeping the house clean a pointless chore that gets almost no sympathy from anyone that wonders why strange stains are on the floors and walls all the time.

      But to answer your question, I don't know the details of your situation, and it could have nothing to do with 5-HTP, BCAA's (which should help) or anything else. Also, regular Niacin should be fine, but NR is way better and can help with other cell stress problems (this all depends on how efficient the NAMPT NAD+ recycling pathway is working). Resveratrol BTW, increases NAMPT (cycles NADH back into NAD+ which is the primary method the body uses to keep NAD+ levels optimal), but a good resveratrol product is unfortunately not much cheaper than NR.

      Also, this "mad" behavior seems more like a loss of inhibition and likely related to dopamine. A long time ago before I was married, there was a kid I was mentoring for a friend of my girlfriend who was 11 or 12 at the time and had severe ADHD (among other issues). Besides compulsively lying and having other conduct disorder type behaviors, he would at times do crazy things that would drive his aunt mad and he would not even understand why he would do them. ADHD has many symptoms that are shared with autism, but is very different in terms of what drives those symptoms, nevertheless both ADHD and autism have dopaminergic signaling issues that can produce these sorts of behaviors even though excess dopamine in autism (driving receptor desensitization and impairing signaling) while low dopaminergic tone in ADHD (impairing signaling from the dopamine itself being too low or the dopamine pathways being compromised in the prefrontal cortex). Wild swings in dopamine can drive wild swings in behavior. I don't know if you stopped doing the BCAA's for a few days or not, but the BCAA's will help normalize receptor levels over time, but won't decrease the core problem of excess extracellular dopamine being produced in the brain (the BCAA's in effect block the fuel supply for excess dopamine but don't stop the production of the fuel supply) so if you stop treatment, you could get these kind of psychotic "mad" symptoms (only speculating).

      What I would not do is do BCAA's off and on or casually, or else as I have found out the hard way in the past, you can get these issues (the same of course would be for risperidone which works differently in that it blocks the receptors but does not deal with the excess dopamine so if you stop therapy acutely you get a nasty pushback).

      I don't think your kid is behaving this way because of a lack of NR, though I won't say this for sure because a lack of NAD+ will compromise a lot of cellular functions, especially mitochondrial function which can have lots of deleterious and hard to predict negative consequences in the brain. Just do regular niacin till you get the NR and then at least you will have a baseline for whether the lack of NR with this therapy is the problem or not.

      Delete
    7. Nat,
      Can you please tell what exactly was the improvement with 5HTP? Thank you.

      Delete
    8. Tyler,I have never had those kind of problems, always left all at his reach and he never touched anything, is the first time. Now, without risperidone, true things come out and the loss of inhibition is the main that worries me, we are on holidays but when school begins this could be a problem. An issue with dopamine is clear and if I tell you that to his HFA diagnosis sums ADHD, things start to make sense, for what you say. I will continue with bcaas and niacin, may be can try 25 mg 5htp, as said Nat. I tell you that after my house was very very clean with a new floor soap with a touch of french parfum created by my son, I started ordering medicines and found a very intersting one, that was given by the neurologist to him at the beginning. It is Somazina, Citicolina and among others things,the prospect says it can be used for chronic dyskinesias. I stopped giving it a long time ago. I know that increases dopamine and serotonin, so don´t know how could treat dyskinesias, but certainly could be a bad interaction with bcaas?
      Valentina

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    9. Valentina, Tyler,

      Somebody I know well had a manic episode when he added very low dose CBD oil to his usual 25mg 5htp. It lasted several months and was quite horrid. I remember that BCAAs were one of the suggested interventions. Valentina, your description of your son's behaviors reminded me of that.

      Delete
    10. RG, I can imagine that this combination must have been like a bomb. I must say that my son´s movements are nonexistent for hours, specially when watching tv , this is a fireproof. The loss of inhibition theme is something that was appearing when I start to suspend risperidone and now we need to give time to bcaas to do the correct job. Whith respect to dyskinesias and involuntary movements, the change is incredible.
      Valentina

      Delete
  14. Peter,

    If sensory issues like extrme itchiness, oral irritation, need to bite and chew and discomfort on palms and arms ease after a dose of anti allergen, can we safely assume that the childs sensory issues were histamine related either due to allergies or histamine intolerance after exposure to histamine producing food/supplements or a combination of both.

    Do anti allergens have other modes of action as well making it difficult to ascribe a clear cause to sensory/begavioural issues?

    I really hope not.

    Kindly give your opinion.

    ReplyDelete
    Replies
    1. Kritika, you may have more than one issue. Mouthing objects, and eating non-food items called "pica", is very common in autism. There is a lot written on this subject.

      https://www.autismspeaks.org/blog/2014/05/30/new-pica-tool-kits-autism-speaks-autism-treatment-network

      Itchiness that responds to an H1 antihistamine sounds looks like an allergy. This you should ask your doctor about, because there are many possible causes and the doctor may tell you it is trivial and not to worry.

      There are different types of allergy medicine and they can have more than one mode of action.

      There are links between autism and psoriasis; your doctor would be able to diagnose psoriasis, if present.

      http://questioning-answers.blogspot.com/2012/03/autism-and-psoriasis.html

      Delete
    2. Peter thanks. But I think I was not clear enough. If someone develops all these symptoms suddenly following a short stint with hay fever like illness and heavy supplementation with products likely to load the liver or cause a reaction like gastrus and high dose cytoflora with its alcohol content, is it possibly an allergic reaction. Actually I am almost answering my own question.
      My son is not displaying pica at present although he has those phases. It is rather irritation or itchy teeth, lips , arms and palms which he is asking me to rub. Actually my son had been displaying symptoms of rhinitis, runny nose and watery eyes and following my 'extreme' intervention with supplements and drugs without giving a time to heal, made the issues snowball into a crisis of sorts with jumpiness followed by days of lethargy, pale face, dry lips, lustreless eyes and bad school days. Some energy has come back but this itchiness increased till yesterday when following a single dose of allegra he seemed settled and comfortable. At one point I even considered PANDAS and cursed for the omnious coincidence as my husband and I are down for the longest time with strep throat and I wondered if my son could have had it. Too many questions. I will dig further into this.

      But I have learnt my lessons. A seemingly gentle and safe supplement/drug with no record of adverse effects can wreak havoc when given to the wrong candidate (my son) at the wrong time (without a gap following illness) at the wrong dose (read high for my son). I am not in future straying anywhere near herbs, tinctures, vitamins, amino acids or even fancy probiotcs. Good riddance!

      Regards


      I know psoriasis..one very very distant cousin, a bright girl, had it and it was quite a trouble.

      Delete
  15. Vasopressin blocker improves social deficits in rat autism model
    BY NICHOLETTE ZELIADT / 19 OCTOBER 2015

    According to the time my son responds to diuretics I can assume that his vasopressin levels are quite high. Vasopressin is the anti diuretic hormone. My nephew seems to have the opposite dysfunction.
    I tried to help this with coffee and tea but maybe this is not enough.
    'But high levels of vasopressin are also associated with anxiety and aggression. Intriguingly, some animal studies have found that higher levels of vasopressin increased aggression specifically in males.'

    ReplyDelete
    Replies
    1. Hi Petra,

      My daughter is somebody who has a positive response to bumetanide from the first dose. I added a second 1mg dose later in the day, and it has been very good. She is so much more cheerful, quite social, talking more. It must partly be the diuretic effect that kicks in quickly.

      Delete
  16. Hi RG, maybe I'll give oxytocin a try.
    Peter, there is a product here, oxytocin/G.A.P. injections, 1ml/5IU in ampoules. If I put it in a nasal spray dispenser, as I did with insulin, do you think it would be similar to other products available?

    ReplyDelete
    Replies
    1. Petra in trials they use different amounts of oxytocin. I just looked at one that used 24 IU per nostril. Some producers make ampoules and sprays like Syntocinon by Novartis.

      Delete
  17. Here is a new idea or rather a new road for ideas for autism interventions, especially for visual sensory hyperactivity:

    Press Release:

    https://www.sciencedaily.com/releases/2017/02/170209090943.htm

    Paper:

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168455

    What they basically found was that beta blockers attenuate visual spatial sensitivity in the primary visual cortex by blocking noradrenaline's effects on the beta-adrenergic receptors.

    So why is this interesting? Well catecholamine(dopamine, noradrenaline, etc.) levels in many autism studies are found to be high. This of course is not new news on this front, and beta-blockers (which have lots of side-effects which makes their long-term use problematic) are a class of drug that many parents with severely autistic children have used to limit the worst behaviors. I even used to know a parent at a previous preschool my children attended who used beta blockers on her adult son and with good success (according to her) till she had to stop using them because of the side-effects. So there are of course the obvious hypotheses for why beta blockers might help with autism as having a chronically elevated HPA axis is going to cause problems all over the brain and body.

    But another extremely common characteristic found in autism fMRI studies is a hyperactive visual cortex which is not too surprising since so many people with autism report having hypersensory issues with vision which can drive cognitive problems in the rest of the brain as the excess signaling from the visual cortex in effect drowns out the higher level cognitive areas and leads to dysfunction in the limbic system and hyperactivity in brain networks that are supposed to decide if something you see or hear is important (salience network, cognitive control network, ventral attention network).

    So the two obvious ideas here which are not new, but perhaps should be given greater import in light of this research is to either reduce noradrenaline levels either directly or indirectly or else block or at least modulate beta-adrenergic receptors in a manner that does not cause the kind of side effects which limit its use.

    ReplyDelete
    Replies
    1. Another interesting bit of research:

      Press Release:

      https://medicalxpress.com/news/2017-02-psychologists-human-vision-sensitive-physical.html

      Paper:

      http://www.mitpressjournals.org/doi/10.1162/jocn_a_01082#.WKKU-NQrKHs

      In effect low-intensity exercise but not high-intensity exercise enhanced cortical activity in the visual cortex of healthy volunteers.

      This got me thinking that if a hyperactive visual cortex in autism drives hyperactive motor behaviors, then those hyperactive motor behaviors could loop back into exciting the visual cortex further via the mechanism described in the paper. Of course, there is probably some steady state in this process, but this steady state is arguably significantly higher in autisms involving sensory hypersensitivity, especially visual hypersensitivity.

      It would be interesting if these researchers or another research group did this same study on those with autism and then did a compare and contrast on the visual cortex activations relative to control subjects.

      Delete
  18. Peter, Tyler, how do you see adding CDP Choline _Somazina to Bcaas treatment? PubMed 6684469 Treatment of chronic dyskinesia with CDP Choline. It may act as an antagonist on the dopamine neurons and receptors. I want to know if it could be a good help to add to bcaa or is one treatment or another.
    Valentina

    ReplyDelete
    Replies
    1. Choline is widely used by people taking nootropics to enhance their cognitive effect. But people can have an adverse reaction to choline. I would be very careful not to use too many supplements, just use what is genuinely effective.

      If it helps, great. If it does nothing or makes things worse, best to stop. I tried it once and it made things worse immediately, but your son has very different autism.

      Delete
    2. Yes Peter, you are right,I will have to find out which are the ones that are worth.Classes start again in March,so the time is running out for risky trials.
      Valentina

      Delete
  19. PANDAS/PANS awareness on the European periphery seems not so bad: when my son was admitted to our local hospital because of episodic distress, PANDAS was one of possible explanations considered by pediatricians and they had diagnosed this condition in children previously. Recently one of my son’s teachers attended an early intervention course held by another tertiary pediatric hospital in Poland and PANDAS/PANS was a topic of a special session there. So perhaps most GPs don’t know much about it, but there are places here that diagnose and treat PANDAS/PANS.

    The Cunningham Panel can be done at a mainstream Swedish laboratory and samples can be sent from Poland, so perhaps from other countries in Europe as well. It is expensive, but it would be my first step if I tried to get IVIG treatment.

    Also ketogenic diet might not be as unavailable as it seems. Last week I discussed it in a pediatric neurology center specializing in epilepsy treatment. I thought I would need to argue about the idea of KD for autism, but instead I received a very knowledgeable advice on KD, MAD and low glycemic index diet, all considered potentially beneficial. The other surprising thing was that there was only one person who asked them for KD in a child with autism before.

    The good news is that even in case of typical KD you don’t need to start it in a hospital setting there, you just need to travel to capital city for a few days if you live elsewhere.

    ReplyDelete
    Replies
    1. I do think the people wanting to use diet to reduce the severity of autism should be aware of their options other than gluten free & casein free. The MAD does not look hard to implement. I think people are frightened to use the KD, unless there are seizures. There is no shortage of evidence to support the use of KD/MAD if you accept the link between autism and epilepsy is more than coincidence.

      Delete
    2. Ketogenic diet seems to help with calming overall. I like the diet but it was difficult to work with in the begining. I have been using it for 3 years and I combine it with GF/CF, low glutamate. I use a lower ratio so that he gets more antioxidants and fiber. I try to avoid processed sugars albeit some help to get under biofilms.

      Delete
    3. MAD might contribute to an increase in pH so I opted for a smaller meat consumption. The practicality of it is difficult too because some children would fill up on the protein making it difficult to finish the rest of their meals.

      Delete
    4. Agnieszka, I would be curious to know what results on the Cunningham Panel would aid in getting an IVIG recommendation. We did this test 3 yrs ago. I'm not sure it helped us learn anything new unfortunately . But perhaps since more time has passed, maybe now new insights ?

      Delete
    5. Tanya, my simple way of thinking is that the positive Cunnigham Panel test result means there is autoimmunity against neuronal antigens in a child with neurological impairment. I would look for a doctor who could agree on off-label IVIG treatment in a hospital setting in such case, just as in other autoimmune encephalitis.

      That’s the idea for my country and I know it’s different in the US. In Poland I myself received IVIG off-label for severe dengue and this was based on presumed immune activation in this disease only, while there are no human studies or guidelines suggesting such treatment.

      I met an immunologist here who says that she would be happy to treat neuroinflammation/autoimmunity in my son, but she doesn’t know how. Papers say IVIG is successfull in 1:10 children with autism, but apparently it is much more if you follow informal reports. The issue is that MAPS docs using IVIG don’t publish the results so our immunologist will never know.

      Anyway, my experience with confirming mast cell activation in my son with urinary N-methylhistamine told me that you can get more serious attention if you can show a lab test proof. Especially if you are the first person in the country with such test done and no one believed that you would find anything in a child raging because of 'autism' ;-)

      This is because of all autism misconceptions present everywhere for years.

      Delete
  20. I know nothing about CDP Choline, though a quick read on it suggested it is pretty safe and not very expensive, though for dopamine purposes it increases dopamine in the brain unless given at high doses, in which an antagonism effect occurs.

    Really, I don't know enough about it to say one way or the other if it is a good idea or not, but considering it seems to be safe and expensive it might be worth a shot at trialing if you think it might help (sounds like dosage is the key variable from the little I have read about it).

    ReplyDelete
    Replies
    1. Tyler, I will start with 500 mg, here it is expensive because it is sold as a medicine, not as a supplement that can be found in amazon and even there, the amounts are very little and it becomes expensive
      Valentina

      Delete
  21. "Stepholidine" -

    ...natural product isolated from the Chinese herb Stephania, possesses dopamine (DA) D1 partial agonistic and D2 antagonistic properties in the nigrostriatal and mesocorticolimbic DAergic pathways.

    ...Also a calcium channel blocker (albeit weaker than Verapamil).

    Peter, glad to see you make reference to the two classes of Dopamine receptors D1 / D2. Have you come across this "natural" product Stepholidine?

    Peter, do you consider that your blog has been neglectful in any way to the dopaminergic system? Is there merit in pursuing investigation on a system that plays important roles in the control of cognitive, motivational and motor functions?

    Generally speaking, D1 receptors function in an excitatory fashion. In contrast, D2 receptors behave in an inhibitory fashion. To me this bears the hallmarks of a circuit that's prone to influences seeking to disrupt operational balance. Can I draw parallels to the heavily discussed GABA E/I balance?

    Basal Ganglia - The paper below introduces a new model of dopamine function in the basal ganglia.

    http://www.sciencedirect.com/science/article/pii/S0306452214005843

    The paper below discusses research on Stepholidine and its implication on calcium channels, dopamine and what benefits it holds for various afflictions.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2644490/

    My discussion on dopamine is extremely simplistic but find it hard to escape the conclusion that a system that's implicated in conditions such as Schizophrenia, Parkinson Disease, Alzheimer's, ADHD etc, is not in some way also linked to Autism.

    I hope at the very least this promotes some attention and discussion.

    Regards,
    D&G


    ReplyDelete
  22. Nicotine as Therapy

    'There's a cheap, common, and mostly safe drug, in daily use for centuries by hundreds of millions of people, that only lately has been investigated for its therapeutic potential for a long list of common ills. The list includes Alzheimer disease, Parkinson disease, depression and anxiety, schizophrenia, attention deficit hyperactivity disorder (ADHD), and even pain and obesity. Why has interest in this potential cure-all been slow to develop? One reason: in its current forms the drug offers pharmaceutical companies no possibility of substantial profit. Another, perhaps more important: the drug is reviled as the world's most addictive. The drug, of course, is nicotine.'

    Peter, nicotinic receptors, at least in some autism subtypes, may play an important role and should be well researched. Maybe you would like to have a closer look at this possibility.

    ReplyDelete
    Replies
    1. Just as some countries now have medical marijuana, I think in the distant future there will be medical nicotine. There is a reason why some people with schizophrenia and some other disorders smoke, they really do feel much better. Which is better smoking or suicide? In some countries like Australia they are close to banning cigarettes. There may well be better ways to take nicotine than smoking, but there is so much desire to minimize smoking that you will not hear about any good effects of nicotine.

      Delete
    2. Peter, if nicotine is the case, then phylosophy has solved this problem, you settle for the lesser of two evils. This sounds ethical and realistic.

      My son told me that smoking a cigarette at the right moment can help him avoid an overload. If not on time, there is a build up. With the build up he gets into a fear state and insulin helps escape.
      He also told me that during an overload raising emotions is important, not cognition.
      One good way to raise emotions is through singing lessons/practice and he likes that.
      Hopefully it may also strengthen the lungs if exposed to nicotine.

      Delete
    3. Hi Petra,

      Thank you for this, it is very helpful. Do you mind describing a little more about the overload, what it is precisely. Is it fear? Also, when you talk about insulin helping escape it, do you mean by eating?

      I understand completely about cognition being useless in an acute situation, that it is emotion. My very good friend's chronic depression and anxiety after a manic episode has been completely alleviated with a few cigarettes a day and Biogaia Gastrus and likely, LDN. Interestingly, nicotine patches were not very helpful.

      Delete
    4. Hi RG,

      In my son's case, I think overload is connected to cognitive inflexibility, the black and white thinking, making him kind of obsessed, filled with intrusive ideas that cannot put in order. In a second stage he messes up with emotions. This state can sometimes lead to fear like a shutdown and tremours and some other times to outbursts, meltdowns.
      I use intranasal insulin whenever he has a fear episode and it works in less than 30 minutes. Smoking a cigarette at the right time may also help him organise his thinking.

      Delete
    5. Petra and RG,
      Petra I may have asked you this before, but have you considered EMDR for the intrusive thoughts? It is apparently very effective for that as well as any issue caused by unresolved trauma, and for OCD, anxiety and depression. It is not a "quack" therapy. It was recommended for my son and is used at Vanderbilt University Hospital where I live - a very respected research university. It seems this could be a missing link in treatments we use for our son - having covered the medical issues for so long - and of course always exploring more. I have noticed more of the emotional stuff the older he has gotten, the more he has healed and become more aware , and especially since his brother left two years ago to start college. RG I am wondering your thoughts on this too? If it is not too wide open a forum to delve in to personal things. I ask because it seems of the regular commenters here you and Petra are the only ones with older kids? Just looking for insights on this area - emotional health. And I agree, in these situations cognition means nothing. I came down from Cloud 9, being too excited over just academic achievements. now I see that is probably not the issue for most. Interesting LDN helped.. But I am intrigued by EMDR - especially if it gives them a tool they can learn to use independently and feel they have some control over. I feel that kind of boost in self esteem no doubt has to help the physical health of the body.

      Delete
    6. Hi Petra,

      Thank you. I didn't realize that you were using intranasal insulin. Are you only using it as needed or also on a regular basis? What is the dosage?

      Have you by any chance tried nicotine patches, are they as effective as smoking? I am not sure I can get my daughter to smoke a cigarette.

      Delete
    7. Hi Tanya,

      Thank you for the information about EMDR. I had not heard of it before so I looked it up. It sounds like an offshoot of Cognitive Behavioral Therapy. I am not sure it will work for my daughter though, because I am not even sure of her traumas, and there is no good way to get them out of her. Moreover, if I even bring up something that I know of, it will agitate her enormously. I don't think she is high functioning enough for it.

      Btw, when I think of something like this for myself, I'd rather just learn to smoke a cig! I cannot bear the thought of sitting in front of someone and recounting, reliving such personal stuff:)

      Delete
    8. RG, I tried very small piece of nicotine patch for my son many years ago - and each time, it caused nausea and he actually vomitted. i would love to know if that gives a clue to something meaningful. Any ideas?

      Delete
    9. Actually RG, from my early understanding, EMDR is nothing like cognitive behavior therapy - which is something I know would be a waste of time for my son and a cig would be more effective haha.

      Delete
    10. Hi RG and Tanya.

      Tanya, thanks for letting me know about EMDR therapy. I've checked and it runs in Greece, I don't know their standards, though.
      According to my experience, I would agree with RG, I mean I would rather spend money and time in activities like singing lessons, golf practice, travelling, meeting different kinds of people, things like that, to motivate my son take part in life.
      As I read nicotine patches don't work as well as an actual cigarette (not telling you to make your children smoke by that) as in schizophrenic trials patches didn't alleviate negative symptoms. It was acute smoking that helped. This may be because a patch gives a mild long lasting effect while smoking gives an acute effect to the brain at exactly the time you need it. A gum, or a nasal spray might simulate the effect better.
      RG, in the beginning of the trial I used intranasal insulin three times a day. Now I only use it when I see he needs it. It's strange but when my son is in a kind of state that insulin can help he has a face expression like children with phelan mcdermid syndrome. I saw pictures with their face expression and it looked familiar.

      Delete
    11. OK sorry Petra, I must have misunderstood - I was thinking the intrusive thoughts and meltdowns were debilitating. I agree about being in the world - that is the best medicine for my son actually - adventure - I have seen his language increase just by being in the waves at the ocean so that alone has convinced me not to biologize everything. We might be understanding two different things about EMDR though?? from what I am gathering it can make a difference in as little as 2 sessions and is nothing like talk therapy but more along lines of acupuncture. But I will let it go here on this blog and not bring it up. Just was curious and thought worth mentioning here in case others had experience. I am intrigued and will try it out.

      Delete
    12. Tanya, I am so glad that I learn new therapies here and I can only thank you for that. We definitely have to go for alternative treatments and actually acupuncture crossed my mind. Please keep bringing up your ideas, it's always interesting to know.

      Delete
    13. Petra, it is very interesting about the dysmorphic features. Before we started the low dose clonazepam and the Diamox, my daughter would often have a similar presentation. Her face would seem wide and features would be fuzzy. We always knew it was increased inflammation, even my husband would look at her and say, "oh, she is inflamed today". During those times, her functioning used to be poor and she would be more withdrawn with a rigid expression and much more prone to meltdowns. I have not seen it at all in over six months since we started the low dose clonazepam and the Diamox.

      Delete
    14. Petra, have you by any chance tried the insulin on yourself? I am keen on trying it for myself as I sometimes get hypoglycemic after prolonged, mentally demanding work.

      Delete
    15. RG,

      Talking about facial attributes, could it not simply be the effect of diuretic on fluid accummulation which might have led to a bloat rather than inflammation...though things are all so intriguingly connected. Inflammation seem to be intrinsic to not only the kids but I am sure we mothers and probably fathers too could do with some anti inflammatory treatments.

      Delete
    16. My understanding is that a lot of inflammation itself leads to fluid accumulation. Moreover, we never had this effect with Bumetanide, though we have been on it for considerably longer.

      Delete
    17. RG,

      Yes, inflammations do lead to swellings/fluid retention. Which amongst the two, clonazepam and diamox, has helped with inflammation the most or is it a combination of both. In fact, I had read somewhere that chronic use of benzodiazepines can lead to inflammatory responses. I do not remember if clonazepam was amongst the drugs studied and you are presumably using very low dose. I ask this because I have been considering using clonazepam low dose for my son for the longrst time.

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    18. I cannot be sure Kritika, since I started the Diamox within a couple of weeks or so after the low dose clonazepam. In my daughter, I find that most of the meds/supplements have cumulative, long term effects. Sometimes its also that I am late to notice. Benzodiazepines at normally prescribed dosages have plenty of side effects. It doesn't seem like we have to worry about any of those at the microgram dose. The .025mg is quite effective for my daughter and I have seen no side effects.

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    19. RG, I only had one spray of insulin, didn't feel anything good or bad.

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    20. About dysmorphic features...
      My daughter used to have that ``sinusitis like`` look after some stressful situations, tantrums, or just after sensory overload. Usually, started after sleep.
      And, yes, she was more foggy in that time.
      I think that has something to do with cortisol and stress.

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  23. 2011 Sep 7;31(36):12916-26. doi: 10.1523/JNEUROSCI.2205-11.2011.
    Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor.

    I also found this paper and thought it may be relevant to discussions here.

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  24. Tyler, I read that citicoline may have an interaction with supplements or medicines that works on dopamine, so I will not mix things up. If I get a good resveratrol instead of NR should be fine? because it is an easier option for me, but i don´t want to change things if it can´t work as good as NR.
    Valentina

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    Replies
    1. No, you want resveratrol for something else. It is complicated but one of the many things resveratrol does is that it accelerates DNA repair which consumes a lot of NAD+. In fact, one of the more popular so-called anti-aging supplements called Elysium is a combination of NR and Pterostilbene (comes from blueberries) which is thought to be better absorbed and more potent than resveratrol.

      So to answer your question, resveratrol on its own is not what you are looking for here, rather you want NR. If all of this advice sounds ambiguous well that is because it is ambiguous, complicated, and I am probably not the best person to explain this stuff in the first place.

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  25. Tyler, completely on a tangent here, when I was at the Mayo clinic last month, I noticed that at least 75% of the people were obese. This included patients and their families and also the doctors. Interestingly, the nurses and technicians were mostly normal. Maybe all the walking, and being on their feet.

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  26. Made a tea from 2 bags of pu-erh earlier, I could swear it feels mildly psychoactive, I found a paper that compared mglur5 antagonists with memantine and they seem to have a partial overlap in effects.
    Will take another tea tomorrow again, also I feel like actually leaving the house on this? very weird, Its obviously too early to say its the tea and could be placebo however instead of obsessing/worrying my mind keeps telling me 'lets go outside and do something'. This was also on memantine that I felt the urge to leave the pc/house and start finding new hobbies, meet new people and do new stuff in general.

    Something weird pherhaps is that I feel LOTS colder and have actually been shivering quite a few times and room temperature has been the same.

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  27. Peter, would you have any explanation why pu-ehr tea might be making me feel so incredibly cold?
    I know it contains small amounts of lovastatin and has an effect on lipid metabolism but I wasnt expecting to feel so incredibly cold due to the tea.

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    1. Aspie1983, pu-ehr tea has numerous constituents. In addition to being a mGluR5 inhibitor, which might make some people feel cold, it contains catechins and caffeine. In China many people drink it to lose weight. Being fermented, I expect the content will vary with age as well as exactly which variety it is. I have some at home brought back from China, but I concluded that it is more a drug than a tea.

      I can see that some people with OCD or other problems might benefit, but some people may need more mGluR5 rather than less.

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    2. Peter whats the rationale by mGLUR5 inhibition possibly increasing cold sensitivity as I never heard of it before.
      Also the benefit allready seems vanished and I was left with aggression/hate :S, After reading up on lovastatin (which is present in pu-erh) I found that statins can induce aggression as early as day1. I just had to take some anti-anxiety tea to calm me down, dont think pu-erh tea is for me.

      Severe irritability associated with statin cholesterol-lowering drugs
      https://academic.oup.com/qjmed/article/97/4/229/1525385

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    3. Aspie, I do not know the precise mechanism, but drugs can have strange unexpected effects that are not always well reported, if they are seen as minor. I think mGluR5 is the main mechanism of action.

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  28. Peter, is the
    Metabotropic Glutamate Receptor 5 ( Pu-erh Tea Protects the Nervous System by Inhibiting the Expression) of the same MGR that would be affected by Acetyl-L Carnitine to alleviate depression? Separately, are any folks using Pu-er Tea?

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    Replies
    1. No, it is a different one, MGlu2 is the one you want.

      L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors
      https://www.pnas.org/content/110/12/4804

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