UA-45667900-1

Thursday, 15 March 2018

PolyPill Updated with Agmatine




After several months of testing Agmatine, including stopping and then re-starting, it is time to add it to my PolyPill.
The idea to trial Agmatine came from our reader Tyler. It ticks all the boxes, it really does have a benefit; that benefit continues for at least several months. When you stop taking it, the benefit stops and when you restart you see the same benefit return. It is safe, inexpensive and widely available if you live anywhere outside the EU. Since it is relatively recent to the market as a supplement, it can no longer be sold in the EU until someone applies for it to be approved; long established supplements bypass this recent legislation.
There were earlier posts evaluating why it might help some types of autism and now there even is one study on an animal model of autism. 





I think the positive effect very likely comes from the vasodilatory effect produced by the increased eNOS, there is also increased BDNF.  This I believe is why it also effective in two models of dementia. Agmatine is also an NMDAR antagonist, like Memantine and this is the mode of action proposed by autism researchers in the animal model above.  My opinion is that at this "bodybuilder's" dose the mode of action is not NMDAR antagonism.




The effect of Agmatine?



The energetic bunny on the left is the one taking 0.7g a day of Agmatine.
In the case of Monty, aged 14 with ASD, Agmatine gives him boundless energy, which in his case is beneficial.
I think the effect will manifest itself slightly differently in different people. In animal models it improves cognitive function.  
If you have autism + ADHD, then it might not be helpful. When I tried it on myself it made me feel slightly nauseous. In Monty's big brother it made him feel "different", but not better or worse and certainly not more energetic.


Other People’s PolyPills
Other readers of this blog have developed their own science-based “Polypill” therapies, for their specific type of autism. What works for my son may not help your child, but other  things discussed in this blog just might help.
High doses of the immuno-modulating Biogaia Gastrus probiotic bacteria clearly help some people greatly; but others get a negative reaction.
Immunomodulation by antibiotic is used successfully by some, but has some drawbacks. 
PAK1 inhibition ticks the science boxes and if you can obtain a potent PAK1 inhibitor it helps some people.

Butyric acid (from sodium butyrate, Miyairi 588 bacteria, more fiber or even rancid butter) is an HDAC inhibitor and is also required for gut wall integrity and likely BBB integrity. It is widely used in animal feed and some humans respond well to it, but the effect is dose dependent. HDAC inhibition can work epigenetically to change the expression of hundreds of "autism" genes, as highlighted in recent research using a potent cancer drug HDAC inhibitor.
Numerous individual amino acids (glutamine, taurine, methionine, aspartic acid etc) seem to help in some people. These tend to be OTC bulk powders like Agmatine.

In a sub-group of people with autism it is clear that digestive issues, unusual gut bacteria or food sensitivity is a major problem that is treatable relatively easily.

People with regressive autism may have (had) mitochondrial disease and this has a very specific therapy to protect from further regression and to allow for remyelination and mitochondrial biogenesis in the short term and hope for neurogenesis in the long term.




31 comments:

  1. Peter here is another tangent to an intervention some people commenting on this blog believe has improved the symptoms of their older autistic children and possibly a mechanism explaining why:

    Press Release:

    https://www.sciencedaily.com/releases/2018/03/180315091253.htm

    Paper:

    http://onlinelibrary.wiley.com/doi/10.1111/joim.12737/abstract

    The research looked at coffee and its effects on the endocannabinoid system as well as the androsteroid system and found that drinking 4-8 cups a day of coffee downregulated cannabinoid signaling and increased the metabolites of androsteroids in urine. Also, in terms of what a cup of coffee happens to be, the researchers don't mean Turkish coffee. Even then, 4 cups of coffee a day to a young child or adolescent has other negatives in terms of caffeine (no idea if decaffeinated coffee has the same effect), but in a teen or adult it might be a different story, especially since it is sometimes more of a challenge to get teens and young adults to reduce their caffeine intake, rather than increase it.

    With respect to autism, as you have pointed out in several other postings about research suggesting a hypermasculine steroid environment in utero leading to some of the noticable phenotypical characteristics of those with autism, so perhaps coffee or whatever happens to be responsible for the androgen dampening effect might improve symptoms in some people.

    As to modulating the endocannabinoid system in autism one way or the another I don't recall you doing a post about this topic before, probably because only recently has strong research in this area been investigated due to the taboo nature of cannabinoid research in the past. I think filling the lungs of a person with carcinogenic burnt up carbon is a terrible idea no matter the substance, but obviously cannabidiol is being looked at seriously by a small but dedicated group of researchers and doctors now for helping with some aspects of severe autism.

    ReplyDelete
    Replies
    1. Tyler, for what I understood reduced endocannabinoid tone with increased dopaminergic activity is seen in hyperkinetic children,so cannabinoid agonists could reduce dopaminergic activity, in theory in my son. You told me about CB2 receptor agonist cayenne, but what about using cannabidiol as CB1 cannabinoid antagonist?
      Valentina

      Delete
  2. There is a relatively famous story about a girl with Dravet syndrome (causes massive seizures) who benefited from a strain of cannabis with a 20:1 cannabidiol:THC ratio. There is a pretty big follow up study to a smaller study going on now showing glowing parental reports going on now and we will just have to wait and see. Cannabidiol is very different than THC and in many ways sort of the opposite in functionality, but that does not mean it should be liberally used yet. I certainly would not give it to my child at this time, especially since my child does not have seizures.

    THC increases dopaminergic tone which is why it gets people "high" so sometimes parents get confused reading about this story and think going to their local pot shop for medical marijuana is going to help their child when in fact it would likely make things a lot worse. This particular strain called "Charlotte's Web" has a relatively low amount of THC and the lead researchers say it should only be considered as a last resort for people with severe seizures and/or autism where life threatening SIB and other problems put those responsible for the person with severe autism in the precarious situation of employing cannabidiol or else using traditional psychiatric medications that have awful long-term side effects. Then again, had I not employed any interventions since my oldest son's diagnosis, I have little doubt he would be in the camp of "severe autism" where he could not be left alone at any time and if in the care of others besides immediate family, the course of treatment would in effect be chemical lobotomy with massive doses of antipsychotics.

    ReplyDelete
    Replies
    1. Tyler and Peter, Iam very interested in adenosine/dopamine interactions, didn´t find the word adenosine in the index.The potencial of this neuromodulator to reduce excess dopamine signaling is very interesting.Could I use adenosine triphosphate as an A2 receptor agonist? D Ribose could also do the trick? Valentina

      Delete
    2. Well, adenosine buildup is one of the triggers for promoting somnolence, which is one of the reasons caffeine helps keep people awake (it is an adenosine antagonist). As for adenosine agonists, there are drugs that exist and new ones in development for a variety of purposes. Naturally speaking ATP which is involved in many cell signaling functions as well as being the end product of the citric acid cycle as it functions like a battery for cellular energy. Nonetheless, you can't just take "ATP" and be supercharged, though some people have take ATP for sports performance reasons, though because it is quickly metabolized to uric acid, it may be the uric acid boosting sports performance not the ATP itself.

      I don't know if D-Ribose would do anything either, but I don't know that much about it other than its relation to Nicotanimide Riboside.

      Delete
  3. Just came across some very promising research that might pan out in 10 years or so (in humans), which involves a very innovative treatment for Alzheimer's disease (in mice):

    Press Release:

    https://www.sciencedaily.com/releases/2018/03/180315130659.htm

    Paper:

    http://www.cell.com/neuron/fulltext/S0896-6273(18)30150-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627318301508%3Fshowall%3Dtrue

    If you read the press release and replace "Alzheimers" with "Autism" you will see the parallels in their efforts at transplanting interneurons (dysfunctional in autism, especially parvalbumin interneurons) with an upregulated sodium channel that Peter has discussed in the past in one of his blog postings. In the meantime, this research at least demonstrates that restoring inhibitory function in interneurons in Alzheimers disease (or lets just say autism for our purposes) via upregulating the Nav1.1 sodium channel (coded by the SCN1A gene) is possible.

    For a description of how sodium channels are important in autism here is a general overview from last year from Spectrum News:

    https://spectrumnews.org/news/distinct-mutations-sodium-channel-trigger-autism-epilepsy/

    ReplyDelete
  4. Also more specific to this post about Agmatine, here is another possible explanation as to how it improves cognitive behavior in some people with autism:

    http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31921-6

    The main takeaway here with respect to Agmatine is these researchers show that in the cerebellum (which seems to be highly compromised in autism) that LTP is initiated by increasing levels of calcium into climbing fiber to Purkinje cell synapses up to a point at which at a certain threshold the synapse changes to an LTP mode which is sustained via nitric oxide (which Agmatine seems to have a lot to do with neurologically). If nitric oxide is production is blocked, then LTD is not sustained and in the cerebellum this is going to cause all kinds of learning problems. Nitric oxide also seems to be important in building up the calcium levels so that this "switch" can occur from LTP to LTD in the first place.

    Also, nitric oxide seems to be most relevant when the calcium signals are weak (i.e. natural conditions) as when they kept adding calcium into the cell past the initial LTP to LTD threshold, LTD would eventually be enacted at the synapse.

    Also, this suggests that if there was not enough nitric oxide being produced, higher stimulation frequencies (greater than 1hz) would be necessary to yield more nitric oxide. This is a bit counterintuitive from my reading as typically in other parts of the brain, increasing the frequency of stimulation yields LTP whereas low stimulation frequencies (1hz) yields LTD. It is also interesting to point out the two most used LTP like and LTD like induction protocols for rTMS use a protocol called intermittent theta burst stimulation iTBS for LTP potentiation and continuous theta burst simulation (cTBS) for depotentiation and iTBS is the same stimulation parameters as cTBS except that after 30 pulses with iTBS, there is an 8 second break in between the next series of pulses, whereas there is no 8 second intermission for cTBS which is hypothesized to fully saturate the synapses with calcium (in essence disabling them temporarily so that cTBS stimulation acts as a virtual temporary lesion).

    Last but not least, presynaptic nitric oxide production depends on functioning cannabinoid 1 receptors (CB1), so one can imagine that if too much nitric oxide or too little is being generated from faulty cannabinoid signaling, you are going to have problems as well. This would suggest each individual is going to have a critical window of therapeutic value for Agmatine depending on all of these factors (this is just my speculation here).

    ReplyDelete
    Replies
    1. First sentence in second paragraph should read:

      "Purkinje cell synapses up to a point at which at a certain threshold the synapse changes to an LTD mode"

      not

      "Purkinje cell synapses up to a point at which at a certain threshold the synapse changes to an LTD mode"

      Basically, I made a typo which could confuse what I am trying to say.

      Delete
  5. Hi Peter and Tyler, thanks for your work on Agmatine. My son's ASD includes regressive type. He does respond to broc. sprouts and I believe cocoavia. I think he has ASD + ADHD -- and NMDA hypo function. Do you think he would not respond to Agmatine? Get too much energy? It seems he has some learning and spatial issues -- would you consider trialing this? What are other considerations? He would take a pill - would the 500 mg be the one to start? Thanks, MH

    ReplyDelete
    Replies
    1. MH, I am using bulk powder, but a capsule will work just fine. I think you just make a trial for a week and then decide if it helps.

      Delete
  6. Peter,

    I think I may have asked this before but please advise (again ?)

    My son has suffered from chronic urticaria since 2016. After two trying years where nothing (Claritin / Loratadine etc) worked, we trialed Montelukast and *knock on wood* it has helped. And his SIBs have gone down (not vaporized completely but reduced).

    My question now is about Verapamil. My son takes 1 mg of Clonidine at night for his sleep issues (Clonidine is apparently a blood pressure reducer) and I was warned against Verapamil as it is also supposedly a blood pressure reducer and both in combination is apparently a strict no-no.

    I really wanted to trial Verapamil before trialing Bumetanide but now it appears that I may not be able to do so as my son is severe ADHD and will not sleep without the Clonidine. I have read online that Bumetanide may sometimes appear to not work unless high intracellular calcium in the brain are first brought down (which Verapamil does).

    In short, the theory is Verapamil -- Bumetanide for max benefit. Did I understand this right ? I understand that you are not a doctor and that you are not giving me medical advise but may I start the Bumetanide without the Verapamil first ? Could Bumetanide still work ? I will be continuing the Montelukast, of course, as that is the only thing that has helped with his hives so far.

    Thanks for any help / feedback you can give me in this regard. Much appreciated.

    ReplyDelete
  7. Here is some more new and very interesting research on beetroot juice as it pertains to Alzheimers disease:

    https://www.sciencedaily.com/releases/2018/03/180320084414.htm

    Of course this is Alzheimers disease, but oxidative stress which is usually an issue with autism for one reason or another may lead to similar pathologies that you find in neurodegenerative diseases like Alzheimers or Parkinsons disease where you have proteins behaving badly.

    In this particular study (no link to a paper at this time), instead of looking at beetroots effects on NOS, they looked at a protein called betanin and concluded it was reducing beta-amyloid aggregates indirectly via measuring a big drop in oxidative stress.

    ReplyDelete
    Replies
    1. Very interesting Tyler. There are some other interesting recent pieces of Alzheimer's research so I will make an Alzheimer's post sometime soon. It is not autism, but it is relevant to developing therapies.

      Delete
    2. Any feedback for me starting bumetanide without Verapamil first, Peter ? Sorry to keep asking, I just feel nervous that we may be screwing up our chances, starting the Bumetanide without the Verapamil, first.

      Delete
    3. GRT, go ahead and try bumetanide without verapamil. Many people now use bumetanide, but only a tiny number use verapamil.

      Delete
  8. I am getting more increasingly interested in Agmatine, but one thing that is holding me back is that it acts as a NMDAr antagonist. At least at some doses. So, my question is if I can use it (maybe at a lower dose) with NMDAr agonizing effects and still have cognitive effects?
    Also Peter, is there any chance that it was the addition of Agmatine that made broccoli sprout powder unnecessary?

    /Ling

    ReplyDelete
    Replies
    1. It is not a strong NMDA antagonist like on the level of Ketamine. Its effects on other receptors are much more pronounced.

      Delete
    2. Ling, one reader commented that he had to keep increasing the dose of broccoli to maintain the effect. I think his current dose after 3 years is 5 times the original dose.

      I did some further trials and I think he is right. I can produce a positive effect, though not as dramatic as at the start.

      Agmatine works very well for Monty. It has no side effects, it is easy to give and it is cheap. After 9 months of use, if anything the effect is greater, it certainly has not faded.

      Delete
    3. Well, I like the 5HT2a antagonistic effect, which is the reason I've started Bacopa (and I think this will in the end upregulate some NMDAr subunits).
      But then we have the inhibition of glutamate-binding to the NMDAr, which probably is bad in my case.
      I also like the alpha-2A stimulating effect at low doses, which might fix yet another SATB2 issue. Seems that high doses do the opposite. Do you think it is this effect that makes the difference for you regarding lower and higher doses?

      The abstract of this very old paper suggests that spermine can potentiate the NMDA current even in the presence of agmatine:
      https://www.ncbi.nlm.nih.gov/pubmed/9918557

      Actually, have we ever mentioned spermine here as an NMDAr agonist? A quick read tells me that spermine is a complicated regulator of NMDArs, maybe concentration dependent.

      Oh no, now I have even more questions than before I started to write this comment...

      /Ling

      Delete
    4. Hi Peter and everyone else,

      Regarding agmatine, I get positive effects from it but the dosing seems tricky, too high doses seems to give me adrenalin like shaky hands (1750-2000mg), 500-1250mg seems to be optimal for me (I weigh 95kg).

      About the sulforaphane/broccoli extract/broccomax, it seems to have a self-regulatory effect on me, as you noticed I used it a few days ago but my body seems to be saying 'nope, no more, you had enough'. Almost as if the intial burst of HDAC-inhibition causes downstream effects to ofset my worries and negative thoughts, helps me overcome them and let go and be free. However repeated use makes me feel like Im not myself? hard to explain so forgive me on that, thought Id share how it makes me feel so some parents can possibly seem some links as it might be harder to observe what it actually does do their kids.

      Delete
  9. Peter, can you explain why you say that you are not sure whether it will have positive or negative effect? "NADPH oxidase and nNOS (Neuronal nitric oxide synthase) redox signaling cascades interact in the brain to affect both cognitive function and social behavior. I am not sure whether Agmatine will have a good or bad effect. " If you have more macroencph. conditions (large head) would this be a factor?

    ReplyDelete
    Replies
    1. I am not clear what your comment refers to. Can you be more precise?

      Delete
  10. Sorry, I had 2 questions in there... and will just ask the first for this comment The article above states that "NADPH oxidase and nNOS (Neuronal nitric oxide synthase) redox signaling cascades interact in the brain to affect both cognitive function and social behavior." Then your article says "I am not sure whether Agmatine will have a good or bad effect. " Peter, Why are you not sure if it would have a good or bad effect. Can you explain this? Sorry if confusing?

    ReplyDelete
    Replies
    1. In my son agmatine has a very obvious good effect in that it increases stamina and exercise endurance. Agmatine should increase eNOS but reduce iNOS and nNOS. Increasing eNOS will dilate blood vessels and so increase blood flow; more blood flow should give more stamina and exercise endurance.

      So my explanation of why Agmatine is helpful in my case is that it improves blood flow. We know from the research VEGF is disturbed in autism and we know cerebral blood flow is different in autism.

      We know that a loss of power (ATP) is a feature of many neurological conditions, so it is not a surprise that it is present in some autism.

      Any reduction in nNOS caused by agmatine does not cause any problems in my case.

      In other people the effect of agmatine changing eNOS, iNOS, nNOS and its other effects may not be the same as in my son.

      If you are a high IQ Aspie who runs marathons, I doubt you are lacking in eNOS. If you are 80 years old with dementia you may well improve with more eNOS.

      Delete
    2. Peter, thank you that was very helpful explanation. My son is athlete (with ADHD and Aspie symptoms) who always seems tired (he has some arthritis symptoms). I had given to him once and he seemed agitated, so don't know if a one week trial would be good given his arthritis (as opposed to lack of energy). Rereading your agamatine posts, it really does seem to affect a lot of areas.. I am taking it and my memory seems better! Any further input would be appreciated.

      Delete
    3. An interesting non-drug therapy for arthritis is vagal nerve stimulation. I was surprised that our reader Nancy is already using transcutaneous vagal nerve stimulation for her son, as directed by the doctor, repurposing an inexpensive device available on Amazon. It is all about damping down the immune response which is often elevated in autism, which is why so many auto-immune conditions such as juvenile arthritis are common.

      https://epiphanyasd.blogspot.com/2017/03/t-helper-cells-in-autism-th1-th2-th17.html?showComment=1529848684500#c6464547300564

      The expensive vagus nerve devices are implanted inside your body, but a nerve in your left ear allows another route to the main vagus nerve. You could also try baking soda which is in this post:-

      https://epiphanyasd.blogspot.com/2018/05/drinking-baking-soda-for-vagal-nerve.html

      It sounds a crazy idea, but the research suggests otherwise.

      Delete
    4. Yes, that seems interesting -- thank you so much! I saw that you couid take a pill filled with baking soda (instead of drinking it) -- do you think that would be as effective? Also, will give baking soda a trial, but weeks after that, would you put agmatine as a possible place in the arsenal with this profile?

      Delete
    5. Very interesting Peter, would you say the effect of bakingsoda could also be due its effect on acid sensing ion channels. Changes in PH can be powerfully anxiogenic for example, just like bag breathing can help stop people hyperventilating.

      Delete
    6. Baking soda in a pill work just the same. I think agmatine looks unlikely to work for your son, since it did not work the first time.

      Delete
    7. Aspie1983, ASICs may well play a role, nobody knows for sure yet the mechanism.

      Delete
  11. Peter,

    Quercetin is pretty unique as a natural molecule that it actually can INCREASE PGE2 (like fever) and inhibit all ASIC's (1-3), bit like how agmatine inhibits ASIC3.

    Now ASIC (ASIC3 in particular it seems) has a connection with parvalbumin and somatostatin which are implicated in anxiety, but also in autism

    The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.

    https://www.ncbi.nlm.nih.gov/pubmed/25937288

    ReplyDelete

Post a comment