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Friday, 9 December 2016

Glutamate Inhibitors to Treat Some Autism and ADHD




 A festive queue at the pharmacy for Glutamate Inhibitors


We have now established that much autism and indeed other disorders, from Down Syndrome to Schizophrenia, features a degree of excitatory/inhibitory (E/I) imbalance.

It is very likely that there are multiple underlying causes for this and so there may be multiple treatments.  We can even potentially use a treatment for one cause (ALS) to improve outcomes in others.  So we can (partially) solve a problem without fully understanding its origin, as frequently is the case in biology.

An E/I imbalance might cause anxiety in the adult with Asperger (treatable with Baclofen), contribute to MR/ID in the child with Down Syndrome and contribute to seizures and cognitive loss in someone with severe autism.

Very interestingly in the comments to a previous post, Agnieszka has pointed out why common penicillin type antibiotics (beta-lactams) improve many people’s autism.  This is very common observation and our other guest blogger Seth Bittker found the same in his son. Nat’s guest speaker at her autism conference also found this in his son.

The Glutamate Transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene.   It is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Glutamate is an excitatory neurotransmitter, so it encourages neurons to fire.

By upregulating the GLT1 transporter you increase the inactivation of glutamate and so shift the Excitatory/Inhibitory balance towards inhibitory.

Agnieszka highlighted this paper from Johns Hopkins:-




Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.



It actually gets more interesting and relevant to treatment.

Mutations in SLC1A2 which decrease expression of the GLT-1 protein are associated with amyotrophic lateral sclerosis (ALS). 

The drug riluzole approved for the treatment of ALS upregulates GLT-1.

This would suggest that Agnieszka, Seth and John Rodakis might want to pay a visit to the pharmacy and pick up some riluzole.  It is certainly worth investigating.

I did check and there is even a trial on Riluzole in autism and evidence of existing off-label use.  They have not of course made Agnieszka’s connection; they seem to be just trying it because nothing else seems to help. That really is trial and error and makes this blog look positively scientific by comparison.
Drug: Riluzole

50mg once daily (QD) for 12 weeks for participants 6-11 years old; 50mg twice daily (BID) for 12 weeks for participants 12-17 years old





A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223 is under development for the treatment of generalized anxiety disorder and mood disorders  by Biohaven Pharmaceuticals.

  
Anyway, are there any other ways to inhibit Glutamate?

Yes, our reader Valentine just stumbled on one, tizanidine, but there are at least two others. 


α2 adrenergic agonists

Three other known inhibitors of glutamate happen to be α2 adrenergic agonists

·        Clonidine

·        Guanfacine

·        Tizanidine


All three of the above are already used in ADHD and sometimes in autism, but not to reduce glutamate.

I wrote a post about Clonidine use in autism a long time ago.



Guanfacine is an ADHD drug known to inhibit glutamate release.



At five sites, children with ASD and moderate to severe hyperactivity were either given guanfacine or a placebo tablet for eight weeks, in a randomized and double-blind clinical trial. The research team collected information from parents and measured each child’s overall response. After eight weeks of treatment, extended release guanfacine was superior to placebo for decreasing hyperactivity and impulsiveness.


Our reader Valentina seems to have stumbled upon tizanidine, but finds it helpful for her son. Tizanidine is a α2 adrenergic agonists but also inhibits glutamate.  It is one of the drugs used off-label by Dr Chez in ADHD and autism




CONCLUSION:


The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.



Conclusion

Ideally you would have a comparison of the four drugs:


·        Riluzole

·        Tizanidine

·        Clonidine

·        Guanfacine


We know clonidine is not an autism wonder drug, but then what is?

I think Riluzole is likely to be a good one, but very likely what works best will vary from person to person.

Perhaps a positive response to beta-lactam (penicillin) antibiotics is a biomarker for people who will respond to Riluzole? It should be.







39 comments:

  1. Peter, you made me laugh with this photo, I am going to ask Baclofen to Santa for Christmas!
    Valentina

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  2. Hi Valentina,
    If you still don't have access to Baclofen, where I live it's OTC and last time I checked 10mg/50 tabs cost something less than 4 euros.
    You could send me your e-mail for details.

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    Replies
    1. Hi Petra, thanks so much,how lucky you are! For now, Tizanidine controls his anxiety very well and sleep improved a lot, it was a grat discovery added to Bacilor. But Baclofen is something I always wanted to try for my son. The great problem I see, is the entrance of medications to the country.
      Valentina

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    2. Valentina, Where do you live where Baclofen is otc? Is there a good pharmacy that you would recommend there? Thanks, MH

      Delete
  3. Hi Valentina,
    You are welcome.
    Since your child responds to antispasmodics, I wanted to ask if you have ever used camomile tea.
    Bisabodol and flavonoids have demonstrated this effect in animal studies. Flavonoids and cumarins are considered smooth muscle relaxants and can have anxiolytic effect, according to Wikipedia.
    There are some drug interactions and when camomile is taken in combination with some drugs there may be exacerbation of effects.
    Baclofen gives some benefit to my son for a few days but then there comes a loop.
    I am having a trial with camomile and thought I should let you and everyone here know.

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    Replies
    1. Petra, Camomile is very interesting, I have used it for my son but not in a regular basis, I will try it again, it is very recommended for its anxiolytic effect. Besides, I saw a study of Jhon Hopkins University about the fungicidal and bactericidal properties of bisabodol.Let me know about your trial.
      Valentina

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  4. Peter, I think camomile exacerbates Low dose clonazepam, so I quitted for a while.
    With Bumetanide he seems ok. As long as we don't have behavioural arousal with this combination, do you think that it might be a problem elsewhere if camomile exacerbates Bumetanide effect?

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    Replies
    1. Petra, chamomile is known to interact with sedatives, blood thinners, antiplatelet drugs, aspirin, and NSAID painkillers.

      Delete
  5. Hi Valentina and all,
    From the very short term chamomile trial, I've concluded that it can be a potent anti-inflammatory drug as I noticed my son acting physically healthy. It can also help with involuntary movements.
    On the other hand, probably due to its binding to Gaba like a benzo, in my son's case, it created more E/I imbalance and didn't help with anxiety.
    I had never expected that an innocent cup of chamomile could create behavioural arousal.

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    Replies
    1. Petra, I am very happy that chamomile has worked for your son. May be it also helps with anxiety, I think involuntary movements have a lot to do with it.
      Valentina

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  6. NAC has also been found to upregulate GLT-1

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    Replies
    1. Thanks Lucia, yet another good reason to try NAC, if you have autism.

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  7. My son is getting better at ceftin ( cephalosporin) antibiotic. Good sleep, good learning and nice boy.

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    Replies
    1. That is great. How long have you used ceftin? How long do you plan to continue?

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    2. Peter would clarithromycin be in this family as well.

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    3. To affect GLT-1 with an antibiotics it has to be in the beta-lactam class of antibiotics, which includes penicillins, cephalosporins, monobactams, and carbapenems.

      Clarithromycin is a macrolide antibiotic, so apparently not a beta lactam.

      http://www.emedexpert.com/lists/antibiotics.shtml

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  8. The first time I gave it 7 days. The doctor said bronchitis. I saw Wow. And it wasn't bronchitis, I think. Later, I twice gave ceftin. 14 and 28 days. And every time son had improved. I'd like to try now Ceftriaxone. I think beta-lactam antibiotics help GLT-1 transporter.

    http://onlinelibrary.wiley.com/doi/10.1111/jnc.13200/full

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    Replies
    1. You can achieve the same effect on GLT-1 using riluzole or bromocriptine. Riluzole looks better and is available as a generic.

      Delete
    2. Could you tell us if your son kept the gains how much did you dose how old is your son.

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    3. Hi
      What is the dose of certain? What exactly is the wow factor? Behavior, speech? After stopping ceftin the effect is still there? What he learned is still there? Thank you.

      Delete
  9. In my country, riluzole is not registered. :(

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  10. Write about the first time the antibiotic.
    The effect remained after cancellation, but something was missing. My son couldn't sleep from 16 months to 42 months. I could spend hours sleep. On the antibiotic he immediately began to sleep well. Fell asleep at 9pm and slept until 7am. He was no longer ADHD. Began to say the word "no" . Praised by teachers in the classroom. After discontinuation of the antibiotic, he again became ADHD. A good night's sleep forever. Verbal skills slow, but improving. Sorry if I wrote bad, English is not my native language.

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    Replies
    1. You might want to consider guanfacine in the above post, which was shown effective in autism with ADHD. The effect may be similar to the beta lactam.

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  11. Hi all,

    Thought I'd leave a comment here after a report of my previous very positive experience with cordyceps militaris, which gave me a strong sense of calm, focus and kindness to others and allowed me to be emotionally open to social stimuly instead of having an aversion to it.

    I have looked deeper into what might have been the reason why cordyceps does this so powerfull for me, even gave me a more positive response than NAC honestly (which allready has a striking effect on me).

    It also seems to completely annihilate any irritability that I have in daily life, but it required consistent somewhat higher dosing than recommended for and these 2 papers that I link below gave me insight in the reason why:

    This paper has only been published very recently, and shows that cordyceps (through cordycepin) lowers glutamate (high in autism in most brain areas), lowers acetylcholine (supposedly high in aspergers), increases GABA and increases 5ht (thats serotonin).

    'Extraction methods and sedative–hypnotic effects of polysaccharide and total flavonoids of Cordyceps militaris'

    http://www.tandfonline.com/doi/full/10.1080/13102818.2017.1336942

    ______

    On top of that it also improves sleep:

    'Cordycepin Increases Nonrapid Eye Movement Sleep via Adenosine Receptors in Rats'

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655593/

    ReplyDelete
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    1. What dose of Cordyceps do you use?

      Delete
    2. I was taking 2x 3grams a day, in the morning on an empty stomach and usually around 2pm (around 2 hours after lunch).

      I found it was not sedating at all, but it definatly gave me a serene calmness and allowed my thoughts to go more naturally.

      I was using the cordyceps militaris version by the way.

      I found the feeling to be very unique and fast acting (it was felt after the very first dose) and it did not seem to lose efficiency over time. However if I forgot to take a dose or took a weekend off, I notice a slow decline back to my default 'autistic self'.

      I will definatly try it again soon.
      The effect does feel different than that of lets say broccomax (sulforaphane) and NAC, who felt somewhat energetic/anti-fatigue.

      Delete
    3. Forgot to add to my last reply, what I found so unique and striking is that cordyceps militaris made me WANT TO BE SOCIAL/AROUND people, NAC and broccomax and no other substance/meds I have used have gave me this effect.

      I strongly believe it has powerfull immune modulation effects that atleast in my own biochemical make up seems to cause alot of drastic improvements.
      Once again the effect is very very very fast acting, im talking within 10minutes of taking first thing in the morning I would feel a sense of relieve of no longer having to carry the weight of the world on my shoulders.

      Also I seemed to easily be able to 'let go' of stressors, where by my normal mental state Im persistent and this exhausts me and frustrates me (to the point of obsessions).

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    4. There is a lot of contradicting infor about Cordiceps. It upregulates pretty much all pro-inflammatory cytokines: TNF-alpha, IFN-gamma, IL-1beta, IL-6, IL-8, IL-10. Yet some literature says that it is anti-inflammatory. It contains tryptophan, which may be the reason why you feel so social on it. Have you tried tryptophan on its own?

      V

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    5. Fascinating! Thank you so much for posting about your experiences Aspie1983.

      Components from Cordyceps have multiple pharmacological activities and many of those could have beneficial effects in autism.


      DIRECT ANTIDEPRESSANT/STRESS-REDUCING EFFECTS:

      Its antidepressant‑like effects are associated with not only the modulation of dopamine, but also the regulation of 5-HT.

      “COR remarkably improved depression-like behavior in CUMS mice and its antidepressant activity is mediated, at least in part, by the upregulating BDNF and downregulating 5-HT2AR levels and inflammation”



      ANTI-INFLAMMATORY, IMMUNOMODULATORY & ANTIOXIDANT EFFECTS:

      … downregulates the activity of cytokines, especially inflammatory cytokines and chemokines.

      … suppresses the LPS-induced activation of the NF-κB pathway.

      … inhibits pro-inflammatory iNOS protein and reduces the expression of COX-2

      Cordyceps militaris Attenuates LPS Induced Inflammation in Microglia Cells: https://www.ncbi.nlm.nih.gov/pubmed/26197508


      PROTECTION OF GUT BARRIER

      (btw levels of bacterial toxins in the blood correlates with severity of autism symptoms)

      "…C. sinensis has gut barrier-protection effect in endotoxin-induced sepsis by promoting the proliferation and inhibiting the apoptosis of intestinal mucosal cells, as well as restoring the TJs of intestinal mucosa. C. sinensis may have the potential to be a useful adjunct therapy for sepsis.


      ANTI-FATIGUE EFFECTS:

      "Cordyceps militaris Improves Tolerance to High-Intensity Exercise After Acute and Chronic Supplementation."

      "CM administration increased ATP levels and antioxidative enzymes activity and reduced the levels of lactic acid, lactic dehydrogenase, malondialdehyde, and reactive oxygen species.
      …CM-induced fatigue recovery is mainly through activating 5'-AMP-activated protein kinase and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways and regulating serum hormone level."

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  12. After doing some more research in my dramatic positive response to cordyceps I have found the following paper:

    _______

    Adenosine and Autism: A Spectrum of Opportunities

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529135/

    "For instance, adenosine, through A2 receptors (and possibly by coactivation of A1 and A2 receptors), reduces perseverative behaviors in rodents (Poleszak and Manuta, 2000; Tanimura et al., 2010) and could aid with this core symptom in ASD. In a parental survey-based study, conditions and events known to or hypothesized to increase adenosine (e.g. fever, high-intensity physical activity, very low carbohydrate diet) significantly improved autistic behaviors, particularly in Asperger’s and verbally-fluent individuals (Masino et al., 2011a)."

    It seems that adenosine is possibly also at play in the improvement we see during fever in individuals such as myself.
    Now, sulforaphane (broccomax I was taking) benefits me alot socially and helps with inflammation, would kids/people who benefit sulforaphane possibly also reap benefits from cordyceps/adenosine agonists/adenosine re-uptake inhibitors?

    If so, how would stacking both sulforaphane/cordyceps work out.

    Funny btw now that I read the paper it clearly says 'particularly in Asperger’s and verbally-fluent individuals', it was so obviously to me anyway when I was taking cordyceps as it has such a pronounced effect on me (I was diagnosed with Aspergers/PDD-NOS) that I just knew deep down inside this could impossibly be placebo.

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  13. Seems theres quite some people on other autism forums having success both cordyceps, cdp-choline and chinese skullcap.
    Allthough cordyceps gets listed as anti-inflammatory there it feels to me as it restores gut-brain axis connection (possibly through immunesupression/modulation:




    http://www.autismweb.com/forum/viewtopic.php?f=4&t=18276&start=200#p225346

    http://www.autismweb.com/forum/viewtopic.php?f=4&t=34583

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    1. Hi Aspie1983,

      I’m looking into Cordyceps for my 4 year old son. He’s more on the severe side of the spectrum. Do you think it would still be effective? Would you have a suggestion for dosage (he’s 17.9 kg)? Thanks!

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    2. Hi Jolone,

      What was your son diagnosed with? Autism is such a broad term these days, I know that Peter is also aware of this and probably fully agrees with me that a more proper approach in the future for science would be treatment dependant on symptoms.

      After all the behaviour and symptoms they display are a reflection of what is really going on inside.

      I can only say personally it has worked for me:
      34y old male, aspergers, high functioning, used to have a strong lack of social insight and definatly score low on empathy (I still would score probably quite a bit lower on the EQ scale, though I have definatly experienced love and have been in love a few times in my life), semi-thirsty around the clock, used to have stomach problems (stomach upsets, bloating after eating), repetitive behaviour, restrict interests, inability to adapt to change and always pre-planning in my mind.

      With doses, I have used 3-6grams, the recommended dose on the bag where it comes in is 1.5grams a day, but I found myself re-dosing this more often and increasing my doses (probably a good indicator I actually liked the effect?)

      It seems pretty save and if you have read my other posts about it has indeed a huge range of benefits for atleast my subtype.

      If you decide to try it I will start off very low, as low as 500mg, this is also considering his weight.
      The smell of it is actually very pleasant, however when mixing it with water it tastes like how it smells with the addition of an earthy/soil like hint, you can always buy a capsuling machine so it will be easier for him to take it.

      This is the product that worked for me:
      https://www.amazon.co.uk/Real-Mushrooms-Cordyceps-Mushroom-Extract/dp/B01BH281W8/ref=sr_1_1_a_it?ie=UTF8&qid=1508570683&sr=8-1&keywords=real+mushrooms+cordyceps

      Im sure there are more that works, but real mushrooms seems to have a very good reputation, the representative of the company also gives detailed explanation on how they test their products and all on reddit.

      Make sure you give him it on the empty stomach by the way, I was taking it first thing in the morning and another dose between lunch and dinner.

      Delete
    3. Just found yet another paper showing the potential of cordyceps and once again confirming its unique properties:

      highlights:
      * Non-Cyclosporin immunosuppressive compounds found in Cordyceps
      * acts as an immunosupressant when the immunesystem is overactive, yet has immuno enhancing properties when underactive, seems it thus has adaptogenic properties for the immunesystem.
      * But Cordyceps is not by any means only an immune suppressant. It has also has been shown in many studies to increase immune function as well as suppress it.
      * This Oriental medicine, so perfectly typified by TCM, is really the result of thousands of years of observation. And people are good observers. They are especially good observers about important issues such as health.
      * The toxicity of Cyclosporin is high and many patients suffer from serious kidney damage related to the use of Cyclosporin. In 1995, a study was undertaken in China, where 69 kidney transplant patients were given either Cyclosporin alone, or in conjunction with Cordyceps sinensis at 3 grams per day. After 15 days it was clearly evident that the group receiving Cordyceps sinensis in addition to the Cyclosporin had a much lower incidence of kidney damage then the group receiving only the Cyclosporin, as measure by the levels of urinary NAG, serum creatinine and blood urea nitrate. (Xu et al 1995)

      You should read this:
      http://www.earthpulse.com/cordyceps_inc/cordyceps_story.pdf

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    4. Hi Aspie 1983,

      Thanks for your reply. As Tyler mentioned in a recent comment on a different post, sharing your experiences is incredibly helpful. I think I can speak for everyone in saying they are very much appreciated.

      You’re right, Autism is such a broad term these days. My son was diagnosed at 18 months with “severe autism.” That’s basically all I was told and given some general information to read. Fast forward to now, I would say he’s still on the severe side since he can only say three words at a time with prompting, still drinks from a bottle, only in the past year has been able to eat table texture food (limited at that), and is not potty trained.

      I am in the process of trying to get lab work done on him, so I don’t know anything about that yet. The problem is I am afraid he will hurt himself getting his blood drawn. He is big and strong for his age, and at age 3 it took me and a male nurse to hold him for a blood draw. I fear it will be way too traumatic for him. Of course I have asked if I would be able to give him something to have him stay calm, but I was told no. There are toys there that can “distract” him. 🙄

      Anyway, thanks again for providing information and insight for parents who are trying to their best for their kids.

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    5. Jolene, I think blood draws are worse for the parent watching (or holding) than for the child. It is soon forgotten by the child.

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    6. Jolene, what calms your son down? make sure he is in a calm state before getting his blood drawn, and if possible let him know when its over that hes getting a reward, something he likes.

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  14. I have an 5 year old son who is ‘on the spectrum’: he is verbal and very smart (no cognitive impairment). Some people may call it a heavy kind of ADHD; GI issues and allergies are under control (with biogaia and quercetine - thanks to Peter and his blog!!! he is not doing well with NAC, Carnetine and i think zinc makes him more active over time); when he was younger he had lots of muscle twitching during the night (probably myoclonic??).
    We tried Bumetanide which helped him immediately (within the first dose of 0,5 mg) with irritability.
    As the hyperactivity and impulsivity became a serious problem at his mainstream school, we tried intuniv (guanfacine) and stopped the bumetanide for now because of blood pressure issues (till he is used tot the intuniv).
    The very first dose stopped all the hyperactivity, impulsivity and verbal stimming (before he was doing this the whole day). All his problems seemed solved for now. As the half life time of intuniv is very long (20 hours) I became curious how long it would work: it helped even the second day especially in the first part of the day. Of course we hope this could help him for a longer period (I think stimulants would never been an option seen his ‘myoclonic tendencies’).
    On the internet I read lots of story’s especially from younger kids, where the intuniv stopped working over time, as it is the same with clonidine. So the question which raises is: could it be helpful to give him the intuniv just every other day and stop with it in the weekend? Could this help to benefit over a longer period?
    I would be very grateful if you would let me know what are your thoughts on this!

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    Replies
    1. Receptor agonists like Intuniv/Guanfacine bind to a specific receptor and trigger a response. After a long time the receptor may lose its response, or need a higher dose. I think the best thing is to use the absolute minimum dose to give the effect you want and take breaks. The weekend may not be long enough, perhaps give it a break in the school holidays.

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