Our reader in Canada, AJ, did highlight a case series from Norway that showed that high dose Betaine/TMG was effective in improving functioning in people with autism due to creatine transporter deficiency. The use of Betaine/TMG was really just stumbled upon and the authors considered what the beneficial possible mode of action could be.
Betaine (TMG) and Gene Therapy as potential alternatives to Bumetanide Treatment in Autism?
The effect was only present at high dose (7-10 g a day) not
the much lower dose used by some DAN/MAPS doctors, who do prescribe TMG and the
closely related DMG.
The paper suggested that one possible effect might have been
lowering chloride levels within neurons.
This is also the effect of Bumetanide.
AJ suggested that Betaine/TMG might be an alternative to
Bumetanide and one that does not need a prescription.
Our reader Nancy reported a benefit in her adult son.
The question is not whether or not high dose TMG is a
useful therapy, we already know that it is, in some cases. The question is
whether it is a bumetanide alternative.
My conclusion is that high dose TMG does not seem to be a
bumetanide alternative. If it was an
effective alternative then I would be suggesting everyone using bumetanide
should go and buy some.
I did try TMG for s couple of weeks and did not see any
additional effect over the continued therapy of 2mg of bumetanide. In our case there is a benefit from
additional bumetanide/Azosemide. If TMG shared the same mode of action as
Bumetanide then 7g TMG + 2mg Bumetanide should show some improvement over 2mg
Bumetanide. It did not.
There is a long list of other modes of action to explain
why Nancy’s son and the two Norwegians improved.
Low
dose Ponstan for sound sensitivity
Low dose Ponstan (Mefenamic Acid) was proposed as a
treatment for sound sensitivity. Within
Europe it seems that Greece is the place to buy Ponstan; it is sold OTC and
cheap. One pack (15 x 500mg) costs less
than 2 USD/EUR.
In some people the effect of 250mg lasts all day, while for
others it lasts for a few hours.
Ponstan is also widely used as a syrup to reduce fever in young children (antipyretic).
In the US the common brand name is Ponstel, but the price is
dramatically higher.
Galavit
+ Cromolyn Sodium
The combination of the common mast cell stabilizer Cromolyn
Sodium, used by many readers, with a Russian drug called Galavit is used by at
least two readers. Dragos recently told us that the combination has put an end
to his adult son’s aggressive behaviors.
Galavit has multiple anti-inflammatory modes of
action. It is not a mast cell stabilizer
like Cromolyn Sodium.
Galavit is not expensive, but may hard to get hold of.
It does look like there is an overlap between responders to Verapamil and responders to Galavit. So, if you respond well to Verapamil but get one of the rare side effects, like Maja’s daughter, it might be worth investigating further.
Humira
Humira is a TNF alpha inhibitor
normally used to treat auto-immune conditions like rheumatoid arthritis, Cohn's disease,
ulcerative colitis, psoriasis and juvenile arthritis.
I was recently contacted by an Aspie
lady with auto-immune conditions, who found Humira not only controlled those
conditions but moderated her autism symptoms, notably sound sensitivity. One injection produced a benefit that lasted
7 weeks.
Kanner’s subject #1 went on to develop
juvenile arthritis and this made his autism much worse. There was no Humira back in his day, but his
arthritis did respond to treatment.
Apparently, many children with autism and GI problems are taking Humira.
IVIG seems to be the “go-to” therapy
for immunomodulation in autism. It is now
quite commonly used in the US, but much less so elsewhere due to the cost.
I wonder if Humira might be an
alternative for some?
HMB
(β-hydroxy-β-methylbutyrate)
Our reader Natasa did mention the sports supplement HMB to
me.
It has many interesting modes of action and it is a
precursor to the ketone BHB, which has been covered in great depth in this
blog.
Ketone Therapy in Autism (Summary of Parts 1-6)
In Europe ketone supplements like BHB fell foul of the
rules on supplements and have been banned. In the US they are widely sold.
If you want to try BHB, by cannot buy it in Europe, you might want to look into HMB (β-hydroxy-β-methylbutyrate).
Cetirizine for Palilalia/Scripting
I am a big fan of the OTC
antihistamine Cetirizine/Zyrtec and I was interested to read the recent comment
below about its effect on one 12-year-old boy.
“I realize this is 5 years old, but as a
result of this blog, I tested cetirizine on my 12 yo yesterday. He has a
nonstop palilalia (obsessive speaking that is nonsense or only makes sense to
him). It's his "chief feature" and inhibits social development. For 4
glorious hours, it went away. Today, I gave him 5 mg of Zyrtec again. Yet
again, the palilalia went away, AND he had strong focus on school (he has
serious attention issues).”
Many
people’s autism gets worse when auto-immune conditions flare up. In some cases, the auto-immune condition is
very mild, but the consequences are not.
For one person the result is aggressive behavior, while in another it is
talking nonsense.
Hi Peter. I was reading about a certain drug CLP290, which is supposed to increase KCC2. There seem to be a couple of rat studies on this, but it seems far from human use. If this comes to the market, this could be the holy grail we have all been searching for. Any idea if there is any ongoing effort to get this approved for human use ?
ReplyDeleteCLP290 was being developed by a Canadian company called Clor ion Pharma, that was looking to treat neuropathic pain, hence the target of KCC2. They went bust a decade ago.
DeleteCLP290 is still used in research studies, like this one from Boston Children's Hospital.
DeleteParalyzed mice with spinal cord injury made to walk again
Small-molecule drug reactivates dormant nerve pathways; could complement regenerative strategies
https://www.sciencedaily.com/releases/2018/07/180719142035.htm
In the case of my son, the constant allergy and inflammation do not allow the medications to act, at first I could see an unexpected calm with the NAC, I keep trying to put the puzzle together, your suggestions will help me a lot
ReplyDeleteMelisa
as a responder to the cromolyn galavit combo, my daughter is sort of a verapamil responder for 3-4 days and then it does a u turn and makes her worse than she ever was.
ReplyDeletePeter, sometimes I find that its best to think that maybe two differing truths can both be true at the same time - the high dose TMG might not work ON TOP of the bumetanide because a) bumetanide may have in some way affected its uptake and b) maybe the TMG has a glass ceiling it can’t cross, which you have already reached with bumetanide so you can’t see any additional improvements?
Anything is possible. In many countries TMG is easy to buy as a bulk powder and it is OTC. For anyone with a learning disability it is certainly is worth a two week trial. It is a white powder that easily dissolves in water, with no apparent negative effects.
DeleteI was considering it as a possible add-on therapy for bumetanide. In that application it did not help.
I'm the parent of the 12 year old. We're on day 10, and the impact of 5 mg of Cetirizine/Zyrtec once a day is still astounding. The non-stop chatter just fades out within 30 minutes of the 5 mg. Conversation is more cogent and complex. He exhibits more initiative (gets his own snacks, tries new things) and haha! more verbal rebellion/arguing, which we view as a huge positive! We're getting a solid 4-6 hours from one dose, and about to test giving 2 doses/day. I've combed over your blog, Peter, to see what else we can reasonably experiment with before needing a dr's prescription. I wish I could get Bumetanide! Thank you so much for all the work you've put into your blog. It's unlocked something crucial in my son that we've spent years trying to figure out.
ReplyDeleteThe next step would indeed be Cetirizine twice a day. People with mast cell disorders are taking high doses of antihistamines, without problems. Good luck with this.
DeleteYou could also see the effect of a first generation H1 antihistamine given at bed time. Cetirizine is designed not to enter the brain (to avoid drowsiness), you may get a benefit from an antihistamine that does cause drowsiness.
If you don't want to go the drug route, I believe quercetin is also a good mast cell stabilizer. There was a paper(if I recall correctly) that claimed quercetin was superior to cromolyn sodium.
DeleteThank you. I'm circling back because we increased his Cetirizine dose from 5mg/day to 15 mg/day (10mg morning, 5 mg afternoon) and all the scripting/pallilalia came back. :( Currently titrating, but this feels much like other supplements/meds: we get 2-3 weeks of measurable improvement, then a dimmer switch slowly fades him back to baseline. We haven't tried H1 like Benadryl because his sibling has an anaphylactic reaction (how weird, we know, but it's documented). I am wondering if anyone has experience like this, and what might be a next step? We have a doctor who is open-minded and I'm wondering if Verapamil or bumetanide would be a good next step.
DeleteIn some people when a drug is given to block a receptor, like you are blocking the H1 histamine receptor, the body reacts and just produces more of those receptors to counter the effect of the drug. This might be happening in your case. I would then move on to a mast cell stabilizer. This actually reduces the amount of histamine that is produced. This means less activation of the H1 receptors. So you may end up with the same as the initial good effect of cetirizine. Ask your doctor about oral Cromolyn Sodium.
DeleteVerapamil may also be effective, but your doctor may not want to prescribe it.
Bumetanide is very different. It is effective in about a 1/3 of autism and the biggest effect is in severe autism with ID. It is well worth making a trial of bumetanide, but the effect can take 2+ weeks to show effect. Any active inflammatory condition can block the effect of bumetanide. So first try Cromolyn Sodium or Verapamil.
Thank you, Peter! Would nasal spray Cromolyn Sodium work?
DeleteGood question.
DeleteYou can buy cromolyn sodium as a nasal spray, eye drops and oral capsules. Some versions are often OTC, depending on the local rules.
If it is easy to get the nasal spray, then go ahead and make a trial. If it does not help, try the oral version.
I am using an intranasal mast cell stabilizer (Azelastine/Dymista) in addition to cetirizine in the allergy season, plus year-round verapamil.
You could also see if Quercetin provides any benefit. It is cheap and OTC.
There is also Rupatadine, another mast cell stabilizer taken by mouth.
hi peter, I'm the parent of the 7 year old boy.Do you think if we use cromolyn sodium as nasal spray, we dont need oral version? do both will be harmful?
Deletebefore we trial bumetanide,would you suggest how long we have to gv cromolyn sodium ?
thank you
Becky, cromolyn sodium, like other mast cell stabilizers, can be very effective to treat specific conditions. People with autism often wait many years to get treated for mast cell activation; many probably never get treated. In these people it is usually oral cromolyn sodium that is the most beneficial.
DeleteIn people with a nasal allergy, the nasal spray should be used.
Mast cell stabilizers often take a couple of weeks to show their effect.
All drugs can have side effects, but most people who benefit from mast cell stabilizers tolerate them well.
In a child with mast cell activation, you need to treat that first before trialing autism interventions like bumetanide. Inflammation itself can mask or reduce the effect of these autism therapies.
In theory, your doctor should be able to diagnose and treat mast cell conditions. It all depends where you live and how well informed your doctor is.
Only a sub-group of people with autism have mast cell conditions. Other people will receive no benefit.
Peter,any recommend doctor in US who well informed for treat mast cell condition ?
Deletei already try neuroprotek almost 6 month,no negative or positive effect.
i read your post about about some of autism kids easly get cold in hand and feet.do you know why? and how to treat it?
until now my son can not tolerate fasting,he eat almost every 1,5 hour ( 6-7 times / day)
thank you
Becky, the best informed doctor in the US is probably Dr Theoharides, the inventor of your Neuroprotek. Write to him and tell him your experience and ask what to do next.
DeleteCold hands and feet seem to affect the majority of autism, even mild autism. This could be caused by poor circulation, low levels of iron, being hypothyroid or some other issues. I think most people never resolve the cause.
Over-eating is definitely a clue worth investigating. Some single gene autism cause this, but many other causes are possible. Good to see a pediatric endocrinologist, because this might be treatable.
hi peter, after 3 weeks takes cromoyln sodium, yesterday i start giving bumetanide ( 0,5 mg )
Delete- 45 minutes after that, he go to toilet every 20-30 minute for urinate.
- this symptom goes away about 4 hour after taking bumet
- he seem more calming,more bubbling, but
today he hiccup about 5 times / day ( after drinking water , the hiccup goes away) do you ever experience with this symptom ( hiccup) ?
during the day i try give pottasium citrate 3 times / day ( each doses about 200 mg)
do you think he lack of pottasium ? please give me your opinion, Peter? thank you
Hiccups are not a common side effect, but it is possible. The only way to know if there is an electrolyte imbalance is to have a blood test. After a week or two it is a very good idea to check potassium, sodium etc. Then you know for sure that all is OK.
Deletepeter, based on your experience, how long will the effect diuretic ( bumetanide) gone? i mean our body will adjust,right? how often you ussually do a blood test ( check pottasium,sodium, electrolyte) thank you
DeleteI would test electrolytes after 7 to 10 days to see what the new stable level is. Since you are giving extra potassium you would expect a normal result. Only in about 10% of cases do you need greater supplementation of potassium.
DeleteHi Peter
ReplyDeleteThinking of trying NAC for my son, he`s 7 years old, what sort of dose & type would you recommend?
Ross, I think you will only have the option of the 600mg NAC in gelatin capsules. I would start with one capsule to check it is tolerated; a small number of people have a sulphur allergy.
DeleteAssuming all is well, I would suggest you try one capsule 3 times a day. The effect of NAC fades away after about 4 hours, so you need to spread it out to give its effect over the waking hours.
Cetirizine/Zyrtec is here Reactine. I bought it to try for my 10-year-old daughter in syrup form, but I am worried because I read that it should be avoided in epilepsy. My daughter does not have epilepsy, but I know that in adolescence, children with autism are more prone to it. Peter it is good idea to try Reactine in the morning and Claritin in the evening! Thank you.
ReplyDeleteClaritin and Reactine/Cetirizine/Zyrtec are both second generation antihistamines and so they do not cross the blood brain barrier.
DeleteThe first generation antihistamines (plus Ketotifen) cross the blood brain barrier and that is why they cause drowsiness. The plus factor is that these antihistamines have numerous secondary effects that can be helpful inside the brain.
Clemastine can have a positive effect on myelination and on calming the microglia in the brain. Some antihistamines increase appetite, while others reduce appetite. Some antihistamines are effective as mast cell stabilizers, Ketotifen is a good example.
A lot depends on what you have available to you.
I would think for Claritin and Reactine, it will be the case of either/or, just see which works better.
A second antihistamine should have different properties to the first one, for example using Clemastine or Ketotifen.
It is a question of trial and error to see what is beneficial in your specific case.
Peter, I notice that Clemastine is not available anymore or there is acute shortage. I checked in multiple countries. Any idea why ?
DeleteClemastine is often out of stock, it is not widely used.
DeleteLook under the names Tavegil and Tavegyl. I found it in stock in Europe.
I wonder if betaine also stabilizes the cell redox status? I know there is an article on here talking about oxidative stress vs. reductive stress and how they may both be implicated in autism. TMG/Betaine is a methyl donor, which according to some researchers (https://pubmed.ncbi.nlm.nih.gov/11348555/), is a protective agent against reductive stress among other compounds like SAM-e, L-carnitine, and phosphatidylcholine. Possibly another helpful mechanism at play? Maybe it could be helpful to increase intake of choline-rich foods alongside antioxidants to avoid reductive stress?
ReplyDeleteOur bodies naturally produce ROS (reactive oxygen species) and have complex systems in place to neutralize them and maintain a balance/homeostasis.
DeleteIf there is too much ROS you are in oxidative stress.
If the body’s antioxidant defences have gone too far you can end up with reductive stress.
The following paper is very good, but does go into a lot of detail.
Reductive Stress in Inflammation-Associated Diseases and the Pro-Oxidant Effect of Antioxidant Agents - PMC (nih.gov)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666780/#!po=20.1807
It points out that over-use of antioxidants in people not needing them, may lead to reductive stress.
The point is that antioxidants like NAC are only beneficial if you have oxidative stress, which you can actually measure via the ratio GSH:GSSG. Healthy young people should not need antioxidants. People with a chronic condition like autism and indeed nearly all older people are likely to be in some degree of oxidative stress.
People with cancer should not take antioxidants or anything to activate Nrf-2, because this will help the cancer cells grow faster. Older cancer-free people can see considerable benefits from taking antioxidants. A good example is people with insulin-dependent diabetes.
Some people with autism have a negative reaction to antioxidants. In the case of NAC, this might be an allergy to the sulfur it contains. But if you also react negatively to other antioxidants like vitamin E or C, something strange must be going on, like reductive stress.
As your paper points out, you can measure reductive stress, they suggest the NADH:NAD+ ratio. But you can also use GSH:GSSG.
If you do indeed have reductive stress, then carnitine, TMG etc should be helpful. This could indeed explain the high dose TMG responders.
Hi Peter, I want to let you know that we are getting better and better. found something extraordinary for Denis, and probably for many children with mastocytosis, it is called hydroxyzine (antarax), this drug is a miracle, it sleeps very well, the face is clean, improved communication, no longer stays in his room, sits outside or on the terrace all day.It seems that Enterosgel opened the pandora's box, I think it eliminated something (mercury, aluminum,) and the body woke up alive, candida is present (I had a very strong rash on the face and scalp, with white tongue and bad smell ), a cold or a sore throat woke up, the problem is that now I see that we can approach each one, but we see that the body started to fight and made our temperature high (I haven't seen this in a long time) , we will start treating candida, do you have any idea what is better and not toxic Peter?
ReplyDeleteDragos, great news.
DeleteYour Hydroxyzine is the original drug that was developed into the modern Cetirizine. 25mg of your drug 3x a day equals 10 mg Cetirizine once a day. Hydroxyzine is sedating and Cetirizine should not be.
For candida. Diflucan and Nystatin are both widely used.
What dose are you using Bugo?
DeletePeter, hydroxyxine apart from being an antihistamine behaves like a ssri, Denis is not sleepy at all, has no fog on his eyes, and does not sedate him, does not give him any appetite, practically goes to bed alone and sleeps until 9 in the morning, I tried cetirizine in the past, but after a dose, the next day it became aggressive and the appetite was great, for us it didn't work, we don't know why, as with nystatin it was very aggressive. that we have been fighting an aggressive candida for a long time, diflucan I have not given so far, I see that it has a certain toxicity on the liver but I think I will take a calculation, it has some new ticks, it fills the cups with water and throws them around He was playing with water when he was little, and he started spitting very badly.
ReplyDeleteDragos, you are lucky there is no sedation. Cetirizine will not affect anxiety because it does not enter the brain. So you have antihistamine effects plus serotonin antagonist from one drug , very good.
DeleteHas the enterosgel brought on the candida problem?
There is also Miconazole for candida in the mouth. It seems less toxic than the others. You could also spit it out rather than swallow it. All depends where the candida is growing.
Peter, I think the removal of the heavy metals was done by the enterosgel, candida was there for a long time but now it probably looks more pronounced, it is possible that its restrictive diet came from this mushroom, I don't think it's just in the mouth, I think is it systemic, do you think miconazole can cover the same as diflucan? I see that miconazole is less toxic.I also ordered Biocidin LSF to see if it works, but the plants do not seem to have the effect that the drugs have.
ReplyDeleteI suggest you consider a chlorhexidine-containing mouthwash (only sold at a pharmacy). This will kill candida in his mouth, with no possible damage to the rest of him. This might be all you need.
DeleteSome people with autism react very badly to just candida in their mouth. This can come from using a steroid asthma inhaler incorrectly, or even a supplement that is contaminated (this happened with Lion's Mane for example).
We all have some candida on our skin or elsewhere, when mucosal barriers are disrupted or the immune system is compromised it can get out of control.
Peter, I found something for candida that is not toxic, it's called lefenuron, do you think it could be a better alternative to azoles ???https://www.drmyhill.co.uk/wiki/lufenuron_-_a_potentially_useful_treatment_to_treat_candida
ReplyDeleteDragos, this is a drug used in cats and dogs.
DeleteI would stick with well known human treatments, where the side effects have been well monitored.
Dragos, i have been using some oils (Pau D'arco, Olive leaf extract, Lomatium) from Brainchild company, but think they are weak generally to eradicate candida overgrowth. I am just reading book called "Gut" by Dr WIliam Davis, it mentions Candibactin Ar and Br which were shown to be as potent (if not more) than strong antibiotics like Rifaximin, but not sure if i can punch capsule to mix with water to give as these oils can be strong and damaging if not diluted properly.
Deletei am planning to do repeat test (usually due to GI profile from Doctor's data) then perhaps consider those canbactins.
Peter, take a look at this article, thanks and sorry for my nonsense://www.ncbi.nlm.nih.gov/pmc/articles
ReplyDeleteSorry, Peter yes I found and read that lefenuron does not do much with candida, but they sell a thousand products that you see help, if you find something that is less toxic, please let me know ..... ..
ReplyDeletehi Peter came across this article on Haploinsufficiency in SYNGAP1 whereby 6-bromoindirubin-3'-oxime (6BIO) that crosses the blood-brain barrier, was tested to restore the function of GABAergic synapses
ReplyDeletehttps://pubmed.ncbi.nlm.nih.gov/34739555/
Dear Peter,you mention that when someone's autoimmune condition flares up their autism gets worse?Now there is a mass body of research that proves that a large subset of folk with autism are in fact suffering from many immune abberations with all having a large autoimmune component.....a leaky gut allowing foreign microbes and toxins into the bloodstream recognised as foreign and attacked by the immune system.....then a porous blood brain barrier allows these same toxins,microbes and foreign material into the brain which are attacked plus hundreds of different autoantibodies have been isolated I dicative of widespread indiscrimitivve autoimmunity ..I'm on Prednisone and never felt better
ReplyDeletePeter, for 7 years old with Pans and regressive autism, which is the dose of galavit and nalcrom? How long is the treatment? When we'll be able to see first improvements?
ReplyDeleteWe are doing ivig as well. Thanks!
Dragos and Tatjana have experience with galavit. Nalcrom is quite widely used. IVIG is likely the most potent of the three. You may not see a further benefit. You would have to experiment to see.
DeleteDespite Ivig 6 days ago my son today had a really bad day: oral and motor tics (he beats all the time), nose and throat itching, compulsively. He's having these crisis since last spring and he stopped only for short periods of time. I don't know if it is yeast or allergies or histamine... or everything! I've just started Nalcrom: do I stop Daosin for histamine?
Delete(All the above tics stop immediately for 5-6 hours after the IVIG premedication with iv steroids and anti histamine drug).