UA-45667900-1

Wednesday 30 October 2019

More Research to support a Trial of Clemastine in Autism and particularly in Pitt Hopkins




                                                

Clemastine is an old antihistamine drug that we saw in earlier posts can stimulate oligodendrocytes to work harder and produce more myelin.

Myelin is needed to learn new skills and to control your body. It only starts to form in the third trimester, as the brain begins to grow rapidly. Myelination continues after birth but the rate appears to be controlled by social/emotional exposure.  The more isolated the baby is, the less myelin is produced.





                          









Interruption of the myelination process is known to cause long term problems.

Loss of myelin and lack of remyelination underlies Multiple Sclerosis.

It appears that loss of myelin may underlie cognitive loss in regressive autism, childhood disintegrative disorder and adult hypoxia.  First the myelin layer is lost and, depending on the underlying dysfunction, the neuron may die.  If it is just a case of lost myelin this can potentially be repaired.

Girls with Rett syndrome regress and lose previously acquired skills at about 18 months.  Is the loss of skills also a manifestation of a loss of myelin?  If so, can this loss of skills be controlled to minimize its effect?

In a previous post we have looked at the repurposing of Clemastine to improve remyelination.  At high doses this is an emerging therapy for Multiple Sclerosis (MS).  MS is a progressive disease where myelin is repeatedly lost.  Myelin is not permanent and constantly needs to be “remyelinated”.

As Ling has noted, the Pitt Hopkins syndrome researchers have published their results looking at mouse models of both Pitt Hopkins and broader autism and they have found that the same oligodendrocyte genes are indeed dysregulated in all these cases.
We already knew that myelin in idiopathic autism is thinner than it should be, which was why I was originally looking at ways to enhance myelination.

The new research gives further support for remyelination as a target for improving learning, cognitive function and motor skills in autism.  The new data shows that this likely particularly applies to those with Pitt Hopkins syndrome.  This syndrome is caused by a lack of Transcription Factor 4 (TCF4) when one of the two copies of its gene is not functional.  A more modest lack of TC4 is likely to be much more common that Pitt Hopkins itself.



Autism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs highlighted oligodendrocyte dysregulation and we confirmed the myelin-associated transcriptional signature in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4, Mecp2tm1.1Bird). We subsequently validated oligodendrocyte deficits in our Tcf4 mouse model which showed inefficient oligodendrocyte maturation in both an isolated oligodendrocyte in vitro cell culture system and ex vivo at day 24 (P24) and day 42 (P42). Furthermore, we used transmission electron microscopy (TEM) to visualize myelination in the corpus callosum (CC) of Tcf4+/tr and Tcf4+/+ littermates, observing a significant decrease in the proportion of myelinated axons in the CC of Tcf4+/tr mice compared to Tcf4+/+ littermates. Similar to our ex vivo IHC results, we observed a significant reduction in the number of CNP-positive oligodendrocytes in primary cultures derived from Tcf4+/tr mice compared to Tcf4+/+ littermates. When comparing compound action potentials (CAP) using electrophysiology, we show the ratio of N1/N2 is significantly reduced in the Tcf4+/tr mice compared to Tcf4+/+ littermates, indicative of a greater proportion of CAP traveling down unmyelinated axons. Moreover, we integrated syndromic PTHS mouse model DEGs with human ASD genes (SFARI) and human idiopathic ASD postmortem brain RNA-seq, and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination. Remarkably, we show that DEGs from syndromic ASD mouse models can be used to identify human idiopathic ASD cases from controls. These results from seven independent mouse models of ASD are validated in human brain, implicating disruptions in oligodendrocyte biology as shared mechanisms in ASD pathology.


Here is more on the same paper:-



Genes involved in the formation of myelin, a fatty substance that sheathes neurons, are altered in brain tissue from autistic people and in several mouse models. The mice also have unusually few myelinated nerve fibers.
Researchers presented the unpublished findings yesterday at the 2019 Society for Neuroscience annual meeting in Chicago, Illinois.
“In general, across the whole spectrum, there’s a defect in myelination,” says Brady Maher, lead investigator at the Lieber Institute for Brain Development in Baltimore, Maryland.
Myelination is the process by which neuronal fibers are coated in myelin. Myelin is made by brain cells called oligodendrocytes, and it enables fast neuronal signaling.
Maher and his colleagues saw hints that myelination is disrupted in Pitt-Hopkins syndrome, an autism-related condition caused by mutations in a gene called TCF4. Children with this rare syndrome are slow to learn to walk, and most are minimally verbal; some have autism.
The researchers analyzed gene expression patterns in five mouse models of this syndrome, each with a different mutation in TCF4. They found that in all of the mice, genes involved in myelination are among those with altered expression.

The researchers then compared gene expression patterns of the mutant mice with those of two other autism mouse models: mice with mutations in MECP2 or PTEN. All three mouse models show alterations in the expression of a shared set of 34 genes, most of which are involved in myelination.
The same genes show atypical expression in two independent gene-expression datasets from autistic people, the researchers found.
Maher says his team is investigating why the TCF4 mutant mice have too few oligodendrocytes. They are also testing whether drugs that enhance myelination reverse the mice’s problems.

Clemastine in Autism

Several readers of this blog have reported a positive effect from Clemastine, you can find their comments in earlier posts.

Monty, aged 16 with ASD, has been using it for many months and it will be added to my Polypill at the next update.

In the US Clemastine is no longer available in the OTC form.  It is available as a generic with a prescription


In the rest of the world it is called Tavegil, or Tavegyl and being a common hay fever drug is usually OTC (no prescription).

In the Baltic states 20 tablets cost Eur 5 (USD 5.50). In the United Kingdom 60 tablets costs GBP 10 (USD 13).  You may have to ask the pharmacy to order it for you, it is not widely stocked, or order it online.

A 1 mg tablet of Clemastine contains 1.34 mg of Clemastine hydrogen fumarate.  This can be confusing because one product is marked 1mg and the identical tablet is elsewhere marked 1.34mg.

The US product by Teva is Clemastine 2mg containing 2.7 mg of Clemastine hydrogen fumarate

The experimental dose in Multiple Sclerosis is so high it causes drowsiness.  Clemastine affects histamine H1 receptors in the brain and so makes you sleepy.

My “autism dose” is less than the hay fever dose and is 1mg Clemastine (containing 1.34 mg of Clemastine hydrogen fumarate) taken in the evening.

Some readers are giving a morning dose and an evening dose, as you would for hay fever.  I would expect this to have a greater effect on oligodendrocytes, but will come at the cost of a degree of drowsiness, which may or may not be important.

I think people should be given clemastine immediately after a regression into autism and also anyone suffering as result of hypoxia. We saw the MRI of a man treated with clemastine after hypoxia in an earlier post and we saw the myelin damage and its repair.

Given 18 months of age is the typical age for the first regression in autism, perhaps pediatricians should take note? Perhaps the Johns Hopkins doctors should try using it on their patients with mitochondrial disorders?

I would also think those with what was called CDD (childhood disintegrative disorder) would be likely beneficiaries.

Comments so far suggest that clemastine benefits some people more than others, but this is exactly what you would expect.  In the case of the man with hypoxia, clemastine really was a silver bullet, it was given very promptly and loss of myelin was his only problem.  Most people with severe autism have more problems than just patchy myelin.


Treatment Window

In some single gene autism there does appear to be a treatment window and this has been confirmed in animal models. One example is the very expensive use of the drug Rapamycin in TSC (tuberous sclerosis complex).

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain


Many interventions however do seem to be beneficial regardless of age.

This can be summed up as “it's never too late, but the sooner you start the better the result will be”.

Will a toddler with Pitt Hopkins learn to walk much earlier if taking Clemastine?  The logic is there to support this.

Will a girl with Rett Syndrome regress less far if taking Clemastine, during the regression?


Conclusion

Most parents naturally hesitate to give drugs to treat children with autism. They do not hesitate to give numerous drugs to their elderly relatives, who are the ones who are most likely to get side effects and have much less time to benefit from them.

Some drugs are much safer than others and the irony is that the drugs commonly used to treat autism by psychiatrists are the ones with known problems.

It appears that many very safe existing drugs can be used to treat features of autism.

Do you wait a decade, or likely more, to see if a safe old hay fever drug might improve cognition and/or motor skills in your case of autism or Pitt Hopkins? Or just buy these hay fever pills and see for yourself?

7 Previous posts on/including Clemastine:- 








42 comments:

  1. Hi Peter, since the virus flare, my son is worse than ever. He is having agressive episodes and can not stop laughing.Clemastine stopped working in this situation.I gave him propranolol and was the only thing that rescue him,helped tremendously. Could I give it daily or is not safe in a regular basis? Something is affecting my son.I don't know if it is virus, bacteria or his adolescence or something else, but he had not been like this since years.
    Valentina

    ReplyDelete
    Replies
    1. Valentina, when there is a sudden shift in behaviour it is worth considering an aberrant immune reaction. There are likely many variations and generally only PANS/PANDAS gets talked about. The simple therapy for many of them is short term use of prednisone.

      I had acute onset hearing loss in one ear and the ear specialist told me this is not a rare condition, but that it is usually ignored or misdiagnosed. It is an aberrant immune response in the inner ear that can be triggered by a common cold virus. If treated promptly with prednisone the problem is solved, if untreated you get permanent degradation in your hearing. The exact mechanism is not understood.

      I would ask your doctor for a 5 day course of Prednisone 40mg.

      Steroids should be taken early in the morning so as to interfere the least with the body's own hormones.

      Short term use of steroids is safe, long term use causes many issues.

      Monty has had a 5 day course of Prednisone on two occasions.

      I think people with autism (and NT siblings) are predisposed to these aberrant immune reactions. There are probably common.

      I would try this before resorting to Propranolol, which may treat the symptom, but will not address the cause.

      Delete
    2. Peter, many thanks, and thinking of the next step, could I use azithromycin as immunemodulator for one month or propranolol daily? or may be both?
      Valentina

      Delete
    3. Valentina, it depends on what the underlying change was, which we do not know for sure. Hopefully things will return to normal after the prednisone, but it may take longer than 5 days, I would wait 2 weeks and then reassess the situation. If you give too many things you may make matters worse.

      Delete
    4. Ok Peter, I give prednisone for 5 days and then wait for 2 weeks.I would think in using an immunemodulator as prevention. Should be something that I can get easly and with less side effects.
      Valentina

      Delete
  2. Hi Peter,

    I was reading your blog and overwhelmed with the amount of information. My boy is almost 8 yrs old and grew out of many asd symptoms. However, from time to time I observe he put hands in front of his eyes and wiggles them fast as if playing with them. Also, he isn’t as social as his peers. It’s more like a happy and shy kid. What does broccoli sprout powder help with? Will it be the switch in here? Which broccoli sprout powder is recommended? Thanks!

    ReplyDelete
    Replies
    1. Caroline, I am answering here the questions from both of your comments.

      Broccoli sprouts, in the presence of an enzyme called myrosinase, produces sulforaphane. Sulforaphane activates Nrf-2, which turns on the body’s antioxidant genes. A secondary effect of activating Nrf-2 it an increase in the level of serotonin in the brain.

      Some broccoli supplements add back myrosinase. Myrosinase is also produced by gut bacteria. The result is that broccoli powder is likely to have a highly variable result. The quality of these supplements was very poor, but may well have improved with all the attention in the last few years given to Sulforaphane. I used an Australian product called Supersprouts. I now use DMF to activate Nrf-2, which gives a precise consistent effect.

      Stimming by putting fingers in front of your eyes is quite common. In many people this type of stimming goes away by using NAC. NAC is a very effective antioxidant. Antioxidants are only helpful if you have oxidative stress, if you don’t have oxidative stress they leave you worse off, because the body over compensates by reducing production of its own anti-oxidants.

      People with mild autism only have some features of the severe condition. These features mainly relate to central hormonal dysfunction. They have issues with Serotonin, Oxytocin, Vasopressin etc. This causes problems with empathy, emotions, social understanding etc.

      These social/emotional issues can be tackled with therapy to teach the learner skills that are instinctive in his peers. This may be the best strategy.

      Adult Aspies who are not happy with who they have grown up to be often seek to “tune up” their emotional response by targeting serotonin receptors. These are “recreational drugs”.

      The next generation of FDA autism drugs are mainly targeted at people like your son who just need a little bit of therapy. These are the drugs that involve Oxytocin and Vasopressin.

      I think the value of therapy (explaining emotions, what is cool, boy-girl behaviour etc) is underrated. With a person of high IQ you can explain to them, while growing up, the things they do not pick up naturally. I think this will be more effective than oxytocin or vasopressin nasal sprays.

      Delete
    2. Peter, next year my son will be on High school, do you think that would be better to change for a man assistant who explains him boy-girl behavior and emotions? My son is very clever but of course there are many things he still doesn't know.
      Valentina

      Delete
    3. Valentina, a good Assistant for high school can be male or female. I think you will find far more good Assistants who are female, because the qualities an Assistant needs are much more common in females.

      Monty has a female assistant who is 10 years older than him. She is accepted by the students as if she was his big sister, not his mother. In high school you do not want the other kids to see the Assistant as another teacher, otherwise they will reduce their interaction with your son.

      You want an Assistant who is fun/cool and definitely not with Asperger’s themselves.

      A good female Assistant will do just fine with boy-girl behavior and emotions, probably much better than most males. Teenage girls also like a big sister (the Assistant) to get advice from. So it actual helps the social interactions.

      Delete
    4. Valentina, in the above I mean that if the Assistant is liked by the girls in class, they are automatically more inclined to include the boy she is supporting.

      Delete
    5. Thank you so much Peter, I will take it into account in the selection process of the new assistant.
      Valentina

      Delete
  3. AJ, was it you who was looking into autophagy recently?
    You probably have seen this article:

    Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412775/

    Mentions resveratrol, trehalose, verapamil, metformin, lithium and a bunch of well-known drugs such as rapamycin.
    Maybe nothing new, but worth taking a quick glance at.

    /Ling

    ReplyDelete
    Replies
    1. Hi Ling!

      Hope all is well.

      Sorry for the late response, it has been super busy on my end, and I'm just finally able to take a few minutes to sit and respond.

      Yes, I had looked at autophagy some time ago, and thanks for the article!

      I actually bought Lithium but haven't trialed it yet, but have been using Pterostilbene (which, if I remember correctly, you may be using as well). I've been operating under the assumption that Pterostilbene is inducing autophagy in neurons similarly to what Resveratrol would do, but it may be that more is needed than just Pterostilbene in my case.

      No single supplement / intervention has had a "wow" impact yet, and I have been in a holding pattern for a while of late. The various researchers working on my daughter's suspected genetic cause are likely to have some updates soon that I'm hoping will help guide my next steps.

      I did just find something of potential interest for you:

      https://medicalxpress.com/news/2019-11-pathway-parkinson.html

      I know your focus is SATB2, but when I saw this, not being an expert on the SATB family, wondered if there was any value to this finding depending on potential relationships / interactions between SATB1 and SATB2, but wanted to share.

      I'm about to post something else of interest to you, Peter and the community.

      Have a great day!

      AJ









      Delete
    2. Thank you AJ! I'm having a busy but also incredible week here to.
      I have no idea yet if your link has any relevance to SATB2, but maybe. SATB1 and SATB2 are somewhat in opposition to each other. I really hope I'm not dealing with zombie cells, they sound nasty. Like a Halloween post of Peter's.

      Thanks anyway!
      /Ling

      Delete
  4. Looking into the NLRP3 inflammasome again - thanks Peter, I enjoy some of your earlier posts on the subject!

    Came across this paper mentioning a two-hit model for neuropathic pain where a short course of morphine actually prolonged the pain (for months) via NLPR3/P2X7/TLR4.
    There is probably a link from pain to peripheral inflammasome to neurons here that I don't grasp yet.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914184/#!po=0.403226

    /Ling

    ReplyDelete
    Replies
    1. There are many such paradoxes and particularly in neuropathy. I found an interesting paper on DMF be effective in treating neuropathy. I have a nerve that got damaged and a tiny dose of DMF within hours has an effect, but it is a negative effect. Then if you cease the DMF the negative effect fades away and you seem to end up better than you were at the start. PEA is effective in my case.

      Delete
    2. That is odd. Do you think it's possible there is an initial negative effect that can be followed by a positive one by long-term use? After all DMF first enhances oxidative stress.

      /Ling

      Delete
    3. Ling, that is possible, but I found there was a positive effect on cessation. So a single dose might well be all that is needed, from time to time.

      Delete
  5. For people using clemastine what are we looking out for in a child , notice if it improves autism. Assuming this is a look term therapy after how many weeks months etc

    ReplyDelete
    Replies
    1. In children whose development is held back by poor myelination, you would hope that Clemastine would gradually reduce that constraint. Depending on the level the child has already achieved it might be seen as improved motor skills (learning to walk, to write neatly, to ride a bike, to swim, tie shoelaces etc). In those who achieved good fine/gross motor skills I think there may be a development in higher level thinking skills, this is the effect I am seeing.

      The effect of Clemastine should not be immediate, if it relates to myelin, it will take weeks or months. The benefit in MS is known to take time. I would try it for 3 months and then decide.

      Clemastine also affects activated microglia and this might show as a beneficial effect rather faster.

      Delete
  6. Peter, have you discussed MD1003 in your blog - another compound trialled as remyelination promoting agent in MS? I stumbled upon MD1003 while reviewing Clemastine once again.

    MD1003 is super high biotin dose and it doesn't seem to be risky treatment.

    https://link.springer.com/article/10.1007/s00415-019-09421-x

    ReplyDelete
    Replies
    1. Agnieszka, I did write about biotin a long time ago. When I tried it, there was a benefit at the start, but then it seemed to make things worse. It seems that many people find that high dose of B vitamins seems to have secondary negative effects.

      The MS dose is 100mg 3 times a day. I think I used 10mg once a day, which is already far above the RDA of 0.3mg.

      "MD1003 achieves sustained reversal of MS-related disability in a subset (13%) of patients with progressive MS and is well tolerated."

      It is certainly worth re-visiting. Biotin is cheap, but I am surprised it was so well tolerated. Perhaps the cheap biotin supplements are not just biotin and contain some "nasties"?

      Delete
    2. Peter, I tried biotin in the past prompted by this paper discussed long ago in your blog as well:

      https://www.ncbi.nlm.nih.gov/pubmed/24399946

      "Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin."

      In Poland pharmaceutical grade biotin tablets are available, the product is OTC, but it's production is regulated. Anyway, I used 5-10 mg for several weeks or even months without significant effects, neither good or bad.

      It seems like there are 100mg capsules sold in the US, but they are all supplements.

      Delete
  7. hi Peter I am writing on behalf of a friend of mine who has a 4 years old daughter with asd, her RMI recently showed delayed myelination, is clemastine suitable for pediatric use? are there supplements for improving myelin sheath? Also, the little girl has mthfr c 677 mutation, is the mutation unrelated to myelin? Carla Marta

    ReplyDelete
  8. Carla Marta, this is what is quoted for Clemastine:-

    "Usual Pediatric Dose for Allergic Reaction
    < 6 years:

    0.335 to 0.67 mg/day orally divided into 2 or 3 doses. Maximum daily dose is 1.34 mg"

    So clemastine is used in young children for allergy.

    The MTHFR C677T mutation is associated with vast range of disease that depend on your ethnicity. It is known to affect myelination and not surprising multiple sclerosis, as in the following paper

    http://www.jneuro.com/neurology-neuroscience/the-role-of-folate-dependent-genetic-susceptibility-in-the-risk-of-multiple-sclerosis.php?aid=19205

    This paper is also good:-

    Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: Epidemiology, metabolism and the associated diseases
    https://www.sciencedirect.com/science/article/abs/pii/S1769721214001931

    I think your friend should consult with a good genetics doctor and read up on the research. It is clear that B12 and folate are beneficial in certain cases, where there is hyperhomocysteinemia.

    Other ways that might improve myelination would include Ibudilast and DMF.

    ReplyDelete
    Replies
    1. very interesting, many thanks

      Delete
  9. Hi there, where can I get clemastine fumarate in Australia? I cannot buy this anywhere from overseas even. Having real problems locating this to purchase. Thanks so much for everything too Peter. Bumetaninde was a game changer for my 6 year old girl based on your advice.

    ReplyDelete
    Replies
    1. You can buy it on eBay or find a friend/relative in the UK to send you some. It is OTC in the UK and some parts of Europe.
      Google "Tavegil ebay"

      Delete
    2. Just quick question how are you sourcing bumetanide in australia through a gp. Or other means

      Delete
  10. https://www.frontiersin.org/articles/10.3389/fcell.2022.841548/full

    This new research says clemastine actually works impair myelination in young subjects. Yet I am not sure if the subjects are rightfully chosen. What if the subject were de-myelinated to begin with?

    ReplyDelete
  11. Guy. at my country clemastine not exist. how can i buy online. from where ?

    ReplyDelete
    Replies
    1. In Europe clemastine is sold under the names Tavegil and Tavegyl. Just google buy Tavegil online. It is cheapest in Latvia and Estonia.

      Delete
    2. how much the dose clemastine per kg you used Peter?

      Delete
    3. I used half the allergy dose. So I used 1mg once a day in the evening, since it does cause some drowsiness. Any effect on myelin is going to take months.

      Delete
    4. what else you think effect on myelin. NAc, SAMe, BHB ...?

      Delete
    5. ALA, NAG (with a G) and ibudilast. In theory a PPAR gamma agonist like Pioglitazone.

      Delete
  12. what about SAme Peter. my kid very slow about new skill. maybe myelin is the key

    ReplyDelete
    Replies
    1. SAMe plays a role in Schwann cells that make myelin in the peripheral nervous system. It is not clear if there is an effect in the brain.

      SAMe can be used to make epigenetic changes if given at the critical moment. In the VPA model of autism you can block the autism effect by giving SAMe.

      Delete
  13. Another mode of action from the Clemastine could be related to the Cell Danger Response theory being investigated by Naviaux with his Suramin trial. There's a thread on phoenix rising for treating CFS https://forums.phoenixrising.me/threads/potential-suramin-alternatives-sytrinol-and-kudzu-anti-purinergic-therapy.52427/page-4. Clemastine is an upregulator of P2X7 which Navieaux has identified as follows: "P2X7 receptor expression was decreased over 50% by gestational poly(IC) exposure and normalized by suramin treatment". Could well be that upregulating P2X7 has wider effects on other Purigenic receptors to treat CDR.

    ReplyDelete
  14. Hello Peter, My son has william syndrome 10 yrs old, following article does recommend clemastine as treatment option for remylination. Wondering if its too late to try? if not what is the dose recommended?

    https://www.frontiersin.org/articles/10.3389/fnmol.2023.1279985/full

    ReplyDelete
    Replies
    1. Impaired or delayed myelination is a common feature in autism. The many pro-myelination therapies that originate from MS research are interesting. Clemastine is a drug already approved for use in children to treat common allergies. The limiting factor in the use of clemastine is drowsiness due to its effect on the histamine receptors in the brain.

      My suggestion is to try the allergy dose given once a day in the evening. I think a trial needs to last several months.

      The effect may indeed vary with age, but 10 is hardly old.

      There are other therapies for myelination, including the NAG supplement (not to confuse with NAC).

      Look in my blog under myelin or MS.

      Delete

Post a comment