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Tuesday 29 March 2016

Verapamil use in Autism – Request for Case Reports from Parents


  
 By Agnieszka Wroczyńska, MD, PhD, 
Medical University of Gdansk, Poland



In June 2014 my son with severe autism was given verapamil as an emergency mast cell stabilizer according to Peter’s blog, as we run out of other medication ordered from abroad. This turned out to be a life changing moment for him and my family. Two days later his chronic diarrhea resolved completely and soon after we also saw improvements in other symptoms and behaviors.

Several months, blog entries and papers read later my son still uses verapamil and now also other medications targeting autism, most of them being included into Peter’s PolyPill. He is still significantly affected by ASD, but his quality of life improved much, thanks to this blog.

Recently I have visited a very open-minded pediatrician, the first one who suspected medical issues behind challenging behaviours in my son and she asked me about papers on verapamil use in ASD, possibly to include it into her clinical practice. Unfortunately I have nothing to recommend although the use of calcium channel blockers for autism had been suggested long before my son was born as in this paper written in 2004: “These findings hint at a potential mechanism that might underlie autism. Future studies will focus on the genetic analysis of Cav1.2 and other calcium channels in the disorder and the potential application of calcium channel blocker therapy” [1]. This did not happen and no clinical trials were done.

Calcium signalling role in ASD is well backed by science [2-5] as Peter described in many excellent posts here, but not a single case report of such treatment was published. That’s why I would like to invite readers who use or used verapamil (short or long term with or without effects) to jointly publish an article on this treatment in a peer-reviewed medical journal as a case series description.  

According to what Peter suggested before, I wrote a questionnaire including basic clinical data and - if available - tests results suggested by Peter and Nat, as a first step to this article. I would really appreciate your contribution, comments or questions about this idea.

There is no deadline date so you are welcome to join if you start verapamil treatment for you or your child in the future. You may consider to do some lab tests according to the questionnaire then.

If you have not used verapamil, but would like to join this idea in other way, please feel free to contact me.

Before the collective article is ready let me quote a recent paper on another class of calcium channel blocking drugs in autism: “Given the excellent toxicity profile of dihydropyridine LTCC blockers, long-term off-label treatment of patients with ASD appears justified based on our robust in vitro findings.” [6]


If you have not used verapamil, but would like to join this idea in other way or just discuss autism treatment without participating in this case series report, please feel free to contact me.


Thank you!

  

Agnieszka Wroczyńska, MD, PhD
Medical University of Gdansk, Poland
verapamil.asd@gmail.com





The questionnaire can be downloaded from here:

The questionnaire filled with my son’s details as an example:







123 comments:

  1. Congrats on the initiative.
    If we had more on the medical community willing to stand up to their knowledge and experience, more kids would receive the health care they need.

    Looking foward to the publication.

    Jane.

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    Replies
    1. Dear Agnieszka,

      I am so sorry I didn't send this report earlier. I thought I did, computer was broken at that time.

      Please notice me if you need more informations.
      As you see, I haven’t done much of the testing. My daughter use to faint when she sees a needle.

      Please, forgive me.

      Best wishes,
      Maja Dj.

      Delete
  2. Agnieszka, I haven't trialled Verapamil yet, but I have bought it just in case I need it. As you may have noticed from my comments, my son seems to respond to Baclofen therapy. This leads me to believe that the hypo NMDA hypothesis applies to my son's disorder. I don't know if he has any allergies but I can see him sneezing quite often.
    Do you think Verapamil would be an agonist/antagonist to hypo NMDA?
    If I trialled it what would be the initial daily dose? What behavioural improvements should I expect?
    Thank you very much and congratulations once again.

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    Replies
    1. Hi Petra,

      I started verapamil at .5mg/kg for my daughter. This immediately led to reduction of anxiety: looping thoughts, repeated talk about past unpleasant experiences, etc..

      At that time, she also had allergy induced seizures (very frequent, unpredictable, even short walks were not possible outside). That did not stop with the low dose. So, I increased to 1mg/kg twice a day and that ended the allergy induced seizures. We have stayed at that dose for almost two years before now switching to an extended release version, which I am not sure about yet.

      The other big change has been that my daughter used to have several throat infections every year with high fevers and seizures. She has had none since verapamil. This last month, my husband and I were down with a nasty cold virus but she did not get it.

      Her heart rate which used to be at around a 100bps, has come down to about 80 which is a good thing.

      She has not had any significant side effects. Her prolactin levels were high, but they came down with levothyroxine which she is on for hypothyroid. So, it is unlikely that it was caused by verapamil.

      Delete
    2. Petra, Monty has mild asthma and no other significant allergies. He has never had any GI issues.

      Until the age of 8 there was no aggressive behavior of any kind, then severe self-injury and aggression to others developed. Using behavioral technique the extreme behavior faded away over about 9 months. The following summer self-injury re-emerged and at that point I had started my PolyPill investigation.

      In the middle of an aggressive episode I gave a 40 mg tablet of Verapamil and watched complete extinction of aggression in front of my eyes. Later on it became obvious that anxiety, muscle tensing, change of facial expression were warning signs of an aggressive episode. All of this disappears with 20mg of verapamil three times a day. You can even see the effect of the last dose fading away.

      The trigger is a mild pollen allergy in our case. But it is clear that in some other people a year-round allergy of some kind may be the trigger.

      Verapamil blocks a calcium channel in mast cells, but the same type of calcium channel is found in the pancreas, where various digestive enzymes are made. This may account for the effect on people with GI problems. Cav1.2 is also present in the heart and this is usual target of Verapamil use. Heart disease is comorbid with autism and this is no surprise.

      I would imagine in a young adult with Asperger's with no SIB, if 20 mg of Verapamil was effective, he would notice a mood change, so less anxiety and more calm. If he does not notice any improvement after a couple of days, then he is not a responder.

      Delete
    3. Hi Peter,

      You mention here that you used some behavioral techniques to help fade undesirable behaviors. Could you share please. When my daughter's behaviors worsened two years ago with sib and raging, it was also the time that her seizures increased in frequency, so we allowed ourselves to be held hostage by them, and allowed the behaviors to go unchecked. Now, I see that sometimes they are purely behavioral with no physiological cause. I am stumped, nothing I have tried so far has helped. This has also come with more awareness and need to control on her side. So, there is a good side to this, and I don't want to crush her spirit.

      Delete
    4. RG, there are two excellent books that are all about understanding behavior and modifying it. They are quite old, as reflected in the tittles, which would put off 90% of parents. These techniques work on people with any IQ. They are very readable and are favorites among the people who have worked with Monty.


      Decreasing Behaviors

      http://www.amazon.com/Decreasing-Behaviors-Persons-Severe-Retardation/dp/0878222642/ref=sr_1_fkmr2_3?s=books&ie=UTF8&qid=1460017919&sr=1-3-fkmr2&keywords=reducing+behaviors+in+autism+and+mental+retardation

      Increasing Behaviors

      http://www.amazon.com/Increasing-Behaviors-Severely-Retarded-Autistic/dp/0878222634/ref=pd_sim_14_1?ie=UTF8&dpID=41O0ogcgmTL&dpSrc=sims&preST=_AC_UL160_SR104%2C160_&refRID=02GTVWTSCWNN9P4ZY3CQ


      Having read the books I made my own approach which is not entirely what a behavioral expert would recommend.

      First, I established zero tolerance of any SIB ,or physical aggression to anyone else. Some people just allow the behavior continue till it self-extinguishes, I do not agree with is.

      So any aggression I would physically halt, be it hitting the head with fists or hitting the car window with the head. This is clearly much easier when you are much bigger than the child. But if you do not stop it now, it will continue into adulthood and future carers may not be as nice as you.

      I would verbally reinforce the zero tolerance by telling my son that the action was not allowed, so “hitting your head is not allowed” and get him to repeat “no hitting my head”.

      If the behavior occurred in the car, I would stop and take him out and not get back in until behavior was stable.
      I showed no emotions on purpose, so no “Oh my poor baby”, “please don’t do that” so I would just say “No!” in a way that he knew I really meant it. Ideally you try and reset behavior by changing your location, go to another room and have the child sit and calm down while you speak calmly but with authority, so more like an old fashioned policeman would talk to a child, not like an emotional parent.

      He/she has to know that you are boss and there is no choice but to follow your instructions.

      Never reward the bad behavior, which is what many parents unwittingly do; then the behavior will reoccur. If after the child stops you give some reward then you have made the link between bad behavior and a nice reward later.

      Never allow SIB as a form of avoidance. So if an academic task triggers SIB, you extinguish the SIB and then restart the original task from the beginning.

      Then there ceases to be any point to SIB; if you engage in SIB you lose.

      If SIB gets rewarded with cuddles and hugs later, it will reoccur.

      SIB in the end becomes just another learned behavior and you do it because you can.

      Delete
    5. Thank you very much Peter. I should be able to read the books by this weekend, amazon can get them to me tomorrow.

      I have tried to stop the sib, but she is pretty strong and if I try to control her physically, it enrages her even further and I end up in a losing tussle. What is your opinion about the following:

      I usually threaten her with a consequence such as loss of time on the iPad or computer, or cancelling her evening drive which she loves. I do follow through with the consequence.

      If the behavior occurs when she is in a group class, I tell her 'this class is cancelled for you' and I will leave and she will follow. She likes her classes and does not want to leave, so I think it is a punishment for her. Recently though, I have become unsure of this, as she reverts to normal as soon as she is out.

      Her teachers have a good attitude, and do not like her to leave class. Instead, they are often able to ignore/work around her raging, and make her continue with the work at hand, which she does. Even if not fantastic, this keeps the session productive.

      I am also unsure of how to be with her after the episode ends. She usually talks about the consequence, accepts it, gives me a cuddle and very much wants to make nice with me. I feel very torn, and unsure of how long I should keep up a stern demeanor.

      Much appreciate your help.

      Delete
    6. Behavioral principles are interesting, but they do need to be adapted to the particular person and their specific daily life.

      Rewards always work much better than punishment.

      Withdrawal of a reinforcer, like the iPad evening drive is an interesting point. If it was me, I would gradually shift the evening drive to be seen as a reward for having had a great day, so it is no longer a right or certainty. The same goes with the iPad, you have to earn it with good behaviors.

      Many parents give their kids the most powerful reinforces “for free”, so there is nothing valuable left as a reward.

      Rules need to be fully understood and so not too complicated for that person. Useful concepts for older kids include delayed reinforcers and the token economy system. The idea is that the reward does not have to immediately follow the good behavior and that multiple good behaviors can yield a single valued reward.

      If your daughter is suited to a token economy, she can earn tokens in group classes for no SIB. For example, 5 tokens = big reward. The teachers have to participate to make this function, but it can be made to be fun.

      First you should start to record the incidence of SIB and put it in a visible place, say in the kitchen. It might show your daughter has 2 issues of SIB at school and 1 at home.

      You have to make it clear that the target is ZERO, but depending on how far away you are from the target you aim at gradual reduction or aim to go straight to zero. I would favor the latter.

      Every day you can review the chart with you daughter, depending on her ability, she can be the one making the chart, drawing a line graph etc.

      There has to a reward for getting to zero incidents and staying at zero incidents.

      Delete
    7. I think this might work well. She is already used to delayed reinforcers, even by weeks and months. Also, instead of me threatening, the chart would be a reminder.

      To clarify, there is a chart which records rewards for being sib free. But, what happens with the sib itself? Are they ignored in that nothing happens, just no increase in rewards? Or does she lose rewards/points from the chart?

      Delete
    8. The chart records the number of SIBs in each day. So the days are along the bottom (x axis) and the number of SIBs is the vertical (y axis). We aim to have a zigzag line appearing that heads to zero. Each time it hits zero stick on a gold star or happy face and give the reward.

      As behavior gets better you can make a big reward for say three days in a row with zero SIB on the chart. Then over time you make it a big reward for five days with no SIB. Eventually it become a big reward for a month with no SIB.

      It is important to gradually fade the big reward in this way, so that eventually SIB stops, and later becomes forgotten about.

      Delete
    9. I have been having problems lately with my 9 yo with a lot of screaming and oppositional defiance. So these tips have been really helpful. Thanks.
      Nina

      Delete
  3. Hi and thanks for comments.

    Petra, I’ve tried to find more in papers to answer your question but I think that with current knowledge it is not easy to predict if Baclofen positive response will mean Verapamil will be effective as well. But what is encouraging is that it seems that effects of Verapamil can be seen very soon. As Peter wrote in the PolyPill table, he could see initial effects in 20 min: http://epiphanyasd.blogspot.com/p/polypill-for-autism.html

    So it should be easy to check.

    In my son the first (GI) effects were seen since the second day of using 20 mg of Verapamil daily.

    My son was only 6 years old then and he was pretty severe with his behaviors at this stage. Apart from GI and skin symptoms with Verapamil help he became more calm. He used to get agitated out of the blue with screaming or giggling and this sometimes escalated into aggression towards anybody close to him. He had little communication skills then to express what was going on with him, but such behaviors disappeared with Verapamil. With regards to things I could count (so no possibility of placebo effect): the number of nights with sleep problems decreased twice also within first few weeks of treatment.

    He did not have obvious allergic symptoms also at this age.

    I usually use 1 mg/kg ususally 2-4 times a day and sometimes higher doses, especially when I suspect mast cell activation flare.

    Peter, Maja and RG (and maybe some more?) have also used Verapamil, maybe they can describe behavioral effects in older children so that could be helpful for you?

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    Replies
    1. Hi Agnieszka,

      I am so very happy that you are going to be presenting. I am sure you are going to be a good voice for us all.

      I am waiting to fill in the questionnaire, since I am currently trialling an extended release verapamil. I am using the same strength as before, so the peak concentration would be lower but longer, so a shorter and wider curve. Will update in a few weeks' time.

      Delete
  4. Hi RG,

    This is very interesting that you use extended release verapamil. I was thinking about this also to make the dosing more comfortable. Can you share what dose are you currently trialling?

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    Replies
    1. Hi Agnieszka,

      My daughter is 50kgs, so I am using 60mg Extended Release, twice a day. I calculated at 1.2mg/kg. I wanted to go a little over 1mg/kg to compensate for the lower peak.

      Delete
  5. Agnieszka, RG, Peter, all of your testimonies have left me completely stunned.
    It's full blown spring in Greece, with very high temperatures and rushing blossom. Last night my son had a throat infection but it's difficult to know if it's from a common cold or allergy. As things might get worse, I thought this is the right time to trial Verapamil.
    I gave 20 mg and watched his reactions. He had good mood and seemed reasonable, so I thought I should skip the last dose Baclofen, but he became a little anxious (hand flapping, hand sweating) and after an hour I gave the last dose.
    Therefore I can't be sure how exactly he feels with it as it's not something that you can measure objectively and instantly.
    Still, after having his dinner, I saw an immediate first stage digestion which caught my attention because I never see him digest so quickly.
    I hope this is a good sign.

    ReplyDelete
  6. Our current standard local pediatrician and immunologist were concerned with side effects and would not prescribe even a 30 trial. I was interested in the cognitive effects. Reacted VERY badly to Zyrtec . We don't have rage but do have very serious allergies/headache. Currently Clonidine and Bumentanide micro-dosing have done wonders. Should I pursue this with my biomed? Why are traditional Dr.s so worried about this one?

    ReplyDelete
    Replies
    1. Verapamil might help the headache and is worth trying. All drugs can have side effects, as you found with Zyrtec. Verapamil is well tolerated by most, but Maja found it effective but not tolerated (no harm was done).

      Until there are published case reports showing a positive effect, clinicians will be risk averse. Most would not prescribe Bumetanide.

      Delete
    2. Peter, Autisee,

      Mayo Clinic and Childrens Hospital and one other hospital from Chicago did a large multi year trial of Verapamil on children with refractive epilepsy. They used doses from 1mg/kg to 3mg/kg. Very good safety profile and the trial was successful.

      Delete
    3. RG, thanks for information about ER Verapamil. The lowest ER dose here is 120 mg, perhaps too high.

      Autisee, is your pediatrician concerned about Verapamil itself or about the interactions with Clonidine? Drug interaction checker that I use warns about "potential for dangerous interaction" if you enter Verapamil+Clonidine:
      http://reference.medscape.com/drug-interactionchecker

      Otherwise, Verapamil is used for migraines and cluster headache in children. I am out of town and don't have access to my resources, but I can send you references when I am back. What kind of headache is this? Is it related to allergies you mentioned?

      My son used to suffer severe headache, Verapamil used as in migraines did not control this. Acetazolamide, melatonin and probably low dose clonazepam helped.

      Can you share what micro-dosing of Bumetanide do you use?

      Delete
    4. Agnieszka, I had the ER compounded to my dose.

      The last two days, I have also gone back to the regular kind of verapamil, as my daughter ended up with four seizures in fourteen days. This was around her menses and has occurred before, but not in the last few months. As for now, the ER trial is suspended. I may try again later, maybe at a higher dose such as 80mg.

      Delete
  7. RG-- would you be able to share the link to that paper? thanks so much.

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    Replies
    1. It was not a paper. They haven't published the full results yet.
      https://clinicaltrials.gov/ct2/show/NCT01607073

      Here are a couple of papers:

      http://www.ncbi.nlm.nih.gov/pubmed/24113539

      http://onlinelibrary.wiley.com/store/10.1111/j.1528-1167.2005.59204.x/asset/j.1528-1167.2005.59204.x.pdf?v=1&t=imtwe4mm&s=24e4bb46e4aca9e21d0484425c58324d1777ec1a

      This very interesting report:
      http://www.post-gazette.com/news/health/2013/08/26/Genetic-findings-bring-new-hope-outlook-on-epilepsy-treatment/stories/201308260151

      Interestingly, this old paper from the Mayo Clinic, that nimodipine was more effective than verapamil at controlling seizures, albeit in animals:

      http://www.mayoclinicproceedings.org/article/S0025-6196(12)61922-3/abstract

      Delete
  8. Peter, I was wondering if the Pgp that verapamil inhibits, could be part of the feedback loop mechanism that causes many drugs and supplements to stop working after a time. In theory, I have accepted that the feedback loop exists, but have never quite understood it.

    ReplyDelete
  9. For those in the US that are trialing Verapamil, how did you convince your physician to prescribe it? Or, are you getting it online from Mexico, if that is even possible?

    ReplyDelete
    Replies
    1. Hi JB,

      We have a supportive family physician who writes the scripts. A friend of mine has scripts from Rossignol for Bumetanide, Verapamil and Baclofen.

      I know that a lot of people also buy meds from Mexico because they are cheaper compared to buying them locally. There are Costco and Walmart pharmacies in Tijuana that are reliable. There are also other local pharmacies that you could call who will mail it to you. I don't think there is a problem with counterfeiting etc because this is a big business there and it will dry up quickly if the medicines are fake. They cross the border and mail so it is not international.

      Delete
  10. Hi Peter, with Verapamil we have considerable improvement.
    My son has started "expose/prevent" therapy by himself with success.
    I give 40 mg split twice a day. I also give 10 mg Baclofen in the same way.
    I don't need prescription from cardiologist, I just buy it from my local pharmacy and costs almost 1.5 euros.
    Of course I talked to my cardiologist and presented him with the facts connected to autism. My son also has chest pain but his check up looks fine. Doctor says it's Ok with him as long as we check blood preassure and heart beats regularly.

    ReplyDelete
    Replies
    1. That is very interesting.

      What exactly is the improvement? Is is relief from chest pain or is it a mood/behavioral improvement?

      Anyway, Agnieszka will now have an Asperger's person in her case series. This would show that Verapamil can be helpful, wherever you are on the spectrum. That itself might surprise some people.

      Delete
  11. Sorry Peter, I wasn't clear enough. I only mentioned chest pain to say that in some kinds of heart diseases, Verapamil is contraindicated and should be first checked by a doctor.
    Now, as for the improvement, it is like a chain reaction improvement in all aspects of my son's Aspergers core symptoms.
    We have less anxiety, good mood, better control over thoughts, better focusing, less obsessional thoughts. Also less stereotypy, more initiative/motivated, better communication/function, less sensory overload.
    I can only wait and see if the effect is stable.
    I would be more than happy to give any details of my son's case report to Agnieszka.

    ReplyDelete
  12. Peter, I forgot to mention that there are some side effects from Verapamil. My son feels cold and shows signs of allergy or common cold in the form of rhinitis. He also had a sore throat but not any more.

    ReplyDelete
  13. Peter, after a week of "normality", on Verapamil, we had some kind of a "sensory overload". It seemed that it was difficult for my son to process thoughts and feelings.
    Aggression raised and in the beginning he was being unreasonable.
    I was just in time to give Verapamil (20mg) and just left there to watch the outcome.
    It was frightening but at least I would find out if it worked for meltdowns/SIB.
    After a while his aggression became "reasonable". He talked about his Aspergers and that he needed a place to "belong".
    All this had started at 7pm. Aggression remained for many hours. I had to give an extra dose at 1pm. Then, not being able to go to sleep, we decided to go for a ride and find a quiet place to walk. He walked and when we came back home he seemed more calm.
    In the morning I was terrified because such aggression usually follows the next day. When he woke up he seemed "normal".
    I am sure he is depressed but he makes plans for himself and wants to go back to his studies with absolutely different terms. He also said he needed a good psycologist to help him out.
    In addition my son started to complain about his short term/working memory and I thought here came another reason for a tandrum. After all I know he is awful in this function. Then I saw him practising on the internet. In the very beginninh he wasn't good enough, but soon after he seemed to rapidly improve.
    First I witnessed that and then read the article which says that Cav1.3 contribute to different types of memory.
    Although I am too alerted, all this can't have been a coincidence.

    ReplyDelete
    Replies
    1. Hi Petra,

      Just wondering if you and your son continue with Verapamil? You've mentioned short term/working memory issues. Was this present before the treatment or happened later, do you think that Verapamil has any effect on that? It is amazing that your son can comment himself the effects of treatments.

      Delete
  14. Peter, I am sorry for being "persistent", but I have to come back with some questions.
    Firt, does all this make sense to you?
    Second, do calcium channel blockers affect the amount of calcium needed for bones, for example, or other parts of the body where calcium is essential?
    Next, is supplementing magnesium and/or potassium helpful in this case?
    According to the articles, do you think that I should check for primary aldosteronism?I know that his prolactin levels are high. Would hormones tests be helpful with his treatment?
    Thank you very much

    ReplyDelete
    Replies
    1. Research suggests that calcium channel blocker have negligible impact on your bones, so no need to worry about that.
      Independent of calcium channels, some people do seem to benefit from potassium supplements. It is easy to try, just take a cheap effervescent potassium supplement (about 250mg)and see if he feels different. In our case it solved the sensory overload problem. We use a tablet that contains 500mg potassium and 150mg magnesium, half at breakfast and half in the evening.
      I would not make too many changes, since there me be external factors that change your son's behaviour. Look for therapies that have a significant positive impact that are well tolerated. You do not want 20 supplements, identify a handful that really work well.

      Delete
  15. Integrated MAPK and calcium signaling

    We further noted that MAPK and calcium signaling pathways overlapped via 8 ASD genes: CACNA1H, CACNA1G, CACNA1I, CACNA1D, CACNA1B, CACNA1C, CACNA1F, and PRKCB.

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153329

    It is interesting. Those genes are related to L-,N-, and T-type calcium channel.

    ReplyDelete
    Replies
    1. Thanks Abdul, there is a really good graphic in that paper to illustrate your point. (figure 3).

      RAS is a key part of much autism and this is just upstream of MAPK/ERK.

      Delete
    2. Hi Peter,

      Does it mean that if science can solve this RAS and L,N,T type calcium channel problem, we can expect some improvements of ASD symptom?

      Delete
    3. Adbul, science solved the calcium channel problem 30+ years ago. There are more recent drugs that can treat L and N type channels together and I came across such a Japanese drug when I was deciding which one to trial. I chose the 35 year old drug Verapamil because it is well studied and available. The Japanese drug, or one of the other ones, might be even better.

      Drugs also exist to affect RAS.

      The problem is that doctors, researchers and regulators think in a way that is not compatible with treating a condition (autism) that has hundreds of variants. The system is set up to find treatments to well defined conditions, where one size fits all. In Autism and Schizophrenia this can never work. There will never be enough research money to spend $50 million on each variant.

      A much more innovative approach is needed and that would not be accepted by regulators.

      In cancer they have finally realized that you have to treat individual sub-types. So not cancer, or even pancreatic cancer, but which of 10 common sub-types of pancreatic cancer. Then they get good results.

      Delete
    4. Peter that is so well said, please turn it into a post. Some things cannot be said often enough!

      Delete
  16. Peter, I used a quarter of a nicotine patch together with Verapamil for two days. My son said this improves his brain performance. The third day we decided to leave it out and watch. He said there was a slight brain decline.
    Do you think it's ok if I use nicotine patches on a regular basis?
    How is Verapamil connected to nicotine?

    ReplyDelete
    Replies
    1. I did write some posts on nicotinic acetylcholine receptors (nAChR). We know they are unusual in some autism. Very many people with schizophrenia smoke and this may be part of the reason why.

      There are drugs like Galantamine that should have a similar effect to a nicotine patch and they are known to help a sub-group of autism.

      A nicotine patch is definitely a better choice than smoking a few cigarettes a day. You would have to ask your doctor about nicotine patch vs galantamine.

      So the effect of improved cognition in your son makes sense entirely. It should vary with the dose, and I think the small dose will be more beneficial than a large dose.

      There is an effect between verapamil and nicotine, but at low doses this may not be significant. People who are smokers and use calcium channel blockers may feels pain less, it may mean people who are have heart problems ignore early chest pains associated with heart attacks.

      I do recall that tiny doses of nicotine had a different effect to large doses. Very few smokers would smoke only 1 or 2 cigarettes a day, which is the kind of level your son is getting.

      Delete
  17. Hi Peter, Our researcher doctor in Thessaloniki evaluated my son and he also saw good results.
    He doesn't know much about Verapamil and Baclofen and expects to find out in the upcoming conference in Brunel University in London.
    He mentioned another child's case report he knows about being on Verapamil.
    So far my son's quality of life does seem to have improved.

    ReplyDelete
    Replies
    1. Hi Petra, it is great that your son has responded to Baclofen and Verapamil. Do you still use NAC?

      You have a big advantage in having a son who can tell you directly what the effects (good and bad) are from various therapies.

      It is a pity more people with Asperger's do not try Baclofen, since it seems to work in the majority of cases.

      The Pediatrician who told me about Baclofen on this blog did not give her/his name. Otherwise I would suggest he/she goes to that conference.

      Hopefully, your new doctor will try these two drugs on his other patients with Asperger's.

      Delete
    2. Hi Peter, not even a single day have I quitted Nac since when I started in November. As you very well explain, we don't know what damage is being made and Nac seems to limit oxidative stress.
      I use 1800-2400 daily, in a combination of normal Solgar Nac with a Now Nac, containing selenium and molybdenum.
      I also use 10mg melatonin as another potent antioxidant/sleep aid. Doctor seemed quite shocked at this amount and advised me on reducing it gradually to 3mg which I may do in the near future.
      B complex "50" agitates my son and stopped it. Still I give 5mg biotin, 8,5mg B6, together with 130mg magnesium as oxide. These never seem to create problems and might slightly help.
      Now that I've mentioned magnesium, there are articles about Verapamil and magnesium, on Wikipedia for example, saying "addition of magnesium oxide to Verapamil treatment protocol enhances the antimanic effect". Just google and have a look at that, maybe you have some explanation.
      You advised me on 20mg Verapamil, but I use 40mg, as I am not sure if my son will engage back to SIB.
      I have been using Verapamil for less than a month and I sense that its benefits go beyond its half life. We seem to have more improvement as treatment proceeds. His focus, for instance, becomes better and better and he doesn't need stimulants, like nicotine patches.
      As for Baclofen, it does seem to help him when levels of anxiety are unbeatable, 5mg of it have worked in this case.
      My new doctor suggested trialling B12 and for GI isuues 22mg zinc with a probiotic called VSL3.
      Peter, I just can't help thinking how/why/how long.. a calcium channel blocker would stabilize my son's disorder. It feels inconceivable.
      I am sorry for being long and sincerely thank you
      for your kind concern.

      Delete
    3. Petra, melatonin has numerous effects in the intestines. Most melatonin is produced there and not in the pineal gland in the brain. It has been shown to help in reflux/ GERD and even ulcerative colitis. I had not realized this before, so I think long term melatonin use is safer than I thought. If it all came from the pineal gland, then supplementing it might lead to the pineal gland stopping to make it. Apparently 400 time more is made in your gut, which is where the supplement is going to.

      People with various GI issues are found to have low levels of melatonin and studies show good results with supplementation.

      Are you giving 40mg of verapamil once a day, all in one go, or split in two doses?

      Delete
    4. I split it in two doses.

      Delete
  18. Peter hi! My 14 year-old son is suffering from Asperger's and Tourette's with his tics being too severe lately. He seems to be having a hard time because he has both, motor and vocal tics. At present, he is on 4 mg Risperdal and 1 mg Clonotril but with no visible imrovement. I am thinking of trying Baclofen or Verapramil. Which of the two works better for Tourette's? In case he starts taking either of these should i stop giving him Risperdal or Clonotril? Thanks in advance!!

    ReplyDelete
    Replies
    1. Baclofen would seem a good choice given how it is used on-label and off-label. It likely will help the Asperger's and/or the Tourette's, based on the evidence so far that most do respond.

      Risperdal has many known problems. It would be wise to trial Baclofen by itself, rather than taking a cocktail of potent substances. I give Clonazepam (clonotril) but a dose 40 times lower.

      Verapamil might help, but you would have to try it to find out. The effect is seen very fast, if he is a responder.

      Delete
  19. Dear Dr Agnieszka Wroczyńska Peter has asked that I direct this question to you please could you answer it .I have a son 7 years 27kg who has done well on loratadine,Zyrtec, sodium cromoglicate.Latter two for abdominal and stomach issues.The decision would be to use Rupafin. I am thinking to cease with the Loratadine and use in its place the Rupafin, to be given in the morning .The tablets are in 10 mg would I still give a 10 mg or divided into a smaller proportion which will be tricky as they have to be crushed.if I mix the Rupafin and the sodium cromoglicate together to give at one time would this be okay?or should I remove the
    Sodium cromoglicate altogether.in other words would rupafin be more effective with the other drugs or less effective. Thanking you.
    We hope to trial verapamil but as for now since we have no way of getting this prescribed we at least want to try this next it will verapamil,out of curiousity would verapamil be able to take the place of all these allergy medications




    Dear Dr Agnieszka Wroczyńska Peter has asked that I direct this question to you please could you answer it .I have a son 7 years 27kg who has done well on loratadine,Zyrtec, sodium cromoglicate.Latter two for abdominal and stomach issues.The decision would be to use Rupafin. I am thinking to cease with the Loratadine and use in its place the Rupafin, to be given in the morning .The tablets are in 10 mg would I still give a 10 mg or divided into a smaller proportion which will be tricky as they have to be crushed.if I mix the Rupafin and the sodium cromoglicate together to give at one time would this be okay?or should I remove the
    Sodium cromoglicate altogether.in other words would rupafin be more effective with the other drugs or less effective. Thanking you.
    We hope to trial verapamil but as for now since we have no way of getting this prescribed we at least want to try this next it will verapamil,out of curiousity would verapamil be able to take the place of all these allergy medications





    ReplyDelete
    Replies
    1. Hello,

      My son has been on Rupafin, Sodium cromoglicate (Nalcrom) and Verapamil for more than a year. He is 8yo and diagnosed with mast cell activation syndrome. Each of these three drugs had its own distinct good effect in my son. The beneficial effects of Verapamil in my son exceeded its mast cell stabilizing effects and this is related to calcium channel dysfunction which has long been associated with autism and may affect a human body in many different ways. You can read many excellent Peter’s blog entries on Verapamil.

      I couldn’t replace other allergy medications with Verapamil in my son, but it was Verapamil which eliminated his chronic GI issues and had a significant impact on behaviors. You can read the information about my son in the questionnaire here:
      https://docs.google.com/document/d/1p7ShmEN-WrP-03kixLH3pAG0ZphjEGWWOFGOvaBrPUI/edit
      Or you can follow my comments from 2014 just under the Autism and Allergies section (caution: they are too long ;-)

      You can use Rupafin together with Sodium cromoglicate. They are used for allergies or mast cell activation and both are considered mast cell stabilizers but have different mechanisms of action so you can expect different effects. It think that is difficult to predict before you try which one is best for your son or if you can use one of them instead of the other. Sodium cromoglicate is a drug targeted at GI tract mast cells but it is reported to have beneficial effects not only for abdominal issues and this is what I can see in my son. Rupafin has many interactions with other drugs, so you have to be cautious with new drugs then.

      Typical dose of Rupafin for allergies in children up to 11 yo and weight ≥25 kg is 5 mg daily, but I also use 10 mg. I cut the pill with a tablet cutter and give it in the morning and evening, but it may be possible that your son does not need 10 mg or can take a pill one time daily.

      I could probably discuss this in details with more medical information about your son, feel free to contact me via e-mail above if you think that would be helpful.

      Delete
  20. I will do,exactly that but will leave out the loratadine will try this and get back to you with any issues Thank you .I will mixed them both together and give at in the morning
    I will start at 5mg and observe

    ReplyDelete
  21. Agnieszka,

    I am happy to report that I finally got a prescription for Verapamil from our new physician. It took 2 years of "selling" it, but finally we have found an open minded physician. We are going to start with 20mg twice a day and increase it 3x a day if we see positive results.

    We should be starting it in a few days so lets cross our fingers and hope for the best!

    ReplyDelete
  22. I am glad to hear about this and wish you success with treatment for your son. Fingers crossed here.

    ReplyDelete
    Replies
    1. Hello Peter and Agnieszka Just wanted to say a big thank you ,for your ever so selfless contributions to this forum
      Peter I wonder if you attended the conference last Weekend ?Agnieszka Wroczyńska was ever so gracious with her time and explanations she even managed to squeeze in time ,to answer questions despite having a plane to catch.
      Peter could I be ever so forward as to ask if you did attend was there anything that caught your fancy and would be of interest to share .Agnieszka likewise you was there anything that you would like to share or discuss .
      Looking forward to your replies .

      Delete
  23. Hi All, need you advice on verapamil.I just started my son, (15kgs) on a very low dose. I quartered a 40 mg pill... so I essentially give him 10 mgs a day. once a day. My son tends to be quite sensitive to meds... and for example with bumentanide he took the tiniest tiniest bit and it was too much for him. So the verapamil at 10 mgs is ceratainly helping his GI... great bowel movements these last few days... but nothing else? What else might I see? Should I increase the dose do you think?

    ReplyDelete
    Replies
    1. Audrey, depending on the individual Verapamil can have different benefits. Some are immediate, but there are other potential long term benefits that are more difficult to assess. My son has no GI issues, but has allergy triggered self injury, but with verapamil and Biogaia Protectis the issue is now 100% resolved.

      Verapamil has a short half-life, so it is better to have more frequent doses than higher doses. Your son is small so 10mg is not such a small dose. I would stay at that, but look at a second dose later in the day. Verapamil increases autophagy/mitophagy which does not work properly in some autism, for those people Verapamil should give long term improvements. Autophagy is the cellular garbage collection service, if this is not working then the cells accumulate things that should not remain there.

      I would only use Verapamil if you see useful benefits, like GI issues. Nobody can really say how long the many other potential benefits might take to become apparent. Excess physical calcium and aberrant calcium channel signalling are known features of autism; Verapamil will have an impact on this.

      Delete
    2. thank you Peter. What is the Half life? How far apart should I space the dose? Is it harmful to give verapamil WITH amantadine?

      Delete
    3. Half life is a very useful term. It tells you how long it takes for the amount of the substance to decay to 50% of the initial peak value. So Verapamil has a half life of say 4 hours, this means after 4 hours the level has fallen to half the initial value. At some point the level is too low to have any effect. In my son 20 mg of Verapamil is effective for 4 hours.

      If in your son the only immediate effect is on his GI, I would give the second dose 12 hours after the first. If you establish that the only effect is the GI one, and this is achieved with one dose a day then I would go back to one.

      The GI effect was covered here:-

      https://epiphanyasd.blogspot.com/2016/10/regulation-of-arachidonic-acid-aa.html

      This effect may last longer than the verapamil itself. So once a day for GI problems may be enough. You may even find that a few days of Verapamil may fix his GI issue. It is experimentation.

      The reaction with Amantadine you need to check. I did not see any when I looked on Google.

      Delete
    4. Audrey, I noticed GI effects of Verapamil within first two days of treatment, but improvement in other mast cell activation/allergy symptoms could be seen after about a week. Then came positive behavioral changes, clearly seen after about 3 weeks.

      Delete
  24. When I used Verapamil I observed some long term improvements, I wasn't able to assess in specific. Now I see that it helps with garbage collection and this might explain some behavioural changes we had.
    Please update with possible recycling service interventions.
    L reuteri DSM 17938 seems a very good idea. Do you think L reuteri ATCC PTA 5289 in Biogaia Prodentis might be helful with garbage collection, or other autism issues apart from periodontitis?

    ReplyDelete
    Replies
    1. There are many ways to increase autophagy. Here are some:-

      http://www.nature.com/cdd/journal/v16/n1/fig_tab/cdd2008110t1.html#figure-title

      Also as pointed out by Tyler, you can use spermidine, which is being trialed in Germany to treat dementia (which can be caused by too little autophagy)

      http://www.karger.com/Article/FullText/356748

      I think other probiotics may be helpful, you just have to try them. The ones I picked out that are available and might do something useful are:-

      Lactobacillus Reuteri NCIMB 30242

      Bifidobacterium infantis 35624

      Lactobacillus rhamnosus GG

      Lactobacillus Reuteri NCIMB 30350

      Lactobacillus Johnsonii NCIMB 30351

      Delete
    2. This is a great list of interventions. I think I need the pac-man effect as my son always complains about rubbish in his brain. Thank you.

      Delete
    3. My daughter is just finishing a course of antibiotics for hpylori
      Would anyone suggest a probiotic that could be used to balance out her good bacteria I do have a bootle of theralac would that do thank you

      Delete
  25. JB - Our 2nd trail of Verapamil can now be considered a success. When we first tried Verapamil, we were instructed to start low at 20mg twice a day (we cut a 40 mg tablet in half). We started it over the summer and did not see any change in behavior. Fast forward to late October, my son started his raging again with SIB and attacks on other family members. I noticed that this behavior seems to appear in Oct/Nov, so I suspected some kind of seasonal allergies and/or disturbance in his immune system. So we tried the full dose of Verapamil (40 mg / 2x a day) and poof!!!...the raging has stopped. There was one incident where the raging started and quickly escalated to the point where he was trying to bite me...like one of those fast zombies in the movie 28-days. We pinned him down and gave him the Verapamil. In SECONDS, he calmed and was back to himself.
    Agnieszka, Peter....it has been awhile since I have been on this blog, but what do you believe the the mechanism at work here is? Is it the calcium channel blocking, the anti-Inflammatory effect, both, or something else? Do you have any new information on dosing? We, as well as others, have also noticed a slight increase in his vocabulary and overall verbal ability, as well as some other behavioral benefits. My wife, who was somewhat skeptical of Verapamil before, pleaded with our Dr to write another prescription and was successful. That says a lot.

    ReplyDelete
    Replies
    1. JB, I am glad you have solved the raging/SIB.

      I think it is the calcium channel blocking effect that is the mode of action, but calcium channels are involved in numerous processes all over the body. The immediate effect is on allergy driven raging; it has no effect on other types of raging caused by inflammatory cytokines. The odd thing is that it does not improve the allergy itself. Mast cells degranulate via calcium channel signalling, by thought is that perhaps the SIB is caused by mast cells in the brain which somehow are stabilized by verapamil, while the ones in the nose are not.

      It cannot be a coincidence that verapamil can stabilize (some) mast cells, pollen allergy causes mast cells to degranulate, allergy triggers the raging/SIB and that verapamil use immediately halts the raging/SIB.

      The long term benefits could have numerous reasons, one being that autophagy is increased by verapamil. Autophagy is the cellular garbage collection process and it does not work well in autism and perhaps this impairs brain function.

      I think the dosing will depend on the person, for example we use 20 mg three times a day. If it takes 40mg to have the good effect then that must be the appropriate dose for you. As always, best to use the lowest dose that does the job.

      Delete
    2. JB I remeber your previous trial and I am very happy to hear about Verapamil being helpful for your son this time.

      Can you share if you use other medicatins at the same time now or is Verapamil the only treatment? Curious about possible interactions.

      Calcium channels affected by Verapamil have so many functions, so I am not surprised by its immunomodulatory/anti-inflammatory downstream effects:

      https://www.ncbi.nlm.nih.gov/pubmed/21467929
      https://www.ncbi.nlm.nih.gov/pubmed/20118567

      But if the effect is so immediate then other mechanisms could be involved (neurotransmission?).

      I hope Peter, Nat and others will share their thoughts on this.

      Autumn has always been a challenging season for my son, I wonder what can this mean? Allergy? Less vitamin D? "Back to school" psychological impact?

      Delete
    3. Peter and others,

      I am not so sure that the immediate rage-calming effects of verapamil are solely due to its mast-cell calming properties. I wouldn't bet on it.

      L-type calcium channels - those that verapamil acts on - are DIRECTLY involved in aggressive and self-harming behaviours in mice (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC24802/) so for all we know the same could be going on in humans.

      Also look up a paper titles 'EVIDENCE FOR ANTIAGGRESSIVE PROPERTY OF SOME CALCIUM CHANNEL
      BLOCKERS' (I only have a PDF version, no link) where again verapamil and other ca blockers eliminated aggressive foot-shock behaviours in mice. The authors speculate that: "These findings
      suggest that calcium channel blockers possess potent antiaggressive activity, which may be attributed to decrease in central dopaminergic and/or cholinergic mechanism."


      Delete
    4. here is the link to the second paper:

      http://www.sciencedirect.com/science/article/pii/S1043661897901493

      There is also this one, again noticing "that calcium channel antagonists have inhibitory influences on aggressive behavior and may facilitate endogenous opioid activity..." in the absence of any mast cell activity!!

      https://www.ncbi.nlm.nih.gov/pubmed/2436103

      Delete
    5. Nifedipine was the calcium channel blocker that stopped the SIB in mice, Verapamil did not help.

      Of course humans are not mice but it would be useful to see the effect of Nifedipine (plus Nimodipine, and Nitrendipine) in human SIB.

      In our case Verapamil only rescued allergy related SIB, we had a period of SIB caused by losing milk teeth, which causes a spike in IL-6, and unfortunately Verapamil had no effect.

      I am sure there are multiple biological causes of SIB. I am just glad I have solved our ones.

      Delete
    6. Peter do you think bacteria affects your son's behavior - re: the teeth? loose teeth, circulating bacteria? I see this in my son. So maybe a little something for bacteria could help with that behavior? Maybe even a probiotic strain that is beneficial for teeth/gums health. Just found an interesting paper on the antimicrobial effects of verapamil combined with tuberculosis treatment. This medicine amazes me.

      Delete
    7. That is true that verapamil had no effects where other ca blockers did, but only in the first study I mentioned. It worked well in the other two studies. It could be due to different ways of provoking SIB and aggression between the studies - the first study used a specific pharmacological agent, the second two a physical/electrical shock from what I remember. The different effects could be linked to different ways of administering verapamil too, and different dosages.

      Delete
    8. Tanya, I looked into what happens when you lose milk teeth and the body uses inflammatory cytokines to signal the milk teeth to dissolve. I think it is these inflammatory cytokines that cause autism flare-ups.

      Allergy also triggers the release of inflammatory cytokines.

      There is a Biogaia product for dental health.

      Delete
    9. Hi Peter and All,

      This is much off topic, but talking about anitmicrobial effects and/or regulating inflammatory cytokines, what shall we think about, if a child's behaviors or cognition improve on anitbiotic treatment given for other reason, say for H. pylori infection, mentioned in some other comment here recently.

      There is a good amount of parental reports of such situations and I could write also a few of mine about cefuroxime effects not listed in the package insert.
      Most reports are about macrolide antibiotics or beta-lactams, including commonly used amoxycyllin.

      By controlling the infection, antibiotic treatment will for sure control inflammatory cytokines release. On the other hand macrolides, as far as I remember, are known to be directly antiinflammatory, regardless of infection control. And beta-lactams, at least some of them, increase EAAT2 glutamate transporter expression. This is supposed to prevent glutamate neurotoxicity:
      https://www.ncbi.nlm.nih.gov/pubmed/15635412

      There is also PANS/PANDAS to be considered in some children.

      And I wonder if some of the effects seen can be related to microbiome issues/probiotic treatment during infection.

      How this all known mechanisms can be used for a child when anitbiotic treatment is finished?

      Also I have heard about children regressing when anitbiotic is over - how can this be explained (and prevented)?

      Trying to make this comment shorter: what can we do long-term if a child is improving on amoxycycyllin given short-term?

      Delete
    10. Agnieszka, this is very interesting and would explain why some people's autism improves while they are on common penicillin type antibiotics.

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

      You would think that people who respond to this might well respond to the other drugs that modulate the E/I balance. Do people who respond to bumetanide or baclofen respond to these antibiotics?

      Has this got mixed up with the fever effect, so people who are sick and on antibiotics attribute the autism improvement to the fever, when it was the antibiotic?

      Delete
    11. So indeed my son responds to both bumetanide and cefuroxime, which is beta-lactam. I was once very surprised to see immediate, next-day behavioral improvement when he got this antibiotic for dental issues and for sure peridental inflammation did not resolve until several days later.

      With regard to fever, it seems that they considered antibiotics in the study about fever effect:

      http://pediatrics.aappublications.org/content/120/6/e1386

      “One analysis considered the use of analgesics, antibiotics, and allergy medications, and a second, separate analysis considered the use of selective serotonin reuptake inhibitors and other psychotropic drugs; however, neither showed differential effects during fever.”

      Delete
    12. Agnieszka, I think for us the fever effect starts long before antibiotics and many hours before analgesics.
      Then being on medication it remains.

      Delete
    13. Of course a fever is the body's intelligent way of killing microbes. This study links fever with oxytocin : http://research.indiana.edu/2015/07/link-between-body-temp-and-autism/

      Delete
  26. Fall has always been the worst time for my son due to ragweed pollen. But not one moment of wheeze or bad allergy episodes since we started verapamil in the spring.

    ReplyDelete
    Replies
    1. Tanya, in your son is the main effect on allergy or behavior? Do you also use antihistamines or other allergy drugs?

      Delete
    2. Relatively quickly saw the improvement in behavior. Then gradually realized I didn't need to give him benadryl or allegra (should add we are over two weeks in trying mirtazapine - but I hadn't given any antihistamines long before the start of mirt.) I wasn't expecting verapamil to help with this and maybe it was a tincture of time or maybe less stress from a bad school placement he was in combined with finding a B complex he tolerates - I can't say for sure. But no doubt verapamil put out a huge fire for my son - and we were trying no other pharmaceuticals when started.

      Delete
    3. I recently started Verapamil for my daughter with GI issue. Also, I would like to try Bumetanide. Should I stop Verapamil while on Bumetanide?

      Delete
    4. You can use both at the same time.

      Delete
  27. I have a daughter who has Autism due to partial biotin deficiency. Will Verapamil help her? If yes. what is the dose and for how long?

    ReplyDelete
  28. I think it is not possible to say if Verapamil can or cannot help a child with autism and partial biotin deficiency without a trial. I remember this short story about a girl whose autism was biotin-responsive, but she also turned out to benefit much from acetazolamide (Diamox) given for another reason:

    http://www.ashg.org/2014meeting/abstracts/fulltext/f140122034.htm

    It may be the same with Verapamil.

    From what I can see the lowest dose used in autism is 1 mg per kg of body weight twice a day. Some people need more. I currently use 30 mg three times a day for my son who is 9yo, 27kg. I use it long-term.

    ReplyDelete
  29. Hello Agnieska again,

    I've always wondered why antioxidants work well only for a couple of days and then seem to stop.
    As I read, the potential benefits in neurodegenerative diseases of some classes of antioxidants may be compromised by their autophagy-blocking properties.
    We know very well that for some people, probably in autism as well, antioxidants are part of their therapy and can't choose not to have them.
    According to this hypothesis, do you think Verapamil might be an option to enhance autophagy so as antioxidants could reach their full potential?

    Regardless of antioxidants use, Verapamil was found successful treatment for people with NAFLD caused by overnutrition and obesity.
    Here is a brief conclusion:

    "Intriguingly, pharmacological inhibition of calcium channels using the FDA-approved drug verapamil successfully restores autophagic flux and suppresses protein inclusions, not only in HepG2 cells but also in mouse liver. Verapamil also reduces hepatic lipid droplet accumulation, insulin resistance and steatohepatitis, suggesting that calcium channel blockers can be used for correction of general NAFLD pathologies. Indeed, there have been a number of clinical observations in which beneficial effects of calcium channel blockers against obesity-associated metabolic pathologies are observed in humans and animal models."
    For the cases above, would you recommend the same doses you mentioned, 1mg/k twice a day?

    ReplyDelete
    Replies
    1. Hello Petra,

      It is plausible that enhancing autphagy with Verapamil may increase the effects of antioxidants, as you suggested, although I think that it might not be easy to check this in practice.

      1 mg/kg twice a day is typical low dose I am aware that parents use in their children with autism. Some need higher as JB reported here few days ago. I tried up to 8 mg/kg total per day divided, which is the maximum dose recommended in children's migraine, but could not see any additional benefit.

      I don't know if this is relevant to NAFLD effects of Verapamil. The paper you pointed to is very interesting, but quite short and without references. They wrote:

      "there have been a number of clinical observations in which beneficial effects of calcium channel blockers against obesity-associated metabolic pathologies are observed in humans".

      So it might be helpful to look for such reports, I will try to find some and let you know.

      Delete
    2. Thank you Agnieska. I sent this paper because it was the best I could find so far, just to have it in mind;I'll keep looking about possible relevance.
      Checking P450 would be wise before trialling Verapamil again.

      Delete
    3. Petra, P450 CYP3A4 is the most significant with regard to Verapamil metabolism. Verapamil is both metabolized by this enzyme and is a moderate inhibitor of CYP3A4:

      https://www.drugs.com/pro/verapamil.html

      I think that it is not very important in practice if you use Verapamil as the only drug interfering with CYP3A4, but of course it would be helpful to know for example if one is genetically prone to increased activity of CYP3A4 enzyme. Then you can suspect that higher dose of Verapamil may be needed.

      And such testing may be very useful if you want to use other drugs/supplements metabolized by CYP3A4 e.g. statins.

      http://www.aafp.org/afp/2007/0801/p391.html

      Tanya suggested Progenity Lab here for pharmacogenetic testing, but they focus on psychiatric drugs metabolism and I couldn't find CYP3A4 on their list.

      I've read a number of parental reports confirming that pharmacogenetics was helpful in psychiatric treatment and I like this idea. The more is known, the less trial and error needs to be used.

      Do you know where to test for P450 CYP3A4 genetic variants?

      Delete
    4. I also have 23andMe testing and ran the raw data through LiveWello to find out about other P450 enzymes. Many years ago we did a test through Genova Diagnostics called DetoxiGenomics.

      Delete
    5. Agnieszka, as you know we are supposed to be on the list of genome sequencing.
      On the other hand there are hundreds of children with severe neurological problems, not only from Greece, but all around EU waiting for this. My researcher doctor works overtime to handle huge amount of work. I can only respect this.
      Even if I went in private, which is over three times the price, and I can afford it, I should need the specific doctor to monitor the procedure. So I have to wait.
      I could also spare the extra money for my nephew's sequencing and we could then make a better case report.
      I may find a lab in Thessaloniki to test CYP3A4, but doing so it would be much more convenient to have as broader genome profile as I can at a time and a doctor to lead this investigation.
      We are "stuck" for the time being and hope not indefinitely.
      Thank you so much for clarifications and putting things in such brilliant order.

      Delete
    6. Thanks Tanya, did you find these genetic tests useful for treatment decisions?

      Petra, I thought about something more simple than WES, like this CYP3A4 genotype test apparently offered at Mayo Clinic to help with statin treatment:

      http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/61241

      Anyway, this is genetics only and there are also other factors influencing drug metabolism. I don't know if this may have a practical impact, but probiotics have been suggested to be involved also:

      "In conclusion, conventionalization and VSL3 alter the expression of many drug-metabolizing enzyme s in the liver, suggesting the importance of considering "bacteria-drug" interactions for various adverse drug reactions in patients."

      https://www.ncbi.nlm.nih.gov/pubmed/26586378

      I wish you good luck with the waitlist for genome sequencing for your son. We are "stuck" here with WES too.

      Delete
    7. Yes I did find this information useful - as a part of the bigger picture - especially when you have a kid who cannot describe what he is experiencing in his body in terms of reactions and when it is not so easy to decipher. I am very interested in what you shared about probiotic and drug interactions (or any probiotic interactions for that matter) - intrigued! many unknowns about the microbes.

      Delete
    8. something to read:
      http://www.caister.com/cimb/v/v16/55.pdf

      Delete
    9. Btw speaking of medicines, I think these site might be a good resource to consider cross checking: nutrient depletion. I entered Verapamil, and it says zinc may become depleted. I read here Peter mentioning verapamil reduces melatonin and the site does list that, but didn't know about zinc.. Useful tool to add to the arsenal
      http://www.mytavin.com

      Delete
    10. sorry I am posting so many separate messages.... Another resource that might come in handy for some is to check certain nutrient interaction with the cyp450 enzymes. Alison vickery has a free download of this info.
      https://gallery.mailchimp.com/c4fd183dde8ed228e2dd57c9c/files/CYP450_Nutrient_Inhibitors_and_Inducers.pdf

      Delete
  30. Agnieszka ,Peter my daughter responds positively to hpylori treatment Amoxicillin.I think is the real game changer the acid blockers help as well .aggression, physical attacks on Carers has stopped ,she responds to nystatin, anthistamies and bumetandine as Peters has explained .
    I stopped the bumetandine ,nystastin,and during her hpylori treatment and true to say shes stopped waving back at us.
    I intend to put her back on bumetandine but need to do more to sort out her potassium level and magnesium levels .I have an effervescent suggested by Agnieszka but also need magnesium as levels are low our problem is magnesium makes her agitated and uncomfortable.
    Peter your biofar brand seems impossible to purchase online I know you say you get it in France do you go there physically to acquire it?
    My non verbal 7 year old daughter is back on nystastin and her anthistimies ,doing well in behaviour no speech though few words pop out now and then especially during the hpylori treatment .This is strange because she was not on nystastin at the time in the past her first short sentence was on her first dose of nystastin it was shocking to hear after that nothing as dramatic .Her receptive understanding has improved as well.
    She is not a responder to Verapamil which was very disappointing to me neither is she a responder to Biogalia Gastrus .A packet of Biologia protectis is left in the cupboard ,I am apprehensive to try it just now .Theralac is another probiotic she doesn't respond too it made her foggy by this I mean she was taking my hand to things she would normally have done without hesitation and looking in the wrong places for items.Culturelle I had previously used but cannot say it did anything for her. Rantadine H2 blocker had awful effects when I say this she was uncontrollable agitated ,biting etc very very bad I was surprised she didn't do well on this either as She has sometimes Reflux /gerd the PPi blocker helps omeprazole does cause her to itch very badly .I should mention she has GI problems and due to this we saw a well known gastrologist in Europe who gave ketotofin for her use a very small quantity .This was a miracle for her but after a year I noticed she was too quiet to calm and asked for another which has not been as much benefit .He has suggested we put her back on ketotofin shes older and has physically changed the results aren't as good as of yet.
    One of the GP gave me esomeprazole which has less of an itchy effect on her during the hpylori treatment ,but has said after this packet she will not give again as its not as good as the former this is untrue but the cost on the NHS is significant more I guess.I think she has at times headaches .Its hard to say .



    My thinking is that maybe I should trial out the statin or Diamox before going back on the bumetandine as to have a clear view of what helps and in which ways.
    Statin I am aware Co enzyme Q10 should given with it ,what dosage of statin and Co enzyme Q10 should be given to a 7 year old.or reading through post could I just give co enzyme Q10 ,50mg a day and see for a week and observe her behaviour ?
    What dosage of Diamox should be given.

    Which of the above do you suggest might be of benefit.
    I am putting so much detail maybe it can help another parent especially in the UK.

    Thank you.


    ReplyDelete
    Replies
    1. For the non-verbal affect, have you considered leucovorin as per recent Dr. Frye study, or tested for FRA antibodies?

      Delete
    2. I would try the Biogaia Protectis, it works for us but Gastrus makes things worse.

      The statin will show effect from the first pill, is she is a responder, so no need to use CoQ10 for your trial.

      I am not in the UK, but there must be a local brand of potassium, ask in Boots.

      Since your daughter has GI problems, you need to solve this first.

      I have never used pancreatic enzymes but some people, like in one recent comment, claim they work wonders. In that comment is was the enzymes plus VSL#3.

      Here is the comment:-

      https://epiphanyasd.blogspot.rs/2015/03/bumetanide-andor-low-dose-clonazepam.html?showComment=1479001215273#c3202429316811375330


      1.Try Biogaia Protectis (this works for us, while Gastrus made a problem for a week), take just a very small dose the first day
      2.Increase Bumetanide to 1 mg twice a day
      3.Try different K+ supplements. They are known to cause GI problems in some people. Or use a potassium sparing diuretic like Spironolactone.
      4.Try Verapamil again
      5.Try VSL#3 or Viviomixx to improve GI problems
      6.Try NAC and,if not tolerated, try ALA (Alpha Lipoic Acid) and see if that is tolerated
      7.Clonazapam is very safe at the low dosage and worth a try
      8. Acetazolamide is also worth a try, ask Agnieszka about dosage
      9.Montelukast is safe and easy to try
      10.Based on what worked for Alli, she might try 500 mg Sodium Butyrate, this might help GI problems and more

      Delete




    3. I am most grateful for your thoughts and time in making these suggestions.One thing that I totally agree on is the dealing with the GI Problems these have been going on for years her Hpylori and tummy issues being addressed is like day and night on both occasions .I am going to answer each suggestion Peter this is incase other parents find some help in them.
      With regards to the probiotics I will try the protectis .The gastrologist suggested that probiotics should be used at bed time .Depending on the outcome I will trial VSL#3 The effects of the probiotics are clear the next morning .my trial will be next week out of all of the suggests this is the one I am most apprehensive as the results if not wanted can be pretty awful and stick for a period of time.
      I have initally trialled bumetandine 2 mg a day this .I think resulted Her feeling dizzy ,effect she was crying and would /could not climb down the stairs on her own she insisted on being carried.Bumetandine works for her just as you said it works but at 1mg a day.
      I will continue to look out for and try other potassium supplements .I have a feeling its the addition of magnesium that might give more benefits than without.
      ALA can I ask what is a safe dosage? and does it matter how its used as in due to its half life does ,does it really have to be used every couple of hours or is this unnecessary.
      I definately have clonazepam on my list to try. Agnieszka has given some information on Acetazolamide its one of thoes that will have a pretty quick response .
      Montelukast although she does not have asthma ,I am aware of the benefits this medication could bring .I will trial this last reasoning is one of the side effects is abdominal pain enzymes always brought this effect of pain ,I am certain she had hpylori during this period .I will retrial the enzymes later on I wonder what the interaction with Nalcrom might be though.
      I will ask the private doctor who is at times useful, to support with the FRA antibodies .Thanks to the poster of this suggestion I am grateful.
      Peter I have a lot of home work to do .Im giving you another big STAR.. thank you ever so much

      Delete
  31. I forgot to include my daughters response to bumetandine was within 4 days.

    ReplyDelete
  32. Agnieszka, Peter and all,

    I have just come across this paper on verapamil's effects and thought to share here as it is I haven't seen it mentioned before. It talks about neuroprotective effects of verapamil on dopaminergic neurons from bacterial-toxin-induced toxicity, but the observation here is that a) mechanism was NOT linked to calcium blocking effects b) it happened via verapamil's calming action on microglia (again not linked to calcium channel blocking action).

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014428/

    "In this study, we report a novel mechanism underlying the neuroprotective effect of verapamil in rodent midbrain neuron/glia cultures. We demonstrated that instead of directly acting on neurons, verapamil protected DA neurons from LPS-induced neurotoxicity by inhibiting the over-production of superoxide from microglial PHOX. Mechanistic studies revealed that verapamil possesses neuroprotective effects not only through its well-known blocking activity on L-type calcium channels of neurons, but also can be mediated through its inhibition on microglial PHOX activity. This new finding suggests a new avenue for further new applications of this series of drugs in other inflammation-related diseases. … Verapamil suppressed over-activation of microglia by reducing the production of superoxide, NO and cytokines such as TNF-α…"


    On the topic of activated microglia, another very interesting paper just came out on them being key in PAIN signalling – activated microglia initiate and amplify sensations of pain. My thinking is that this could well be involved in disturbed pain signalling in autism (insensitivity to external pain stimulus, while at the same time suffering ‘out of nowhere’ pain, the one stemming from activated glia producing ‘imaginary' pain signals?). could possibly be another reason why verapamil reduces and/or stops aggression and SIB in some of our kids?

    'Pain-initiating function of glial cells identified for the first time’ http://medicalxpress.com/news/2016-11-pain-initiating-function-glial-cells.html The paper itself is interesting and talks about purinergic px2 receptor being central here (remember suramin!). “…If the presently identified gliogenic (long term potentiation) also existed at some brain areas, it could be of relevance not only for pain but also for other disorders such as cognitive deficits, fear and stress disorders, and chronic immune-mediated diseases"

    ReplyDelete
  33. This is highly speculative, but could these "autism flare-ups" that are mentioned be related to the biology behind ODD (oppositional defiant disorder, highly comorbid with ADHD)?
    /Ling

    ReplyDelete
  34. We tried Verapamil (40mg) for a few days during meltdowns this week but it seemed to make our son super anxious shortly after/clingy.

    Not sure how to stop the meltdowns/stomping feet when he doesn't get what he wants, will keep plugging away :-/

    ReplyDelete
  35. For anyone interested in convincing their doctor to prescribe a calcium channel blocker like Verapamil for a trial. These excerpts from relevant papers that I've gathered might be useful:

    Channelopathy pathogenesis in autism spectrum disorders
    Front Genet. 2013; 4: 222.
    Galina Schmunk and J. Jay Gargus

    The sum of the growing evidence supports the role of calcium signaling as one of the major participants in the pathogenesis of ASD, making it a promising therapeutic target.

    L-type calcium channels as drug targets in CNS disorders.
    Channels (Austin). 2016
    Ortner NJ, Striessnig J.

    L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases [..] Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value. [..]
    Despite their different biophysical properties and physiological functions, both brain channel isoforms are similarly inhibited by existing calcium channel blockers.

    CACNA1D De Novo Mutations in Autism Spectrum Disorders Activate Cav1.3 L-Type Calcium Channels
    Biol Psychiatry. 2015 May 1

    A Pinggera, A Lieb, B Benedetti, M Lampert, S Monteleone, K.R. Liedl, P Tuluc, and J Striessnig
    [T]he discovery that Cav1.3 gain-of-function causes [..] seizures, neurologic abnormalities, and intellectual disability, suggest that Cav1.3 gain-of-function mutations confer a major part of the risk for autism [..] Our findings have immediate clinical relevance because blockers of LTCCs are available for therapeutic attempts in affected individuals.

    The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions.
    Cell Calcium. 2015 Dec
    Marschallinger J et al

    Thus, modulation of LTCC activities may have a crucial impact on neurogenic responses and cognition, which should be considered for future therapeutic administration of LTCCs modulators.

    New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy.
    Hum Mol Genet. 2017 Aug
    Pinggera A, Mackenroth L, Rump A, Schallner J, Beleggia F, Wollnik B, Striessnig J.

    Additionally, we also found that mutant channels retained full sensitivity towards the clinically available Ca2+ -channel blocker isradipine. Our findings [..] encourage experimental therapy with available channel-blockers for this mutation.

    Hopefully this saves someone time and effort.

    /Ling

    ReplyDelete
  36. Just have to share some disappointment...
    Our neurologist refused to prescribe Verapamil, mostly based on the fact that it had not been used before in any similar case. Ouch! I worked like 4 weeks full time preparing scientific research for her.

    /Ling

    ReplyDelete
    Replies
    1. Ling, I think this is not a surprise. You need to find an open-minded doctor who admits he/she does not know everything and is open to try something new, but safe.

      Doctors are naturally wary of anything unproven, particularly when treating a young child. It anything goes wrong, it becomes their fault.

      Maybe you should go and see Agnieszka for a consultation.

      Delete
    2. Well, at least she did an effort to understand the science and asked colleagues for experience. I can not blame her too much. My consolation prize was prescribed melatonin, so at least I can check that off my list.

      This paper is a bit off from the topic, but it touches upon Verapamil.
      https://www.dovepress.com/enhancement-of-absorption-and-bioavailability-ofnbspechinacoside-by-ve-peer-reviewed-fulltext-article-DDDT

      It's about oral bioavailability and intestinal absorption kinetics and the substance tested in the study was Echinacoside. I haven't heard about it before but is common in chinese traditional medicines and has antiosteoporotic, vasorelaxing, neuroprotective, hepatoprotective and antioxidant effects so maybe something to check up. Anyway, to enhance the poor absorption of Echinacoside different substances were tested, among them verapamil, probenecid and clove oil.
      Verapamil and clove oil showed the greatest results.
      Not sure what conclusions to draw, but interesting at least.

      /Ling

      Delete
  37. Ling, I did not do near the scientific preparation you did in the area that you did but I can tell you this. I found a connection to electrosmog and mast cell degranulation, seizures, motor dysfunction, and dysautonomia. My son was having one to two seizures a week at school on the keto diet and with a VNS. I was also using CBD. I knew the seizures were related to neuroinflammation and I knew that electrosmog was the culprit. I asked to allow an engineer to measure the fields in the new school and I was denied. The science is in the NO/ONOO cycle, electrical models of epilepsy, and calcium channels. I faced the same issues with the many neurologists ignoring my data and requests and science presented to them on the cause. My son spends 23 days seizure free when he is not at school under the electrosmog. Most of his seizures occur from viral infections causing temperature increases. What is severe is the bio persistent exposure and the acquired environmental sensitivity where he suffers many disabling symptoms that severely adversely effect learning and function.

    I was told by Dr. David Carpenter that the only treatment for electrohypersensitivity thus far is avoidance and that has worked the best in my case. I have not received report of denovo mutations where you have listed.

    I am just giving you an idea. For me the mast cell degranulation rash looks the same as I have seen in other children who have allergies. His face is very puffy and he has anger and agitation at school.....Of course this all resides to a more manageable baseline under non exposure conditions. The disorganization and sensory seeking behavior is a phase one exposure sign I see and then it moves into other phases but I get him out of the exposure zones as soon as possible to avoid the worst case scenario seizure. Every store seems to have wifi where we live in the US. Hope this story helps someone.

    ReplyDelete
  38. Hi Peter, got hold of the Verapamil today, 40mg sourced online. The medication clearly works for this inflammatory type of ASD.. I felt a reduction in nasal congestion and making small talk with people and eye contact felt improved (locked eyes with a girl and she smiled whereas I'm usually just an awkward mess, even managed to have a chat with the cute girl sat across in Starbucks), however I experienced a flutter of the heart (once) later on in the afternoon. I'm slightly concerned as the information leaflet says to tell the doctor immediately if palpitations occur. What are your thoughts on this? This Bupa article on Calcium blockers mentions palpitations as being a common side-effect (https://www.bupa.co.uk/health-information/heart-blood-circulation/calcium-channel-blockers) but the other information specifically on Verapamil refers to it more as serious and rare. I'm not sure what to do as I've not had this prescribed and don't have a doctor to consult with. I might just try 20mg tomorrow and avoid caffeine as I'd had a coffee before which might not have helped.

    ReplyDelete
    Replies
    1. Adam, all drugs and supplements can have side effects. Palpitations are listed as a rare side effect of Verapamil, so clearly for some people Verapamil will not be suitable.

      Since you are self prescribing, you have to balance the risks. If you worry too much about side effects you will give yourself palpitations. Trying a lower dose would seem a good idea. If you conclude that Verapamil does cause you palpitations, you should not take it.

      A rare side effect that affected one doctor reader's daughter is gingival hyperplasia. This is gum enlargement/inflammation.

      Most people take Verapamil with no side effects, but a small number of people do not tolerate it.

      Delete
  39. Thanks Peter. I've lowered the dosage to 20mg and no sign of the any palpitations but still very effective. It's incredibly effective for me but my aspergers is quite mild. You're doing truly great work with this site, Peter. I'd encourage everyone who can't get Verapamil from their doctor to source online from a CIPA listed pharmacy - totally a needs must considering all the drugs supplied are safe and legit.

    ReplyDelete
    Replies
    1. I really want to try Verapamil again, but I'm scared of the palpitations. I just want to take this under medical supervision but can't find someone suitable. Any ideas of an approach to try Verapamil and have my heart monitored by a medical professional? Happy to travel outside of NZ.

      Delete
    2. Adam, there is more and more evidence to support the use of L-type calcium blockers in autism. There will be another post on this.

      The downside is that these ion channels are widely expressed outside the brain and so some people will have side effects. There are other L-type calcium channel blockers, like Nimodipine, and they have slightly different side effect profiles. Verapamil rarely has side effects.

      I think every doctor would tell you not to take Verapamil if it causes palpitations. I think many people with autism have palpitations caused by anxiety, but if yours are caused by Verapamil, it is not a good choice.

      If you find an enlightened cardiologist he might have other ideas like Propranolol + Verapamil, but he more likely will warn you off. I did take my son for a full checkup with a cardiologist (ultrasound/ECG etc) because many autism therapies can potentially affect your heart and care has to be taken.

      Delete
    3. I was just thinking about having an ECG whilst on it. I might just take some and then go to the doctors to have an ECG and check my heart rhythm. Haven't taken it for a month so should be all good.

      Delete
  40. Is there any more published material about verapamil's affect on autism. My son has Autism and Cluster Headache. He was prescribed Verapamil for the headaches. I am interested to know how this works for both conditions and does this medication have an effect on reducing oxalates. My son has symptoms of high oxalates and a numerous amount of people with Cluster Headache tend to have kidney stones or other issues with their kidneys. I want to see if I should have my son's kidneys looked at.

    ReplyDelete
    Replies
    1. There is material on cluster headaches and verapamil, but even that is pretty basic.

      Verapamil blocks L-type calcium channels. If you look at the relation between genes implicated in autism/epilepsy the genes encoding L-type calcium channels and genes encoding some sodium channels are all inter-related. So a person with autism or epilepsy might find a benefit from Verapamil even if they do not have a genetic dysfunction directly affecting Cav1.2 (the presumed main target of Verapamil).

      Verapamil has broad effects because L-type calcium channels are all over your body, not just in your brain and heart.

      Kidney stones are made of calcium oxalate.

      Verapamil is effective in reducing urinary oxalate excretion in hyperoxaluric patients.
      https://pubmed.ncbi.nlm.nih.gov/8322624/

      On cluster headaches:

      Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives
      https://pubmed.ncbi.nlm.nih.gov/31339562/

      Calcitonin gene-related peptide (CGRP) is elevated during CH attacks and can provoke CH attacks. CGRP is believed to play a role in central sensitization and CGRP-release is controlled by voltage-gated calcium channels.
      Potential Mechanisms of Verapamil in Cluster Headache.—The hypothalamus and trigeminal autonomic reflex play a major part in CH pathophysiology, but the integrated disease mechanism remains unresolved. Thus, understanding verapamil’s effect mechanism might increase our understanding of the disease itself. Based on the available studies, we hypothesize that verapamil modulates circadian oscillations or CGRP-release through its ability to block calcium channels.

      Delete
  41. This makes so much sense to me. I was diagnosed with severe panic disorder and Asperger’s when I was quite young. My panic attacks were so intense that I would try to jump from a moving car. In my mind I believed that if I was running, my heart would not stop - I thought I was dying. The tachycardia led them to put me on isoptin, no idea of dosage. So many of my symptoms changed when they put me on this medication. My anxiety decreased so much, I gained weight (had been severely underweight) and my behaviours completely changed.

    ReplyDelete
    Replies
    1. Isoptin is a branded version of Verapamil, for others who read this interesting comment.

      Delete
  42. Just to add my 2 cents, I was diagnosed with Asperger's and generalized anxiety disorder. I used to have intense anxiety attacks at night, and my heart would beat so fast that I was scared I was having heart attacks. The intense anxiety would prevent me from sleeping until 2 or 3 am. I tried verapamil for my allergies and so much of my behavior changed suddenly.

    Like the above commenter, I was also underweight, and without anxiety, my weight shot up. I am also better able to control my emotions.

    ReplyDelete
  43. I guess verapamil increases autophagy in the gi tract. Probably would be a good addition to decrease "leaky-gut" symptoms.

    Verapamil-induced autophagy-like process in colon adenocarcinoma COLO 205 cells; the ultrastructural studies

    https://www.sciencedirect.com/science/article/abs/pii/S1734114012708964

    ReplyDelete
  44. This too.

    Verapamil alters eicosanoid synthesis and accelerates healing during experimental colitis in rats

    https://pubmed.ncbi.nlm.nih.gov/1312974/

    ReplyDelete

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