Today's post is Agnieszka's new guide to the safe use of bumetanide as an autism therapy in children.
Since most people actually read this blog on their smart phone, the document is repeated below and it will be much easier to read on a smartphone in the blog format, rather than the PDF document, because your phone should adjust the formatting.
It is clear that most people treating autism are using Facebook and a smartphone. I am doing it with a big computer monitor and twenty windows open, each with a different scientific paper. In the end all that matters is the result.
It is clear that most people treating autism are using Facebook and a smartphone. I am doing it with a big computer monitor and twenty windows open, each with a different scientific paper. In the end all that matters is the result.
Practical Tips for Parents and Professionals
Agnieszka Wroczyńska MD, PhD 1, Peter Lloyd-Thomas MEng, MBA2
1. Medical University of Gdańsk, Poland
wroczynska@gumed.edu.pl
Bumetanide is a prescription diuretic drug usually used to treat heart diseases or hypertension in adults. It also affects neuronal chloride regulation and was found to improve the quality of life of autistic children targeting core autism symptoms in clinical trials in Europe. Bumetanide has been used off-label in children and adults across the autism spectrum for several years, mostly in France. It is a safe drug with a long history of use in medicine and well-known precautions ensure side effects are avoided.
Details of bumetanide’s mechanism of action and its beneficial effects in autism were discussed elsewhere – see the references below. According to the most recent review of bumetanide clinical trials in autism:
"Current evidence suggests bumetanide, with close monitoring, may be useful in patients with moderate to severe ASD when traditional behavioral therapies are not available or an irritability-modifying pharmacological agent is not required” [James et al. 2019].
#1 Myth: Bumetanide is an experimental drug.
No. Bumetanide has been used in medicine for years. It’s safety profile and recommended precautions are well known and understood. Bumetanide has been studied in both adults and children and found to be well tolerated.
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Bumetanide treatment should be supervised by a physician. Multinational phase 3 trial of bumetanide for children with autism aged 2-17 years of age started in Europe in 2018. If you live elsewhere and consider bumetanide, this article can be used as a practical companion to ensure safe treatment. It is written for parents and physicians who are not experienced with diuretic use in children or bumetanide itself. While bumetanide’s safety precautions can be summarized in short as “drinking more water, eating bananas and if required, use potassium supplementation”, this document aims to explain those in detail and provide practical tips for a variety of clinical scenarios.
Who can use bumetanide? What should you do before starting bumetanide?
If you are considering using bumetanide, make sure to check with your doctor if there are any contraindications in your child. Bumetanide is a sulfonamide drug. Children with allergy to sulfonamides should not take bumetanide. Another sulfonamide drug commonly used in children is an antibiotic called trimethoprim/ sulfamethoxazole (TMP/SMX), also known as co-trimoxazole. In many European countries co-trimoxazole’s brand name is Bactrim. If your child is allergic to co-trimoxazole (Bactrim) or any other sulfonamide drug, then bumetanide should not be used.
It is important to make a distinction between sulfonamide drugs and other sulfur-containing medications and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group. Allergic reactions associated with sulfonamides are not associated with sulfur, sulfates or sulfites intolerance.
The full list of bumetanide interactions with other drugs is long, but most of the drugs included are not usually used in children.
Children with liver or kidney diseases as well as those with abnormal ECG (electrocardiogram) findings were excluded from the French bumetanide trials. If your child suffers from one of these conditions you need to discuss bumetanide safety with the relevant specialist. Epilepsy does not preclude bumetanide use. In fact, preliminary research showed bumetanide has a positive impact on seizures in temporal lobe epilepsy in adults.
What laboratory tests are needed before and during bumetanide treatment in children
Bumetanide is a safe drug, provided basic precautions related to its diuretic mechanism of action are taken. One of the most important safety considerations associated with bumetanide use is electrolyte balance. Bumetanide can affect electrolyte blood level and increase potassium loss. Extremely low potassium levels are dangerous, but this is preventable with simple measures in a person using bumetanide.
#2 Myth: Bumetanide use in children with autism is associated with significant risk of dangerous adverse effects.
No. Clinical trials and off-label prescribing experience proved that bumetanide adverse effects can be easily prevented in children. No dangerous symptoms were related to bumetanide in studies on its use in children with autism.
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No serious symptoms associated with low potassium levels or electrolyte imbalance were seen in children included into bumetanide trials and case reports so far. However, they might affect a child’s well-being and possibly reduce bumetanide’s positive behavioral or sensory effect. You may not see the expected results of bumetanide treatment if an adequate potassium level and hydration are not ensured in your child.
That is why it is necessary to test electrolytes levels (potassium, sodium, chloride, magnesium and calcium) before bumetanide introduction and repeat them, especially potassium blood concentration, after the treatment is started.
In the French bumetanide trials several other blood tests were offered to children i.e. g-glutamyltransferase, transaminases, alkaline phosphatases, glucose, uric acid and creatinine. While it is not required to order all of them in a similar way as in the research clinical studies, they are basic and cheap tests, available in most laboratories and it is prudent to check these parameters at least once during early phase of the bumetanide treatment. In clinical trials children were examined by a physician on a regular basis and had their heart rate, blood pressure and weight checked. Such approach also improves safety of bumetanide use. In turn, all these simple steps increase the chance of experiencing positive effects of bumetanide treatment. Bumetanide proved to be a safe treatment in the trials. Blood pressure and results of the routine tests did not differ between the bumetanide and placebo groups. Kidney ultrasound did not reveal any abnormalities during treatment. Children in the trials had also ECG (electrocardiogram) done as a precaution. It is prudent to offer a child such test as they are non-invasive and can be done in a stress-free manner.
As bumetanide is a diuretic drug, it is highly recommended to explain its effects prior to treatment and with the use of the communication means used by that child. Social stories, visuals and AAC tools can be helpful for some children. This approach can reduce psychological stress potentially related to the diuretic treatment in children prone to anxiety in new situations.
Fig. 1. Visuals can help a child anticipate and accept bumetanide diuretic effect prior to start of treatment.
The diuretic effect of bumetanide is strongest within the first 2 hours of taking the drug. Bumetanide given early in the morning (straight after waking up) lets the child avoid unnecessary toilet visits at school or kindergarten. Giving bumetanide once a day may be much more convenient depending on the person’s particular circumstances.
Starting bumetanide - what dose should be used and what to expect?
In the first randomized clinical trial in France the dose of 0.5 mg bumetanide was given twice daily to children 3-11 years old and was found effective in many of them. However, for some people this dose may not be sufficient as actually only about 1% of bumetanide can cross the blood brain barrier and act on neurons. In the 2017 bumetanide study doses up to 2 mg twice daily were trialed. While using higher doses may increase the amount of bumetanide that would reach the brain and so enhance the positive effects of the treatment, it also was found that drug-related adverse event risk is dose dependent and 0.5 mg b.i.d (twice daily) dose was found to be the best tolerated. It is a matter of a careful, individual trial to find an optimal dose for each person.
The benefits of bumetanide treatment can sometimes be seen as early as after 2 weeks, but it is not uncommon to have to wait longer. It is recommended to continue up to 3 months to assess the full impact of bumetanide use. Minor effects may indicate that the child is indeed a bumetanide responder, but the dose needs to be increased.
The beneficial effects seen in a child taking bumetanide are highly variable and individual. In general, this drug targets core autism symptoms and improvements in communication, social skills, including eye contact, speech and sensory issues were reported on bumetanide, as well as stereotyped behaviors decrease, better mood or increased cognition. Many parents can notice more awareness in their children and describe it as if “the fog has lifted”. Behavioral improvements were also reported on bumetanide e.g. reduction in aggressive behaviors.
The only known indicator of which people with autism respond to bumetanide, is a previous unexpected negative reaction to Valium (diazepam), or other benzodiazepine drug. These drugs should be calming, but in some people with the GABA neurotransmitter dysfunction targeted by bumetanide, the effect can be agitation and aggression.
How to control hydration in children using bumetanide?
Bumetanide belongs to the “loop diuretics” class of drugs which can lower blood potassium level and increase the body fluid loss. You need to monitor hydration in a child treated with bumetanide. If fluid consumption is increased to compensate for the diuresis, there will be no significant blood pressure lowering effect from bumetanide, nor will there be dehydration. The daily amount of fluid required varies, but it usually needs to be significantly higher than the volume drank by a child before bumetanide treatment.
Some children drink up to 3 liters (3 US quarts) per day while on bumetanide, others need less. It is safer to err on the side of too much fluid intake rather than too little. Drinking 3 liters of fluids a day in a teenager on bumetanide is not unusual.
In children who still wear diapers/nappies the amount of diuresis may cause a problem with leakage.
Monitoring hydration and potassium control are two key safety precautions in bumetanide use in children with autism. |
No severe adverse clinical symptoms related to dehydration were found during the bumetanide pediatric trials. However, a child who develops dehydration issues on bumetanide may feel unwell, so it is highly recommended to prevent it.
An easy way to check hydration status in a child is an assessment of mouth mucosa. You can ask your child to present her or his tongue and compare the tongue look with another member of the family. It can be made a good fun for younger children. If the tongue mucosa looks drier in a child on bumetanide, then you need to help the child drink more. Most children automatically drink more fluids, but some refuse to cooperate and drink more. Finding out beverages attractive for your child (e.g. drinking water from a dispenser, juice with ice-cubes etc.) may be useful in such a situation.
Fig. 2. Monitoring hydration may be done in a funny way to make the treatment stress-free.
Monitoring hydration with weight checks or measuring urine volume, while used in other situations, are impractical in a person on bumetanide.
You can read more on child dehydration symptoms here. It is useful to learn about those symptoms as a parent even if you do not plan to use bumetanide.
How to ensure enough potassium intake in a child on bumetanide?
Simple dietary modifications can provide necessary additional potassium and are recommended for every child on bumetanide. Use potassium salt and increase other dietary potassium in your kitchen. Bananas, kiwis, dried fruit, tomatoes are all examples of foods rich in potassium. The daily recommended intake of potassium is 3 to 4 g depending on age. A medium sized banana contains about 0.5g. Most people do not achieve the RDA for potassium but exceed the maximum limit for sodium, which is about 2g. More on potassium food content can be found here.
#3 Myth: Potassium supplements can cause serious heart rhythm issues in children on bumetanide.
No. Recommended potassium daily intake is well above the supplement doses usually used with bumetanide. Provided normal kidney function, there is no significant risk of dietary/oral supplement potassium overdose when typically recommended doses are considered.
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Apart from dietary modifications, low dose potassium supplementation can be used in addition to bumetanide from the beginning of the treatment. In the first weeks of bumetanide use it is also necessary to test potassium blood level. In the French trial blood potassium levels were checked before bumetanide introduction and then at 7, 30, 60 and 90 days after the treatment started. You may consider potassium blood level test sooner than after 30 days: it can be scheduled 2-3 weeks after bumetanide introduction to detect low potassium level early. The normal blood level range of potassium is 3,5 - 5,0 mmol/l. In case of abnormally low blood potassium level (which is called “hypokalemia”) you need to consult your doctor and add or adjust the dose of potassium supplement for your child. The target is to keep the potassium level well within the normal range. In the first bumetanide randomized clinical trial 22% of children taking bumetanide 0.5 mg b.i.d. (twice daily) experienced benign hypokalemia (low potassium), which was resolved by giving potassium gluconate syrup. In the next French trial the potassium level fell below normal range in 30% of children on that dose, but no serious potassium-related adverse event was seen. A potassium supplement was given to all these children to correct the low blood level.
The potassium dose should be adjusted individually according to blood level and repeat tests may be helpful. As some autistic children seem not to tolerate even minor drops in potassium level, you and your doctor may consider increasing potassium supplementation to keep its level in the upper normal range in those cases.
Side effects of bumetanide and how to manage them:
- “Accidents” caused by diuresis: need to plan ahead. Don’t give bumetanide before starting a long car journey or before sleep.
- Dehydration has many effects that you may not notice. Make sure your child carries a water bottle and so has easy access to fluids.
- Low potassium has many effects and so add potassium to diet as a precaution. Most people are nowhere near the recommended intake of potassium, so add potassium-rich food to diet.
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The optimal dose of potassium varies and is highly individual: few children need dietary modifications only, some use as low as 100 mg potassium daily, while some require 500 mg t.i.d. (three times a day) to maintain normal potassium level on bumetanide. Potassium supplements come in different forms e.g. syrup, effervescent tablets, slow-release capsules. Liquid supplements, including effervescent drinks, seem free from the risk of GI distress associated with tablets, which may be especially important in a child who is not able to communicate the pain. It is very hard to do harm by eating too much dietary potassium, because it is absorbed very slowly. Many potassium supplements are absorbed quickly and so giving more than 500mg at once is unwise. Note that in America most potassium supplement tablets do not contain more than 100mg.
It is necessary to actively prevent dehydration and potassium loss while on bumetanide treatment. The good news is that it is easy to achieve with simple steps described above. These precautions become even more important in children who struggle to report thirst and distress due to communication difficulties as well as in situations which make a child prone to dehydration regardless of diuretic use e.g. diarrhea, vomiting, fever or very hot summer temperatures, especially during physical exercise. If such issues occur, you need to be vigilant, consider a doctor’s appointment and potassium blood level check with additional supplementation as needed.
In case of persistent low blood potassium concentration it is recommended to check blood levels of magnesium as well. Magnesium deficiency may contribute to hypokalemia (low potassium). If this is the case, supplementing magnesium along with potassium is a solution. Low potassium levels can also be made worse by high sodium levels.
Is long term bumetanide use safe and practical?
#4 Myth: While on bumetanide every child is required to have often blood draws to check potassium.
No. Repeated blood draws are required at the beginning of bumetanide treatment to assess individual supplemental potassium needs. Later there is no need to test potassium on regular basis.
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Over time, on a proper diet and potassium supplementation, a child treated with bumetanide usually achieves a stable electrolyte balance, so control blood tests are rarely required on long term bumetanide treatment. In fact long term bumetanide use is very practical, and the simple safety precautions required are nothing compared to coping with untreated symptoms common in severe autism e.g. sensory suffering, which may significantly improve on bumetanide.
If a blood draw is an issue in a child with anxiety or sensory disorders, this is what might help:
- Visuals to reduce anxiety in a child e.g. picture social stories explaining blood draw procedure
- AAC used for communication in a non-verbal or minimally verbal children
- Video modeling or blood draw play at home before the procedure
- Skilled nurse and friendly environment, which can be arranged in advance
- At home blood draw service.
Fig. 3. Visuals can help with reducing the blood draw related anxiety.
It needs to be stressed that in general, presumed behavioral difficulties should not be a barrier to necessary medical examinations or procedures needed for health in autistic children, as avoiding them can result in increasing the medical risks in a population already prone to co-morbidities and poor health outcomes. It is the responsibility of the health provider and the parent to find the most convenient and effective way to perform the examinations needed. It is not unusual that all medical procedures get easier over the time in a child who uses bumetanide and develops communications skills and improves their cognitive function and awareness.
How to deal with the “bumetanide has stopped working” problem?
After some months or even years some parents may feel that “bumetanide has stopped working”, this may well not be their imagination and it can be very disconcerting. A little science is required to explain what may be happening. It appears that bumetanide responders have too many NKCC1 transporters in their neurons and too few KCC2. Only about 1% of bumetanide can cross the blood brain barrier where it blocks the NKCC1 transporter. An inflammatory response elsewhere in the body sends inflammatory signals throughout the body and some reach the brain where this causes an increase in NKCC1 and a reduction in KCC2 expression. This effect can wipe out the beneficial effect of that tiny 1% of bumetanide that is present. You can increase the dose of bumetanide and try and reduce the source of inflammation, which might be as simple as an allergy, or the cause might be harder to identify. There will be many other biological reasons why a shift in NKCC1/KCC2 might occur, so some detective work will be needed. The beneficial effect of bumetanide will then be restored.
Conclusions
Almost all parents whose children were included into the first bumetanide randomized clinical trial in France asked for treatment continuation after the study finished. Safe use of bumetanide for up to 2 years later were reported in this group. According to personal communication, bumetanide has been successfully subsequently used off label for at least 8 years in children and youth with autism, and no long-term issues emerged on long-term treatment. While this treatment does not offer an “autism cure”, it could significantly increase the quality of life of autistic persons thanks its potential to bring about improvements in sensory processing and hypersensitivity, cognition and acquiring communication skills (see published studies, linked below, for details on potential positive effects of bumetanide).
Acknowledgements: Thanks to Natasa Blagojevic-Stokic for language editing and comments.
Conflict of interest: none
References:
1. Lemonnier et al.: A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry 2012 2:e202. https://www.ncbi.nlm.nih.gov/pubmed/23233021
2. Lemonnier et al.: Treating Fragile X syndrome with the diuretic bumetanide: a case report. Acta Paediatr. 2013, 102(6):e288-90 http://www.ncbi.nlm.nih.gov/pubmed/23647528
3. Grandgeorge et al.: The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. BMJ Case Rep 2014 pii: bcr2013202092. http://www.ncbi.nlm.nih.gov/pubmed/24488662
4. Bruining et al.: Paradoxical Benzodiazepine Response: A Rationale for Bumetanide in Neurodevelopmental Disorders? Pediatrics 2015 136(2): e539-43 http://www.ncbi.nlm.nih.gov/pubmed/26216321
5. Lemonnier et al.: Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl Psychiatry 2017, 7(3):e1056 https://www.ncbi.nlm.nih.gov/pubmed/28291262
6. James et al.: Bumetanide for Autism Spectrum Disorder in Children: A Review of Randomized Controlled Trials. Ann Pharmacother. 2019, 53(5):537-544 https://www.ncbi.nlm.nih.gov/pubmed/30501497
7. Gharaylou et al.: A Preliminary Study Evaluating the Safety and Efficacy of Bumetanide, an NKCC1 Inhibitor, in Patients with Drug-Resistant Epilepsy. CNS Drugs. 2019, 33(3):283-291 https://www.ncbi.nlm.nih.gov/pubmed/30784026
Free AAC symbol source:
Roger, a great deal has been published. Bumetanide blocks NKCC1, which lets chloride ions flow into neurons. Some people with autism, Down Syndrome, Huntington's Disease etc have too many NKCC1 transporters and not enough KCC2 that let chloride leave neurons. They have abnormally high levels of chloride in their neurons, the result is that the GABA neurotransmitter functions in reverse, it is excitatory and not inhibitory.
ReplyDeleteThis drug also helps adults with autism and high intra-cellular chloride. It is not just for children.
It appears that this dysfunction is common in a wide range of neurological disorders.
Hi Peter and Agnieszka,
ReplyDeleteI just wanted to say Bravo and thank you for this incredible document! When I tried (unsuccessfully) to get Bumetanide, I had to put together the various papers on Bumetanide's impact on ASD, and then tried to explain safety and how one can mitigate potential issues (i.e. ensure hydration and use potassium supplements, etc.).
What I provided was too cumbersome and ultimately cobbled together by a parent, whereas this document is from a physician, is succinct, and easy for other physicians to read. What a great tool for all parents!
Thank you so much again Agnieszka and Peter! I will be taking another stab at the Bumetanide script later this year, and I think having this in hand will provide me with infinitely better ammunition.
AJ
Great great work! :)
ReplyDelete/Ling
Roger, it could be a mutation in the gene that expresses this cotransporter, but more likely it is an "acquired channelopathy", this means the gene is fine but something is causing it to be miss-expressed.
ReplyDeleteIn babies under 2 weeks old NKCC1 is mainly expressed, but then a switch takes place and NKCC1 fades away and is replaced by KCC2. NKCC1 allows chloride to enter neurons while KCC2 allows chloride to exit. Immature neurons have high chloride while mature neurons have low chloride.
Many different things trigger this GABA switch. In many people with autism the switch never flips and they have immature neurons their entire life.
Thanks for putting this document together, will be really helpful for those of us trying the get a doctor on board.
ReplyDeleteThank you Ling and AJ for kind words.
ReplyDeleteAJ, good luck with bumetanide approval for your child. In the US there are doctors who have already started prescribing bumetanide off label and I was recently told that Canada is less strict in requiring physicians to follow the prescribing labels and doctors should rather use the best available evidence in their clinical practice there.
Hi Agnieszka, thank you for the well wishes on Bumetanide. I certainly hope to access it this year. In the meantime, I have been trialing GS15-4 as a natural alternative further to the following paper:
Deletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142013/
It's always hard to tell what may be natural improvements versus improvements due to a new intervention, but my wife and I have noticed what we believe are cognitive improvements, which may be attributable to GS15-4.
I'll keep everyone posted, it's only been about 6 weeks or so, but it certainly appears to be trending favourably.
Have a great evening!
AJ
AJ, what dose of GS15-4 are you giving?
DeleteFor other readers, ginseng was covered in this old post
https://epiphanyasd.blogspot.com/2018/09/ginseng-as-gabab-antagonist-as-add-on.html
Another reader also highligted ginseng compound K.
Hi Peter, I'm using 100mgs X 2/day (morning and evening).
DeleteI too had trialed Panax Ginseng in the past, and I don't believe we saw improvements from it at that time.
Of course, we are also using Ketone salts right now (low dose), so there may be some synergy there that may explain why Panax Ginseng didn't work for us in the past, while GS15-4 seems to be showing some benefit.
I'm hoping to use any noted improvements, in conjunction with the fantastic Bumetanide document you and Agnieszka developed, when I look to get Bumetanide, using the rationale that if GS15-4's NKCC1 mechanism of action appears to be helping my daughter, that she is more likely to be a Bumetanide responder. By demonstrating an increased likelihood that she is indeed a responder via the GS15-4 experience, coupled with the risk mitigation protocol and therapeutic rationale in your and Agnieszka's document, I'm hoping to make a very strong case to doctors here.
I hope this is helpful Peter!
AJ
Brilliant guide, thank you both.
ReplyDeleteRS
Thank you very much Anna and Peter, this guide from a Doctor and a Scientist will help parents access Bumetanide from theiir children's doctors.
ReplyDeleteMy Daughter is now being treated by a Psycharist rather than her peadatrician, her Speech Therapist recommended we see him. This has helped greatly, as he uses amino acids with his other patients. He has been open to prescribe parts of Peter's poly pill and Bumetanide after reading the research.
My Daughter is still doing well academically, musically and is playing more interactively with her peers, taking their lead and spontaneously commenting to them. She has become a skilled drawer through watching YouTube and has taught herself to spell using sounds as well as sight words from her love of independent reading. She has hyplexia but understands what she reads, I believe because of the bumetanide.
Peter, thank you again for your research, it has made a massive impact on my Daughters quality of life. I am not her only advocate, her teachers, therapists and friends all believe in her now, which makes me hopeful for her future beyond my lifetime.
Peter, I have been looking at the papers on Methylfolate for use in autism for anxiety, do you believe this may benefit our children with ASD? I know it is used for depression and folate deficiency but can it also help with poor impulse control associated with flight risk and anxiety in children with ASD, if not what can, please?
Thanks Liz
Liz, folate is a B vitamin that is available in several different forms that should should broadly have similar effects.
DeleteB vitamins can react with each other. Folate (B9) together with B6 and B12 reduces homocysteine in your blood. Large doses of one B vitamin can have negative effects in some people.
The most potent is calcium folinate (Leucoverin) is a popular autism intervention in the US, in effect this is folinic acid. It slightly different to folic acid, but does have some of the same effects.
There are other types of folate, one being methylfolate.
Dr Frye’s “autism dose” of calcium folinate is 1-2mg per kg, which is a huge dose. The recommended daily amount of folate in an adult is just 0.4 mg (400mcg).
Some people with autism have a problem passing folate through the blood brain barrier and have folate deficiency inside the brain.
Calcium folinate has an unrelated effect that may help people with mitochondrial disease. It quenches peroxynitrites, which are produced in the process of nitrosative stress in the malfunctioning mitochondria.
Lower doses of folate have been used for a wide variety of conditions, including depression and anxiety.
Other possible treatments for anxiety in autism include Propranolol, which your psychiatrist will be very familiar with. It is widely used off-label and in recent comments in this blog has been found to be helpful at a low dose, such as 20mg twice a day or splitting the tablet and giving more often. Here is the relevant post.
https://epiphanyasd.blogspot.com/2019/04/the-autonomic-nervous-system-ans-heart.html
In some people Verapamil reduces allergy-driven anxiety.
This paper below on hyperlexia may be of interest.
The Neural Basis of Hyperlexic Reading
https://www.cell.com/neuron/fulltext/S0896-6273(03)00803-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627303008031%3Fshowall%3Dtrue
Children with autism spectrum disorders in very rare cases display surprisingly advanced “hyperlexic” reading skills. Using functional magnetic resonance imaging (fMRI), we studied the neural basis of this precocious reading ability in a 9-year-old hyperlexic boy who reads 6 years in advance of his age.
Hi Liz,
DeleteThat is great news!
Liz, I had trialed L-Methylfolate a lot time ago for my daughter, who had major speech delay and was also hyperlexic (but now always understanding what she was reading) and it wasn't helpful to us as I'm assuming getting folate across the BBB wasn't our issue.
Based on my research at the time, the best supplement I could find was:
https://ca.iherb.com/pr/Life-Extension-High-Potency-Optimized-Folate-5000-mcg-30-Vegetarian-Tablets/64992
Also Liz, are you in Canada? I've been trying to find a doc in Canada who prescribes Bumetanide and have been finding this a challenge (to say the least).
Thanks!
AJ
Thank you Peter, I will speak to my Daughter's Psychiatrist about the medications you mentioned, as our Daughter's 'flight reaction' is triggered by her anxiety.
ReplyDeleteAJ, I am happy your Daughter is reading and understanding, we are lucky to have that communication with our children. Thank you also for your feed back on L-Methyfolate.
No, I live in Australia, unfortunately it took five and a half years to find a Doctor who would look at the Bumetanide research. My Daughter's psychiatrist is very sympathetic to children with ASD, and believes in her intellect.
AJ, we use an IPAD Pro with a pen for our Daughter as she often reads and writes, more fluently than she speaks. She can also have longer interactions with her peers, who happily use the IPAD, as she can read their response and respond.
I hope you find a Dr in Canada soon,
Thank to You and Peter,
Liz
Hi Liz,
DeleteThanks for the kind response!
Yes, the Ipad has been incredible for us. In fact, that is what really helped my daughter with her hyperlexia - we bought her "Endless Alphabet" and "Endless Reader' (and Endless Numbers, etc.) and then we noticed she was able to put words together ata much earlier age than her peers.
The Ipad has been a life-changer for us, and it's also great on long trips :)
Have a wonderful day Liz!
AJ
Hi AJ,
ReplyDeleteSorry, for the delay, my sons have had Uni exams.
I used the originator kids app, when my Daughter was younger. Thank you, for the 'endless reader' heads up, it looks fantastic,
I have been using a PDF written by speech therapists on Hyperlexia and have found it to be very helpful, hyperplexia-therapy-that-works.pdf, for anyone that is interested.
Thanks
Liz
Hi Liz,
DeleteI completely understand, no worries about delays.
I'm so glad you like Endless Reader. I can tell you that my daughter also loved Endless Numbers, and could count to 100 (and by 10's) much younger than her peers thanks to that app. The people at Originator are brilliant for making an app that is both educational and so entertaining (and visually appealing). If you haven't tried Endless Numbers, check that out too.
Have a wonderful day Liz!
AJ
Hi Peter,
ReplyDeleteI would like to restart Bumex at 2mg per day to see if there is any added benefit.Last time it was 1mg and did not workDo you know of any potassium supplements that I could buy?
Thanks
SB
SB, potassium bicarbonate seems to be a good choice. You can buy it as a bulk powder. 1.2g of potassium bicarbonate contains 500mg of potassium. You add to water or any other drink.
DeleteDid anyone already link to this on Bumetanide?
ReplyDeletehttps://www.frontiersin.org/articles/10.3389/fnins.2019.00310/full
/Ling
Hi everyone
ReplyDeletehas anyone increased the dose of Bumetanide to 0.5mg 3 times daily?
What were your impressions? my son is 3 years old, non verbal.
Thank you in advance
HI.
ReplyDeleteMy son has a deletion on 1q41, which I also have. He is severly autistic, I am not, so the doc concludaed there is no correlation between this deletion and my sons autism. That was 4 years ago.
I just found out that this means my son has a deletion of the gene that is coding the protein KCNK2. This gene is coding a Potassium channel in the CNS. In our case, would the use of bumethanide be advised or rather prohibited? Or is this mutation rather irrelevant to the use of bumethanide?
Thank you so much for all that you do!
Enam, I think this gene is highly likely to be relevant to your son's autism. Often autism is caused by "multiple hits", one of which in his case probably was KCNK2.
DeleteThere is no obvious reason to connect this gene to bumetanide use. I think this mutation is irrelevant to the use of bumetanide. I would go ahead and make a trial of bumetanide.
All, so I have had my 5yo on bumetanide now for 22 days. We are seeing results in regards to spontaneous speech. Today he said "I'm hungry" he has never said that nor been thought it in aba. Normally he would just say "crackers" or the food he wants. He has always only just drank water. He is drinking more than normal and pees a bunch but there are no other adverse side effects. We are giving him .5mg first thing in the morning and .5mg in the early evening. The second dose may be less cause the pills dont cut into equals easily and I give the smaller half in the evening. We are seeing positive results however and I will continue giving it to him for now. He is moderate to severe but without any other medical issues, no allergies, etc. I wouldn't call it a game changer yet but we are definitely seeing results. Good luck all and hope everyone has a great school year!
ReplyDeleteScott, I'm glad your child responds to bumetanide.
DeleteThe effect is dose dependent. The lead ASD clinician came up with 0.5mg twice a day, whereas the French clinician using Bumetanide for Parkinson's uses 5mg once a day, which surprised me. In the autism trials the higher the dose the greater was the benefit, but the larger chance of diuresis-related side effects.
I found 1mg once a day much more effective than 0.5mg twice a day and more convenient.
I think you have to find the right balance between the benefits of a higher dose and the onset of side effects. The side effects usually relate to loss of potassium caused by diuresis.
Thanks Peter. I would have never found out about Bemetanide as a treatment for ASD or felt comfortable about giving this to my son without your blog.
DeleteI will probably switch to the 1mg in the morning. I'll also update if we start seeing other improvements in addition to spontaneous speech.
I should also mention we are supplementing electrolites with a product called hi lyte from amazon, we add it to his water 2x daily. We are in the us.
ReplyDeleteScott,
DeleteI have a 5 year old on the spectrum too. How did you get access to Bumetanide in the US (we are in Tennessee)? Our doctor won't prescribe it.
Hello Peter,
ReplyDeleteMy 8 years old son (classic autism, non verbal) has just joined the phase 3 bumetanide Servier/Neurochlore clinical trial for about 20 days (France).
Clearly he's receiving the drug, not the placebo as diuresis is there.
We're seeing new things he never did before (he calls his dad now, he plays more normally with his toys, better sleep,...). I'm glad to see he seems clearly to be a responder.
Is there any simple way to maximize the bumetanide effect?
I read for a while your blog and I want to thank you a lot for the deep knowledge you're sharing.
I'll keep you posted about clinical study progress if you're interested.
Regards,
M
M, you can maximize the bumetanide effect by increasing the dose. The higher the dose the bigger the loss of potassium, but this can be managed. You can also minimize any source of inflammation, since this opposes the action of bumetanide. For most people this means treat allergies and mast cell activation. Good luck.
Deletehttps://www.nature.com/articles/s41398-020-0692-2?fbclid=IwAR2ebcy3f3Oxrer6bLnsB0AgQqLoFBZQDrkqRuQy5zEgTdRhG93LNwoKxlc
ReplyDeleteI gave my 23 yr old his first Bumetanide dose of 0.5 mg today and it did not go well. He has very low cognition and also has OCD, hyperactivity, epilepsy. He only drinks water and is highly oppositional ( to the point of violence) at any attempts to increase his intake. Visual stories aids/ stories have never been successful for him either. One hour after the dose he completely flooded the kitchen and seemed completely unaware that he needed the bathroom. Would it be worth trying a much lower dose? Does the diuresis effect remain as strong throughout treatment?
ReplyDeleteThe diuretic effect is much stronger in some people than others. In some people it does fade, but not in most.
DeleteUntil a new purpose-designed drug is created and approved, you have to work around the problem.
Most people get used to the need to use the bathroom, but accidents are inevitable at the start.
To get the "autism effect" in a 23 year old you are going to need 1-2mg a day.
One doctor/professor reader of this blog had the same problem in his child and chose to use low dose clonazepam instead. It is a different mechanism, but it worked for his son.
I would keep trying bumetanide and hope your son learns the signs of needing to visit the bathroom.
If that fails, try low dose clonazepam.
Thanks so much for your reply and advice Peter.
ReplyDeleteOne comment with regards to this -- if GABA is an issue for a kid could one try a GABA supplement as a pre-cursor to bumetanide? In other words would GABA supplementation be a stepping stone to identify whether this is a root cause?
ReplyDeleteDan, if you want to identify a Bumetanide responder, one way is to take a dose of Valium/Diazepam. It is positive allosteric modulator of the GABA type A receptors. The normal effect would be calming, but in a bumetanide-responder the effect is likely to be the opposite.
DeleteGABA taken as a pill does not cross the blood brain barrier.
Picamilon is modified version of GABA that does cross into the brain.
I did try Picamilon, in my son and he had a negative reaction pretty fast, suggesting that even taking bumetanide, GABA is still not inhibitory. In other words in my son's case bumetanide is only partially effective. This makes sense because I see a further benefit when I add Azosemide to Bumetanide.
I spoke with a doctor (dr:Stefano Pallanti in Florence) about the bad reaction my daughter had to Valium and he said the cause is intestinal dysbiosis, in other words the response to benzodiazepine is altered because the microbiome is altered....does it make sense ?? carla marta
DeleteWe know from the French researchers that a bad reaction to Valium is a sign of a bumetanide responder. This makes perfect sense. If GABAa is working in reverse, triggering it with Valium will give the opposite effect to the one you expected.
DeleteThere are very likely other reasons why people react negatively to valium.
Dr Pallanti probably knows nothing about GABAa receptors, intra-cellular chloride levels and immature neurons. He is just doing what he knows.
The only reliable way to know if someone responds to bumetanide is to make a 1-2 month trial of the drug itself.
DeleteA negative reaction to valium might end you up in hospital.
If you had a previous negative reaction to valium and have autism, you really have to make a trial of bumetanide and at a high enough dose to lower chloride to more normal levels. Some people do not appear to respond to bumetanide because the dosage is not potent enough to overcome their elevation in chloride levels. Those people might need first to reduce the inflammatory cytokines that are driving chloride levels higher.
Hi Peter, we began bumetanide trail 2 weeks ago with my daughter. We give 500 mg potassium daily. In school days we give her 0.5mg bumetanide in the morning and 1mg in the afternoon (4pm). In school off days we give her 2mg (1mg in the morning and 1 mg in pm). Before bumetanide trail she eats very salty. Now she wants salt even in the her drinks (water and milk). She drinks every day around 1.5 l of water + orange juice. I am worried about the salty drinks. Do you think that is ok to drink water with a sprinkle of salt for each glass of water? Thank you.
ReplyDeletePrada, your body has a system in-built to try to regulate electrolyte levels, so some people may react to low sodium by craving salt.
DeleteI would suggest you test your daughter's electrolytes, and note sodium and potassium in particular. There is also a relation between these two, so someone high in sodium will tend to be low in potassium.
I would add salt to food rather than drink, if she has low sodium. Low sodium would be something to ask her doctor, because there might be an underlying reason for it.
Thank you Peter. We have a appointment with her dr. only on 26 February. Definitely I will ask for electrolytes test. Many thanks.
ReplyDeleteHi Peter, this coming Friday is a months mark in our bumetanide trial and we cannot see any effect. We still have bumetanide for more 3 weeks. When it is suppose to see an effect? We can see some more irascibility, in the first week she had a cold, the cold has passed by the irascibility remained. Also the constipation get worse and the prescribed laxative stopped to work. We notice also a facial tic that she never had had before. Could be all these only coincidences? Thank you for any thoughts.
ReplyDeletePrada, a tic can be a symptom of an electrolyte imbalance. This is why bumetanide use does require a blood draw to check electrolytes.
DeleteSome people see a clear response to bumetanide in 10-15 days. The researchers say it can take 2 months.
The recent study from China suggests in some people the improvement is small (a reduction in the CARS autism scale of 4) and parents may not notice a real, but minor, improvement.
You also have people who stop being responders, when they have an auto-immune condition. The increased inflammation counters the chloride lowering effect of bumetanide. In the summer bumetanide appeared to "stop working" in my son. What if I had made my original trial in summer?
Ultimately, only you can decide, but do so on the basis of electrolytes being well into the reference range.
Roger, it still works where inflammation is present, as in my son, but you have solve the auto-immune problems first.
DeleteWhat is the Potassium level that is recommended for different ages?
ReplyDeleteLocal testing here shows these levels:
Potassium - Reference Range:3.20 mmol/L - 4.50 mmol/L
Age 4y9m = 4.09 mmol/L
Age 4y5m = 3.64 mmol/L
Age 4y0m = 3.84 mmol/L
Age 1y5m = 4.93 mmol/L
Different labs have different reference ranges.
DeleteExamples are:-
3.5 – 5.5 mmol/L
3.7 to 5.2 mmol/L
Your local lab has very low limits.
Anyone recommendations on how to get Bumetanide in the US. We live in Tennessee and my 5 year old is on the spectrum and has significant speech delays.
ReplyDeleteIn the US you have a network of alternative medical doctors called MAPS, which does include some mainstream-type doctors as well as 100% non-mainstream types.
Deletehttps://www.medmaps.org/clinician-directory/
Some of these do now prescribe bumetanide to some of their patients with autism (Dr Frye, Dr Rossignol).
Until recently, people in the US did buy Bumetanide online from Mexico, but it seems that they have stopped production in Mexico.
Hi peter,
ReplyDeleteI am a mum to a 5yrs old diagnosed with autism. I find your research and blog useful but need guidance with autism treatment for my son. Are you open for consultation please? How can I get in touch.
Regards
Cyndy
Cyndy, I am not a doctor, so I do not do consultations. I write this blog to share my ideas on using the research to treat autism.
DeleteIf you want medical advice you need to find a helpful doctor.
Feel free to post questions on the blog about your child's autism, you may find the responses helpful and then you may figure out what to do.
Hi Peter,
ReplyDeleteyour blog is very interesting to read and I found interesting information I do not find in scientific literature I read. What puzzles me is the decreased effect of bumetanide and how you link it to inflammation, in particular with seasonal effects. I was not aware of fluctuation of symptoms with seasons. Do you know if this is a common observation or if this is something that you find rarely. You also mention auto-immunity and I wonder if there is solid scientific evidence for this theory or if it is your personal experience with autism that leads you to think this way.
And again, thanks for sharing.
baudy, the ratio of NKCC1 (that lets chloride into neurons) and KCC2 (that lets chloride out of neurons) can constantly change. One factor determining if you get a KKC2 transporter or an NKCC1 transporter is any inflammation present. This is well known in the research, for example here:-
DeleteModulation of chloride homeostasis by inflammatory mediators in dorsal root ganglion neurons
https://journals.sagepub.com/doi/pdf/10.1186/1744-8069-4-32
This means that the presence of inflammatory mediators (eg IL-6) will tend to raise the level of chloride in neurons and counter the beneficial effect of bumetanide. When you have allergy, mast cells release histamine and other factors including IL-6.
Some people report Bumetanide "has stopped working" in their child; this is very upsetting for them. A very plausible explanation is that a source of inflammation has raised chloride levels to the extent that Bumetanide has no apparent effect. Bumetanide does not normalize chloride levels, it just lowers it and quite possibly not enough in many cases.
I think it is widely accepted that there often altered immune responses in people autism and this is reflected in the comorbidities they exhibit (asthma, GI dysfunction etc).
Peter often wonder with your polypill using statins, nac , clemstanie etc combine to reduce inflammation and lower or at least not increase chloride levels. Which helps bumetanide work better or do you think these things target individual problems their no symbiotic relationship between all drugs.
DeleteSuppose what I'm asking is if trialing bumetanide should we focusing on reducing forms of inflammation as well
Thanks for the response, this is very useful!
DeleteIn a potential Bumetanide-responder, reducing sources of inflammation will help Bumetanide be more effective. In someone who reports "Bumetanide has stopped working" I think the likely cause is an inflammatory response somewhere in the body that has resulted in chloride levels rising and wiping out the benefit of Bumetanide.
DeleteMore generally, "inflammation" can be considered as a core feature of autism. The immune system is very complicated and it can go astray in many different ways, so there is no silver bullet that can work for all. Normalizing inflammation/immune response should improve your autism.
Hi. My son is about 2y 9m old.
ReplyDeleteHe was regressed at ~26 month and loosed his skills such as speech, bye-bye, cognition and social skills.
He had some antibiotic diarrhea when he was about 12 month old.
Currently he has wandering, aggression, anxiety, cognition (but he recognizes something like sit down, come here, let's get out and etc), meltdown, social (specially with his little sister) and speech problems. The only speech he has currently is when he is hungry/thirsty (echolalia from past speech).
I remember he had some sensory issues when he was younger (like loud noise) and some developmental delay (like late speech and learning) but he was good. he was saying papa, mama, give me water (repeating), give me that, yes, some animal sounds.
He has enlarged adenoids and difficulty breathing.
He is taking Risperidone, Omega3, Zinc Plus, DHA and Vitamin D3 (because of vitamin D insufficiency =24.4).
Please help me. Thanks.
Enlarged adenoids are common in children and can lead to sleeping and behavioural problems, as well as breathing problems.
Deletehttps://www.hopkinsallchildrens.org/Patients-Families/Health-Library/HealthDocNew/Enlarged-Adenoids
Your doctor should advise on whether the adenoids should be removed.
Giving Risperidone to a 2 year old does not look like a good idea.
Your son has a 40-50% chance of being a Bumetanide responder, so it is very well worthwhile making a trial.
Many people with regressive autism seem to have mitochondrial dysfunction.
A trial of Dr Kelley’s therapy in the link below would be a good idea.
https://epiphanyasd.blogspot.com/p/regressive-autism.html
Hi Peter
ReplyDeleteMy son is 12 years old he has autism and ADHD he is non verbal. The whole Exome sequencing showed a variant in click2 genes.will bumetanide help him in his learning process. Also would like to know the dosage for him.
Genetics cannot currently predict response to Bumetanide, but you would expect people with the same mutation to respond the same way. I would make a trial of Bumetanide for at least one month, you could use 1 mg every morning.
DeleteYou probably already know about your gene, which I assume is CLIC2.
CLIC2 is associated with a condition called “Mental retardation, X-linked, syndromic 32” also known as mrxs32. This is often a non-verbal condition.
You can learn about the CLIC2 gene here:-
https://www.genecards.org/cgi-bin/carddisp.pl?gene=CLIC2
CLIC2 plays a role in inhibiting the function of ryanodine receptor 2 (RYR2) and inhibits calcium influx. It looks like disrupted calcium signaling is your son's main problem.
CLIC2 affects glutathione transferase/peroxisase activity. This very likely means a low level of glutathione and so oxidative stress. This is treatable with NAC, a drug also sold as an OTC supplement. I would try 600 mg 4 times a day.
CLIC2 activates something important called the cAMP-Dependent PKA super pathway.
You could potentially activate/deactivate cAMP. Activating is quite easy (caffeine/theophylline etc) but you may need the opposite. Here you should go back to whoever diagnosed you son and get them to do some more work. They should not diagnose and then do nothing.
Thankyou Peter. This is very important information you gave me.
ReplyDeleteHi Peter,
ReplyDeleteI started Bumentanide on my kid 3 days ago - he is 28-mo, 14kg.
I started with 0.25mg morning and 0.25mg noon in formula milk.
Together with 500mg K+ because he is restricted on diet.
He has behaved "normal" so far - no dry mucous, and trying to rehydrate properly.
Yet he has grown hyperpigmentation under his both eyes.
I recalled a similar comment from another reader, but not sure if that is self-limiting or found out to be a symptom of a much bigger issue? Mind shed some lights? Thanks Peter.
MH
MH, there is drug-induced photosensitivity, which leads to hyperpigmentation, via increases in melanin production. Changes in hormone levels can have the same effect.
DeleteThere actual is an old study that concluded that Bumetanide has no effect on photosensitivity.
Investigation of the photochemical properties and in vitro phototoxic potential of bumetanide
https://pubmed.ncbi.nlm.nih.gov/14606756/
I think it is likely to be dehydration.
“Dehydration is a common culprit when it comes to sunken or dark skin around the eyes. This is because the skin around your eyes is very close to the underlying bone, and a lack of fluids can cause blood vessels to become more prominent.”
I would make sure your daughter drinks more.
Hello Peter,
ReplyDeleteStarted bumetenide 10 days ago
we don't see any cognitive improvements
But We saw improved mood from the day one- in this case can we assume that bumex is working for my kid
The reason I am asking is it's very expensive and difficult to get bum. To my country
Riza, if there is a clear benefit, which is lost when you stop the drug, then it must be working.
DeleteGreetings from México. What do you think about using bumetanide in a 43 year old man with a "extended autistic fenotype" diagnosis or mild aspergers (i'm that man)? I know this is an old publication but i found it until now.
ReplyDeleteHola Charlie
ReplyDeleteI think it is unlikely that you will benefit greatly from bumetanide, since you have mild Aspergers. Since you live in Mexico it is very easy/cheap to make a brief trial, so I would go ahead and try it for a month.
For Aspies, it is well worth trying Baclofen, which is also easy for you to obtain. It seems to work very well for some Aspies, but does nothing for others.
Thanks Peter. I'm gonna ask to my doctor if i can take baclofen and side effects, because bumetanide causes me uncontrollable urginary urgency all day (almost wet myself) and potassium pills hurt my stomach really bad.
DeleteHello Peter,
ReplyDeleteHow soon we should see the affect of Bumetanide in a 7 year old kid. He is non verbal and really struggling with repetitive play, like buckle/unbuckle, tie/untie, drop anything and watch it fall. He can do this for forever and it very hard to see him like this. We have tried life extension Nac and haven't seen benefits. Please let me know if anything specific I can use for repetitive behavior. Thanks
In most people it is a couple of weeks, but you should keep going for longer. The researchers suggest 2 months.
DeleteNAC is often effective for stimming , but your behaviors are more like a simple kind of play. I would try and develop them into more complex activities.
Thanks for the response. I am planning to start 1mg in the evening. He wouldn't buzz from what he is doing no matter how hard we/therapist try. It's definitely stemming but we don't know how to reduce it.
DeleteAre there a way to test/measure intracellular chloride level?
DeleteNo test exists
DeleteNew research on Bumetanide.
ReplyDeletehttps://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad132/7134130
-Stephen
I have a son 8 years old, nonverbal.
ReplyDeleteHis EEG is normal, MRI normal.
We sequenced his genes in hong kong and he doesn't have a single mutation that could be linked to autism.
He has one surgery when he was 13 months old and he remained under anesthesia longer than it should have been.
After that we lost eye contact and he just go off.
Now he understand a lot, sleeps ok, but he is like adhd and add (don't play with children, he doesn't play with toys, in all other things he is normal, swimming, walking, going everywere with us)..
He has binding antibidies in blood (FRAT test), so he is taking Leucovorin.
He also has increased pyruvate, so he takes DCA and mito cocktail.
Also Respiredone (5 drops in the evening for start).
We took out adenoid and tonsils because his ASTO was 747 (high) - I suspects PANDAS.
Now is down but still not normal.
We have doctor who gave him Clemastine and Bumetanide (and Potasium).
When I gave Clemastine he was nervous and the ocd got worse.
So I stopped.
Now I am thinking to start Bumetanide.
He has 34kg.
What should I pay attention to?
Does bumetanide help in such cases?
Thank You.
You have a 40% chance that you will be lucky and your son will respond to Bumetanide. A good trial would be to give 1mg once a day for a month.
DeleteIf he is a responder, you may notice a change after 10-15 days, but it can take longer.
Cognition, mood, stereotypy can all improve. Learning new skills should become much easier.
In my son's case the school noticed that he became "joyfull", I noticed how he was then able to learn basic maths and how to use prepositions. These had been impossible to teach previously.
Hi Peter, can you please read over this article. I might be wrong but I think Bumetanide is a mast cell inhibitor in the colon...
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252977/
If thats the case it might stop the release of histamines food allergens.
-Stephen
I guess bumetanide stops histamine too.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858891/
How interesting.
-Stephen
Histamine also plays a role in neuroinflammation.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764847/#:~:text=Once%20released%2C%20these%20neuropeptides%20induce,in%20neurogenic%20inflammation%20is%20established.
Stephen, there indeed a lot of interactions with histamine, Cl- and indeed L type calcium channels, with Cav1.3 getting a mention.
ReplyDeleteTrue. I guess there is a drug called Cinnarizine that's otc that might block Cav1.3
Deletehttps://classic.clinicaltrials.gov/ct2/show/NCT05686993
Stephen
And cinnarizine is seen as a nootropic and even there is a suggestion to combine it with piracetam.
DeleteIsradipine also blocks cav1.3. Here an article about two asd twins and a gene malformation
Deletehttps://molecularautism.biomedcentral.com/articles/10.1186/s13229-019-0310-4#:~:text=There%20is%20increasing%20evidence%20that,without%20neurological%20and%20endocrine%20symptoms
At least one reader has a child with a Cav1.3 mutation. Verapamil helps a lot and later Amlodipine was used. Grandfather also takes Amlodopine and it solved his problem with bad headaches.
DeleteAll very interesting and shows how great benefits are possible from ion channel therapies (calcium, sodium and potassium).
Hi Peter, my boy is 9 yo, doesn't understand question. So doesn't have any productive language. He is a chatter box , keep saying what he knows. Do you think Bumetanide will help him? What should I be cautious before introducing Bumetanide? Thanks for your reply.
ReplyDeleteMita, read the above post again, it tells you all you need to know to make a trial of bumetanide.
DeleteMake a trial for a month or so. I would use 2mg once a day. If he is a responder his behavior and cognition should start to change after 2 weeks or so.
If he is a chatterbox he has expressive language. Can he read and write?
Hi Peter i have start the bumetanide 2 weeks ago fory son 13 years old with moderate autism i didn't notice any change for the moment i give him 800mg of potassium as well.What do yuo think i have to increase the dose or just wait few weeks more?
ReplyDeleteWhat dose of bumetanide are you giving? I suggest you use 2mg once a day.
DeleteHi Peter i'm doing 1 mg so i will try 2 mg a day before give up for how long?the potassium 800 mg a day plus 2 banana is fine?
DeleteIf you are already giving 1mg bumetanide and so did not make a pause, increase to 2mg and try of 2 more weeks. If you stopped bumetanide, then try 2mg for 4 weeks.
DeleteNot all children are bumetanide responders. At least you will know which group your child is in.
Random Bumetanide facts-
ReplyDeleteBumetanide inhibits anti-ige release.
https://gut.bmj.com/content/36/3/395
Anti-ige can release histamine from mast cells
https://link.springer.com/article/10.1007/BF01965069
-stephen
Peter, have you ever heard of the drug Etacrynic acid? It's another nkcc1 inhibitor as well as a loop diuretic. I guess it does a pretty good job blocking histamine release from mast cells.
ReplyDeletehttps://pubmed.ncbi.nlm.nih.gov/75076/
Stephen
That is a new one to me. It is not widely used because it needs more careful dosing than other loop diuretics.
DeleteMost interesting is that it is the only loop diuretic that is not a sulfonamide drug. People with a sulfonamide allergy cannot take bumetanide.
The question is does it block KCC2 as well. This is why you cannot use furosemide in place of bumetanide.
Possibly it would be a bumetanide alternative for those with a sulfonamide allergy. It is an approved drug.
I'm not very educated in mitochondrial dysfunction but I guess ethacrynic acid blocks cellular resp rate.
DeleteForgot the link
Deletehttps://pubmed.ncbi.nlm.nih.gov/6195000/
Hi Peter,
DeleteHere are a couple of other studies on bumetanide and lipopolysaccharides.
Na+-K+-2Cl- cotransporter 2 located in the human and murine gastric mucosa is involved in secretagogue-induced gastric acid secretion and is downregulated in lipopolysaccharide-treated mice.
https://www.sciencedirect.com/science/article/abs/pii/S0014299920302545
This above study talks about how bumetanide decreases the production of histamine in the GI tract.
This other study talks about how bumetanide decreases the level of anxiety.
Bumetanide prevents diazepam-modified anxiety-like behavior in lipopolysaccharide-treated mice.
https://pubmed.ncbi.nlm.nih.gov/34004209/
-stephen
Hello Peter and everyone,
ReplyDeleteIts been ages since i posted here, I mainly came here for myself in the past testing endless amount of supplements in an attempt to improve my own symptoms of PDD-NOS comorbid ADHD.
Ive became seriously ill 4 years ago but I have recovered since, during that time Ive also become the father of a beautiful son.
Which is why I am posting here now and today. Our son has quite some severe autism spectrum disorder/global development delays.
He has been seen and has had his diagnose. He is 3 and an half years old.
He seems really behind on his speech and eye contact. Distracted all the time and headbangs loads as coping. Every small change like me or my girlfriend simply going to the toilet is overwhelming for him since one of us leaves the room.
We even had to take the doors out inside the house cause he cannot handle a door being closed temporarily.
I do think he is very capable and smart, he seems to mumble a lot in himself when doing things hes like.
Definitely has a tendency towards restricted interests, currently obsessed by colours, letters and numbers, but as you guessed not so much in playing with other kids.
Ive always been kind of against true medication, but I can see simply giving him some magnesium is not going to help his development either.
He is going to a special day time group soon for the first time where he will be about 6 hours per day for 3 days per week.
We hope that will help him lots but we are afraid of his behaviour and that he might get send off even though they specialize in treating children like our son.
I feel like this is a desperate call out for help cause it seems his development is severely stagnated. We do seem some very very mild progress but its so incredibly slow.
He has had some speech therapy too which helped a bit but due to him being so distracted and destructive behaviour at home we have not been able to apply the program (Hanen program) as often as we would like.
Me and my partner are none stop sleep deprived and drained even though we love him so much.
PRT has been advised by professionals. Which he is not yet having.
Even though the help is slowly on his way I feel like he is so behind and he needs his brain to be calm and sleep to be optimal in order to learn.
I was wondering what dose of bumetanide would be a good starting dose and where we would be able to buy it from to give it a try (We are in the Netherlands).
Hello Aspie83, sorry to hear about your child's problems.
DeleteA good dose of bumetanide to trial would be 0.5mg once a day. It can be bought online from Mexico, just Google "buy miccil online". In much of Spain you can buy it as Fordiuran without prescription. Also easy to get in Egypt while on holiday I am told.
For severe autism the sooner you treat it the better the result will be and drugs are absolutely necessary.
Definitely a good idea to also give NAC. For a young child you could try 200mg three times a day. It should produce a short term effect and also do long term good.
You could go see Dr Ramaekers and ask about leucovorin. He is not far from you and he is very friendly. Look him up.
Thank you for you quick response Peter,
DeleteI will try and order it. Agencies over here are so slow. I feel by the time he would get a chance to get something decent prescribed we are 2-3 years further on.
I tried to look up Dr Ramaekers on google and I can only find him in Maastricht, is that correct? I cant seem to find anyone with the name of Ramaekers that specializes on ASD.
I have tried NAC for myself in the past, its definitely a strong mood stabilizer but I found it emotionally so flattening.
Not sure if I want to do that for my son, but he might need something like that though since he is so distracted and upset a lot.
Just trying to see what could be beneficial for him so he can actually learn. My son seems on the higher end, if he is in the right zone he picks up things really quickly.
The whole problem is getting him in that state where he is not distracted. He is literally like a ping pong ball.
The moment you only keep 1 toyset in his room at a time (I dont want to sound cruel cause we do switch between them loads) he seems to actually be able to somewhat understand the concept and try to discover how to play with it.
The moments there are too many toys in his room it is all throwing all day and same in the livingroom.
By the way any advice on a website, the prices for shipping that get asked internationally is insane, im talking 40 dollars just for the shipping.
DeleteI agree. Make an appointment with Dr. Ramaeker and start the Leucovorin. Until the appointment you could probably get away with PQQ, CoQ10, and 5000mcg of methylcobalamin (all OTC) to help push folate into the brain through the RFC. Give all those in the morning and see how he responds. Hydroxyzine, melatonin, or emodin for sleep at night.
Delete-Stephen
You can do light therapy with this at night for a few minutes but be careful it gets extremely hot.
DeleteOrdro LN-5 IR Night Vision Light for Camera, 2023 New Upgraded Version Infrared Night Monitor for Enhancing Camera Night Shooting Visibility, 56PCS IR Lamp Beads 850nm Rechargeable IR Light
-Stephen
Look up Professor Vincent Ramaekers Liege. He is well known.
DeleteSend me a message via the "contact me" facility on the right side of the web page and I will send you his email address if you cannot find it.
Shipping is expensive from these kinds of sites and the drugs are all marked up 10x.
I am not using these sites so cannot recommend. I expect prices vary greatly.
Buying in Spain will be a few euros for 20 pills. Ask around if someone you know is going for a holiday trip there.
Thank you for all of your advice.
DeleteUnfortunately Dr Ramaekers is in Liege which is in Belgium and we do not own a car so it might be quite hard.
We are getting some help here now for our son, its nearly our turn for an intake at the Leo Kannerhuis (which is one of the leading organisations when it comes to professionals in Autism).
As for bumetanide it would be nice if someone succesfully ordered online and could share their source with me.
Even it means paying 40$ for delivery. I just want it to be a reliable source.
Hi Aspie83, long time no see!
ReplyDeleteFirst of all, congratulations to having a fine son. :-)
I'm sorry to hear he is on the severe side of the spectrum.
Without knowing what you are already doing or using and what kind of tests have been done, it sounds like you really should look into anything that can improve sleep (for all of you). Nothing helps as long as a kid is sleep deprived, and as a parent you will have better chances of helping your kid if you get enough sleep.
Sleep won't cure autism, but it's integral for everything and especially for behaviour.
Also, since there's a chance there is a genetic component here I'd suggest both a gene test, and that you review what have been of help for yourself. Maybe the same treatments could help your son?
/Ling
Hi Ling,
DeleteLong time no see indeed and thank you, we love our son so much. He seems to pick up quite quick when the environment is optimal but it has to be spot spot on in order for him to learn.
The things he does learn he seems to amazingly learn in one go, some words he just instantly knows.
So i think targetting distractability is a main thing. I decided yesterday out of desperation myself to give him 1.5mg of ritalin. He is only 13kg so really didnt dare to give him anymore.
He instantly started to say: 'I know' when i pointed at a cow on a youtube video while watching with him and trying to teach him.
We never even learned him to say 'I know' so it show he must have picked it up watching something on tv at times.
He seemed much much more focussed on things, and I think he started to say 2-3 new words just yesterday from us doing things together with him trying to teach him.
He seemed very very hyper though and never seen him so aggressive once the ritalin started wearing off ( peak plasma instant release ritalin is about 3hours), by the time we were 6 hours in he was raging so badly it was kind of scary for us.
Long story short I think he has loads of potential to learn, it just the right environment that has to be created thats the tricky part and indeed sleep.
We have been applying sleep routine like our own lives depend on it.
3mg melatonin daily an hour before bed seems to help him fall asleep but not stay asleep.
He knocks his drink over at night quite often next to bed. He then goes so angry and whacks the wall so so hard its scary. This is usally around 11pm when we tend to get ready for bed.
Also during the day the whacking his head and kicking against the walls is so much.
We have tried everything from mildly ignoring it to try and teach him different coping methods when he feels overwhelmed it doesnt seem to stick with him that he can for example go and have a look at his favorite book to calm down.
He watches tv a fair bit I have to say and whenever and ad comes on... well you guessed it, its hitting things, whacking things, he just cant handle an ad, not even 5seconds.
We fled from our old house in Amsterdam cause we were getting severe threats at our door by our downstairs neighbor and violently trying to kick in our door multiple times.
We were advised to also get genetic tests done while we still lived in Amsterdam when Victor got his diagnosis.
PRT and genetic testing was one of the many advices we got given by Levvel (the agency that did the diagnosis) in Amsterdam.
It was a horrible time for our family and we are still recovering from it. Where we live now is calm and far more remote in a village and we got calm neighbours but I still get anxiety attacks every time our so gets angry and whacks a wall or an object.
Long story short with regards to the single small dose of ritalin that I gave him is that it was a day and night difference in focus n concentration. He seemed to be very amped up about things, all of a sudden he started to bring his shoes to us and trying to get them on himself.
We have been struggling teaching him to get his socks or even trying to get him to use his own hands to help get them on.
He was nearly pulling his own socks on completely by himself without asking, we just saw him all of a sudden and he tried to pull his socks up. My mouth kind of fell open in a good way.
The mood shifts it cause in him are just unbearable though
Do I regret giving my own son the ritalin once? I do not, it was a very small dose and I have used it myself i know the effect can be seen instantly and it did. The effect was profound but also the side effects that it had on him mentally. He seems ok now again this morning not so upset anymore so thats good.
@Peter:
DeleteI do consider NAC, eventhough i personally found it a bit dulling but focussing. (understandable cause of how NAC works with the antiporter system to recycle glutamate into glutathione, glutamate is definetely important in hedonic tone and reward, if you everywhere on the internet even reddit, it is the most common complaint about ppl stopping NAC, even ppl who dont have ASD do not like the flattening effect on affect that it has).
In my experience it feels different than SSRI's that i have been on in the past but still.
Peter, do you think the mood stabilizing effect of NAC might help our son be a bit more in the here and now rather than being so distracted and upset?
I do like your advice to try and i think it could be beneficial and set a path towards calm learning.
Also our son cannot tolerate strange textures, he will chew on a small melatonin pill that tastes horribly before and just swallows it after chewing, however a gritty powder like calcium citrate ive tried cause he doesnt want much dairy he spits it out instantly if theres a bit mixed in his grape juice.
Would you recommend a dissolvable instant release NAC?
I remember the sustained release ones from Jarrow were huge when i took them i got no problems taking pills as i have done it so often in my life but i cant see my son taking that.
Sorry for all the questions and the chaotic writing I feel a bit like a Neanderthaler at times, but im sure a lot of parents here on this forum can relate lol.
@Anonymous:
Thank you for your tip about the PQQ and coQ10 I suspect i have mito dysfunction myself and i benefitted from PQQ myself (I am myself on the spectrum).
In the early years I think that oxidative stress and neuroinflammation disrupt how the brain develops. If you can "put out the fire" normal development should be more likely.
DeleteIn some countries they have NAC as a powder to dissolve in water. One brand is Fluimucil and it is given to babies. Regular NAC in gelatin capsules does taste bad, but you could add it to apple sauce or jam. You will need to see what works best.
Regarding Ramaekers, if you get a diagnosis from him you should be able to take it to your child's doctor. Since he is a professor, your doctor will hopefully note his advice and prescribe the suggested drugs. Then you may well get the drugs for free.
Aspie83,
ReplyDeleteYour son is lucky he has such an observant father who also knows where to look for answers. Your post above is full of useful details.
For sleep, I agree normal melatonin is only helpful for sleep initiation. You could either try slow-release melatonin (three small 1 mg tablets in yoghurt could eventually work even if tablet swallowing is hard at your son's age) or go the old H1-antagonist way (allergy drugs that pass through the BBB). Or both, if needed. You might not need these solutions forever, but for now it sounds like it would help the whole family.
For ritalin, it has an effect on dopamine and norepinephrine so now you have a few topics to explore. Internet is full of people who are looking for alternatives to the usual ADHD medications and you already know what worked and what didn't for you. What about PDE-inhibitors, for example? Bacopa? Tyler had a few posts on regulating brain dopamine here somewhere on the blog...
Of course, dopamine could be a downstream effect (and if so usually with serotonin abnormalities - serotonin is linked to aggression). So it might not be the ultimate answer, but one that will help normalize life.
If NAC or antioxidants in general are not working as you wish, maybe try a few interventions aimed at energy/mitochondrial function. NAD? keto? And then as a third step try things for neuroinflammation.
Some of it will work.
My best wishes to you,
/Ling
How do you know when it's time to stop bumentanide? My son started off with 0. 5 mg per day for about 2 weeks, then moved up to 1 mg per day for about 3 weeks, and just moved up to 1.5 mg per day for the last 2 days. He is just over 100 lbs. We honestly can't tell if it's helping. Getting mostly bad reports from teachers at school regarding his willingness to engage and do work, mixed with an occasional good report. He is still "thundering" in the yard and seems quite inattentive when I try to work with him on school work. Should we keep going with 1.5 mg, give it a bit longer? We always tend to stop things, maybe too soon, when they don't seem to be working. Also, are there any possible negative effects on mental/emotional health and well-being? We haven't had his potassium re-checked yet, are there possible symptoms if his potassium has dropped? Thank you.
ReplyDeleteAW, most people cope with bumetanide without potassium-related side effects. Nonetheless potassium should be checked in case that person suffers reduced potassium which can cause both behavioral effects like mood swings and anxiety but also things like fatigue and high blood pressure.
DeleteSince you have come so far I suggest you continue for 10 more days before you conclude that your son is not a bumetanide responder.
Also, we are thinking of trialing a non-stimulant medication for inattentive ADHD, such as Straterra, Qelbree, Intuniv, Kapvay, or maybe Buspar for anxiety. Can bumetanide be taken at the same time as those?
ReplyDeleteAW it is best you look up each drug combination individually.
DeleteThe link below let's you do this.
https://www.drugs.com/drug_interactions.html
Thank you, great information. We will definitely continue for at least 10 more days to be sure.
ReplyDeleteHi Peter,
ReplyDeleteAfter reading your book, I'm about to start administering bumetanide to my 4yo (asd, major regression on 2.5 years, suspected subclinical epileptiform activity). I have two questions:
-We have scheduled our second attempt to have a sleep EEG next Wednesday. The first attempt failed because there was a paradoxical reaction to chloral. Now the neurologist says he is going to give him melatonin. Would it be better to start bumetanide after the EEG? I'm just anxious if we fail this time also.
-I was wondering about the optimal time of administration. The morning seems better for management but I'm thinking that since knowledge is consolidated during sleep, wouldn't it be better if the chloride reduction effect took place during sleep? So PM is better than the AM hours?
I would very much appreciate your thoughts on the above.
Regards,
Mauro
Mauro, I suggest you do the EEG before the bumetanide. If you are successful with bumetanide you can always come back later and repeat the EEG and see if any anomalies are reduced by bumetanide - this is quite possible.
DeleteThe chloride-lowering effect of bumetanide is very gradual. After being on bumetanide for two weeks there will not be a great difference between the AM or PM level. The choice of when to give bumetanide is usually about being the least disruptive. Some people get a lot of diuresis and it may or may not be all over 60 minutes. In some people it disrupts classes at school and then the teachers complain. The important thing is to give it every day, if you start missing days it will not work. Some people think they can just give it at the weekend - this will not work.
Mauro, also of note is that the Chloral sedative is a positive allosteric modulator on GABA A receptors. The paradoxical reaction is almost certainly because in your child GABA is "working in reverse". In which case you really have a 90% certainty that your child will be a bumetanide responder.
DeleteThis also means that other sedatives like benzodiazepines will cause a similar negative reaction.
receptors
For me the reaction to chloral was what it made me to actually buy bumetanide. I had already read all about bumetanide and benzodiazepines in your book and then it just clicked on me during the desperate hours of the first EEG attempt.
DeleteI see that there is a whole post about ASD and EEG abnormalities which makes me thing what I am going to do if they do exist and the neurologist prescribes an AED (of course he will not want to hear about bumetanide).
I will give feedback on this. Thank you for your answers and of the awesome book (and blog!)
Regards,
Mauro
Back from the EEG session. This time the neurologist was present too (the first time it was only a nurse). He insisted to use chloral again (I suspect he wanted to witness the effects himself) and thankfully this time there wasn't a paradoxical reaction. The kid was awake from 2.30 am and the test began at 8.30 am, he fell asleep pretty easily.
DeleteThe EEG showed subclinical epipletform activity as suspected. The neurologist told us that the pattern of the discharges matches with the Landau-Kleffner syndrome and he prescribed us sodium valproate. He told us that we might see some improvements on the autism symptoms.
We talked briefly about lamotrigine and corticosteroids and while he did accept that these are legit treatment options, he insisted on the valproate but we are going to re-evaluate things in a couple of weeks based on the reactions. He told us that lamotrigine is better for cognition but weaker than valproate on treating the discharges.
I think I will stick only with valproate for the time being. I understand tha bumetanide might be beneficial too but I think it's best to try one thing at a time. I would appreciate your thoughts on this developments (and as a matter of fact everyone's thoughts/experience with a similar case)
Best regards,
Mauro
Mauro, Landau–Kleffner syndrome (LKS) is an acquired childhood epileptic aphasia. I think this would often be diagnosed simply as regressive autism with seizures or abnormal EEG.
DeleteLKS is an observational diagnosis with no known cause. The prognosis is mixed.
You are in a tricky position.
The real question is what has occurred to cause the loss in receptive/expressive language. If you guessed the cause correctly, you might act quickly and improve the child’s prospects.
I would imagine that the problem sometimes is auto-immune and the suggested idea to use prednisone looks a very good one.
Clearly treating the abnormal EEG before the onset of seizures is essential.
There is a Russian doctor who tries to treat children immediately after they regress into autism. It makes sense that there would be a window of opportunity. But you do have to avoid falling into attractive looking expensive pseudoscience therapies.
If you can access it, IVIG therapy done now would be what I would do. I did have a quick check and there are case reports of it being effective.
https://www.sciencedirect.com/science/article/abs/pii/S0887899497001574
A detailed history of a boy with Landau-Kleffner syndrome is presented, demonstrating a close relationship between language functioning and paroxysmal electroencephalogram activity. During a 3-year 6-month follow-up period, three abrupt deteriorations of all language functions occurred: the child became totally noninteractive with his environment within 1 week's time. Two of these deteriorations were reversed with steroid treatment, with an identical recovery phase. Intravenous immunoglobulins had a very dramatic and comparable effect in the third relapse; both language functions and electroencephalogram abnormalities were influenced significantly by the intravenous immunoglobulin treatment.
While trying to arrange IVIG, I would immediately start the prednisone.
I wanted to share another success story with bumetanide. Our pediatrician, who facilitated our bumetanide trial for my son, has a 5-year old granddaughter with autism. As we underwent our trial, she also trialed it for her granddaughter, and has seen much improvement. Her granddaughter went from one-word sentences to much improved speech, among other notable things. Our doctor now plans to prescribe this for some of her other patients with autism. Unfortunately it didn't seem to do anything for our son, but I am so happy that she has seen benefits and plans to use it to help others in her practice. I've also introduced her to this blog. Thank you so much for sharing all of this amazing information with the world!
ReplyDeleteA.W. that is great news for your pediatrician. I hope she gets inspired to treat other features of her granddaughter's autism. Anecdotal evidence seems to take you a lot further that randomized clinical trials when it comes to treating autism.
Delete