Wednesday, 6 November 2019

Metformin to raise Cognition in Fragile X and some other Autisms?

I started to write this post a long time ago, when Agnieszka first highlighted an interview with Dr Hagerman from UC Davis.  Hagerman is experimenting in using Metformin to treat Fragile-X.

Having again be reminded about Metformin, I realized that I never finished my post on this subject. With some extras about autophagy and a nice graphic courtesy of Ling’s excellent paper, here it is. 

Metformin has already been covered in 5 previous posts.

One interesting point is that the researchers at UC Davis are using the measurement of IQ as one of the outcome measures in their trial of Metformin.  I have been suggesting the French Bumetanide researchers do this for a long time.

It is my opinion that simple medical interventions can have a profound impact on the IQ of some people with severe autism. I mean raising IQ not by 5-10 points as at UC Davis, but by 20-50 points.  IQ can be measured using standardized tools and is far less subjective than any autism rating scale.

The big-time potential IQ enhancers we have seen in this blog include: -

·        Bumetanide/Azosemide
·        Statins (Atorvastatin, Lovastatin, Simvastatin, but they are not equivalent and the effect has nothing to do with lowering cholesterol)
·        Micro-dose Clonazepam
·        Clemastine
·        It seems DMF, in n=2 trial

The good news is that these drugs are all off-patent cheap generics (except DMF), as is metformin.  No need for drugs costing $50,000 a year.

For those that do not know, metformin is the first line medication for type-2 diabetes. It was introduced as a medication in France in 1957 and the United States in 1995.  In many countries Metformin is extremely cheap, with 30 x 500 mg tablets costing about $2 or Eur 2. In the US it costs about $10 for generic, so not expensive. 

There are sound reasons why Metformin could increase IQ in someone with autism or Fragile-X. In the case of idiopathic autism is there a likely biomarker to identify a likely responder? One has not yet been identified.

Clearly Metformin will not work for all people with autism and MR/ID, but even if it only works for 10% that would be great.

Are all parents going to notice an increase in IQ of 5-10 points?  You might think so, but I doubt it.  I would hope therapists, teachers and assistants would notice.

I think basic mental maths is the best way to notice improved cognitive function in people with IQ less than 70.  You can easily establish a baseline and then you can notice/measure improvements.

Improved cognitive function does not just help with maths, it helps with learning basic skills like tying shoe laces, brushing teeth and later shaving.  This does also involve many other types of skill.

In the study, researchers from the UC Davis Medical Investigation of Neurodevelopmental Disorders Institute in California tested the long-term effects of metformin, delivered at 1,000 milligrams (mg) twice a day, for one year in two male patients, 25 and 30 years old. Genetic analysis confirmed that both patients had mutations in the FMR1 gene, confirming their fragile X syndrome diagnoses.

The younger patient had autism and was also diagnosed with generalized anxiety disorder. First prescribed metformin at 22, he is currently taking 500 mg of metformin twice a day and 10 mg per day of simvastatin — used to lower the level of cholesterol in the blood.
The second patient was also diagnosed with anxiety and exhibited socially nervous behaviors, including panic attacks. He had severe limitations in language use, and communicated in short sentences and by mumbling. He had been on an extended-release formulation of metformin, taking 1,000 mg once a day for one year.

Both patients showed significant cognitive and behavioral improvements. After one year of treatment with metformin, test results revealed an increase in the patients’ IQ scores, from 53 to 57 in the younger patient and from 50 to 58 in the second patient.

Verbal and nonverbal IQ — the ability to analyze information and solve problems using visual or hands-on reasoning — were also improved in both patients. Non-verbal IQ increased from 50 to 52 in the younger patient and from 47 to 51 in the other. Verbal IQ went from 61 to 66 in the first patient, and from 58 to 68 in the second.


Researcher Randi Hagerman is a big proponent of metformin — a diabetes drug that helps people manage their weight. In fact, Hagerman takes the drug herself as a preventive measure against cancer.
Metformin has also unexpectedly shown promise for improving cognition in people with fragile X syndrome, a leading genetic cause of autism characterized by severe intellectual disability.

A study published in 2017 linked impaired insulin signalling in the brain to cognitive and social deficits in a fruit fly model of fragile X, and the flies improved on metformin. A second paper that year showed that metformin reverses abnormalities in a mouse model of the syndrome, including the number of branches the mice’s neurons form. It also improved seizures and hyperactivity in the mice — issues we also see in people with fragile X.
I began prescribing metformin to people with fragile X syndrome to help curb overeating. Many of the people I treat are overweight because of this habit — it’s one of the symptoms of a subtype of fragile X called the Prader-Willi phenotype, not to be confused with Prader-Willi syndrome.
I was surprised when the families of these individuals told me they could talk better and carry out conversations, where they couldn’t before. That really gave us impetus to conduct a controlled clinical trial.
It’s not a cure-all, but we do see some positive changes. It doesn’t resolve intellectual disability, but we have seen IQ improvements of up to 10 points in two boys who have been treated with metformin. We are very excited about that.

Individuals on metformin tend to start eating less, and often lose weight as a result. I could kick myself, because metformin has been approved to treat obesity for many years, but I never thought to use it in fragile X syndrome. Oftentimes children with fragile X syndrome have so many problems that you aren’t thinking about obesity as the top priority.
We’ve also seen a gradual effect on language, which we can detect after two to three months. Sometimes there are improvements in other behaviors too; I’ve seen mood-stabilizing effects. Many people with fragile X syndrome have issues with aggression, and it’s possible these could be moderated with metformin too. 

Individuals with fragile X syndrome (FXS) have both behavioral and medical comorbidities and the latter include obesity in approximately 30% and the Prader‐Willi Phenotype (PWP) characterized by severe hyperphagia and morbid obesity in less than 10%. Metformin is a drug used in individuals with type 2 diabetes, obesity or impaired glucose tolerance and it has a strong safety profile in children and adults. Recently published studies in the Drosophila model and the knock out mouse model of FXS treated with metformin demonstrate the rescue of multiple phenotypes of FXS.

Materials and Methods

We present 7 cases of individuals with FXS who have been treated with metformin clinically. One case with type 2 diabetes, 3 cases with the PWP, 2 adults with obesity and/or behavioral problems and, a young child with FXS. These individuals were clinically treated with metformin and monitored for behavioral changes with the Aberrant Behavior Checklist and metabolic changes with a fasting glucose and HgbA1c.


We found consistent improvements in irritability, social responsiveness, hyperactivity, and social avoidance, in addition to comments from the family regarding improvements in language and conversational skills. No significant side‐effects were noted and most patients with obesity lost weight.


We recommend a controlled trial of metformin in those with FXS. Metformin appears to be an effective treatment of obesity including those with the PWP in FXS. Our study suggests that metformin may also be a targeted treatment for improving behavior and language in children and adults with FXS.

Recruiting: Clinical Trial of Metformin for Fragile X Syndrome

While a growing number of families are trying metformin and reporting mixed results, metformin has not yet been systematically studied in patients with Fragile X syndrome. This open-label trial is designed to better understand the safety and efficacy of this medicine on behavior and cognition, and to find the best dosages for children and adults.

20 children and adults with Fragile X syndrome will take metformin 250mg twice a day for the first week, followed by metformin 500mg twice a day for the next 8 weeks.
The study will measure changes in the total score on the Aberrant Behavior Checklist-Community (ABC-C) after 9 weeks of metformin treatment. The ABC-C is a 58-item behavior scale which is filled out by a caregiver. In addition, Transcranial Magnetic Stimulation (TMS) will be used to look for changes in cortical excitability and Electroencephalography (EEG) will assess levels of synaptic plasticity.
Participants in this study must be Canadian residents and be able to travel to the University of Sherbrooke in Quebec, Canada, for several visits. If you are interested in metformin but this trial is not convenient, there are two alternatives. FRAXA is funding a new trial of metformin in New Jersey, and Dr. Randi Hagerman is currently recruiting for metformin trial at the University of California at Davis MIND Institute.

Metformin has emerged as a candidate drug for the targeted treatment of FXS based on animal studies showing rescue of multiple phenotypes in the FXS model. Metformin may contribute to normalizing signalling pathways in FXS in the central nervous system, which may include activities of mTOR and PI3K, both of which have shown to be pathogenically overactive in FXS. In addition, metformin inhibits phosphodiesterase, which would lead to correction of cAMP levels, and MMP9 production, which is also elevated in FXS. Looking at the potential signalling pathways, metformin appears to be a good candidate for targeting several of the intracellular functions in neurons disrupted in FXS and, therefore, has potential to rescue several types of symptoms in individuals with FXS. The researchers have utilized metformin in the clinical treatment of over 20 individuals with FXS between the ages of 4 and 58 years and have found the medication to be well tolerated and to provide benefits not only in lowering weight gain and normalizing appetite but also in language and behavior. In this controlled trial, the researchers hope to further assess metformin's safety and benefits in the areas of language and cognition, eating and weight loss, and overall behavior.

mTOR and P13K

Hagerman highlights Metformin’s effects on mTOR and P13K pathways.

This is a highly complex subject and the graphic below from an early post shows how interconnected everything is.  If mTOR is not working correctly you can expect many things not to work as nature intended.

Numerous things can cause an imbalance in mTOR and so there are numerous ways to re-balance it.

Not surprisingly much of this pathway plays a role in many types of cancer.

Hagerman herself is taking Metformin to reduce her chances of developing cancer. I think that is a good choice, particularly if you are overweight.  My anticancer choice, not being overweight, is Atorvastatin which targets inhibition of PI3K signalling through Akt and increases PTEN.

Hagerman is 70 years old and I think many cancers actual initiate years before they are large enough to get noticed and to be effective any preventative therapy needs to be started before that initiation has occurred. Hopefully she started her Metformin long ago. 

Given that 50% of people are likely to develop one cancer or another, I am with Dr Hagerman on the value of prevention, rather than treatment/cure.

The Wrong Statin for Fragile-X?

In the first article highlighted in this post, there is a case history of a man with FX being treated by a Statin, it looks to me that he has the wrong prescription (Simvastatin). Perhaps Dr Hagerman should read this old post from this blog:-

Choose your Statin with Care in FXS, NF1 and idiopathic Autism

   Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.
So  ? = Does NOT inhibit

The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.

For anyone really interested, the following graphic from a previous post shows the fragile X mental retardation protein, FMRP.  Lack of FMRP goes on increase neuroligins (NLFNS) this then creates an excitatory/inhibitory imbalance which cause mental retardation and features of autism.

This all suggests that the 25 year-old young man with Fragile X treated at UC Davis (case study above) should switch from Simvastatin to Lovastatin.

Metformin and Autophagy

I also think Dr Hagerman is less likely to get dementia now that she is talking metformin.  If she takes vigorous exercise at least once a week, I think that is also going to keep her grey cells ticking over nicely. Like Dr Ben Ari, Hr Hagerman is working way past normal retirement.  If you love your job, then why not?  As with many things, in the case of neurons, “use them or lose them”.

Autophagy in Dementias

Dementias are a varied group of disorders typically associated with memory loss, impaired judgment and/or language and by symptoms affecting other cognitive and social abilities to a degree that interferes with daily functioning. Alzheimer’s disease (AD) is the most common cause of a progressive dementia, followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV associated neurocognitive disorders (HAND).
The pathogenesis of this group of disorders has been linked to the abnormal accumulation of proteins in the brains of affected individuals, which in turn has been related to deficits in protein clearance. Autophagy is a key cellular protein clearance pathway with proteolytic cleavage and degradation via the ubiquitin-proteasome pathway representing another important clearance mechanism. Alterations in the levels of autophagy and the proteins associated with the autophagocytic pathway have been reported in various types of dementias. This review will examine recent literature across these disorders and highlight a common theme of altered autophagy across the spectrum of the dementias.

Below is an excellent graphic from a paper highlighted by Ling. Note metformin, above AMPK.

Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

I would highlight the presence of IP3R, the calcium channel proposed by Gargus as being a nexus in autism, for where multiple types of autism meet up, to do damage.

Verapamil, in Monty’s Polypill, increases autophagy independently of mTOR in a complicated mechanism  involving IP3R and likley calpain.  It is proposed as a therapy for Huntington’s Disease via this mechanism. At the lower right of the chart below we see calpain, a group of calcium dependent enzymes, not well understood.  ROS can activate calpains via L-type calcium channels.

I would not worry about the details.  The take home point is that if you have autism, dementia or many other neurological conditions, you might well benefit from increasing autophagy.  There are very many ways to do this.      

Fortunately, I am not a doctor.  I do recall when my doctor father was out visiting his sick patients at their homes, he did have not only his medical bag, but also some useful gadgets always kept in his car, that might come in handy.

The autism equivalent is the personalized Polypill therapy for daily use and the autism toolbox to delve into to treat flare-ups in autism as and when they arise.

I do think some people should have metformin in their daily Polypill therapy.

I think we can safely call Fragile-X a type of autism, so we already know it works for at least some autism.  Metformin is a very safe old drug, with minimal side effects and it is cheap.  It ticks all the boxes for a potential autism therapy.  Will it work for your case?  I can tell you with certainty that it does not work for everyone.

Metformin has been trialled to treat people with obesity and autism, since it can reduce appetite.

Metformin forTreatment of Overweight Induced by Atypical Antipsychotic Medication in YoungPeople With Autism Spectrum Disorder: A Randomized Clinical Trial.


Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years.


The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication.


Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005).


Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD.

My guess is that a minority will be responders, the benefit will manifest itself in different ways and so it will be a useful part of polytherapy for some people, but it will not be a silver bullet.  Other than via an IQ test, I think the benefit will be hard to measure, even when it is very evident. 

In the end there will be a clever way to predict who will respond to which therapy.  Today’s post actually replaces one that will look into genetic testing and DEGs (differentially expressed genes). Most likely testing for DEGs will be the best predictor of what drugs work for whom.

Intelligent, cautious trial and error using safe drugs is an alternative strategy.  It is available today; it is cheap and it does work.

I have not tried Metformin yet, in recent years I have had most success with my own ideas. I have some of Dr Frye's calcium folinate sitting at home waiting for a trial.  Both Metformin and calcium folinate should be trialled.  The other obvious thing to trial is that Japanese PDE4 inhibitor Ibudilast (Ketas).  Thanks to Rene we now know you can acquire this is via any international pharmacy in Germany, with a prescription. It also reappeared on the website of a Japanese online pharmacy. The Western PDE4 inhibitors, like Daxas/Roflumilast are not selective enough and so are emetic (they make you want to vomit). Low dose Roflumilast has been patented as a cognitive enhancer, but you may need to have a bucket with you at all times.



  1. I have been trying to figure out how to ask my doctor for a statin for months but I'm worried they'll just say no. Metformin has been on my "wishlist" since before even finding your blog. I also wonder if I would do better on immediate release verapamil because I'm prescribed extended release. I have been finding fluvoxamine and clemastine helpful.

    One other thing I've been curious about is if your research on memantine would also apply to admantadine. I take 100mg amantadine twice a day.

    1. Martin, I am glad that you are finding useful interventions.

      Amantadine has 3 main effects:-

      NMDA antagonist/blocker
      Muscarinic acetylcholine receptor antagonist (like many antipsychotics and antidepressants)

      Memantine has these main effects:-

      NMDA antagonist/blocker
      Seratonin 5-HT3 receptor antagonist/blocker
      antagonist at different neuronal nicotinic acetylcholine receptors (nAChRs) including alpha7, which is relevant
      agonist at the dopamine D2 receptor

      So the two drugs do have some overlap in their effect, but there are some big differences.

      I don't think Amantadine had had much mention in this blog, but it is used by psychiatrists and even in autism.

      Amantadine: A Review of Use in Child and Adolescent Psychiatry

      Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder.

      How would you describe the effect of your extended release verapamil?

  2. Hello Peter, thank you so much for all of this information. I read so many research studies but find the information inconclusive or contradictory. My daughter would be classed as having Asperger's, although a milder form of asd, in her case this is quite severe. Before finding this blog I tried Swanson's sulforaphane for a few weeks with no difference. I also started Tau-Biotic butyrate. I have stopped both now. She struggles with irritability, aggression, tiredness as usual but despite a high IQ she isn't open minded or interested enough to start any 'talking' therapy. Please can you advise what you would try? I saw on another post you said Asperger's is more of a hormonal problem. Any advice is much appreciated. Thank you!

    1. It is best to narrow down the type of autism/Asperger’s, which can be done by looking at any medical comorbidities and just observations like “tiredness”. Many Aspies do share what works for them on sites like Reddit.

      The Amantadine used by Martin in the comment above looks not a bad place to start.

      Amantadine: A Review of Use in Child and Adolescent Psychiatry

      Antioxidants like NAC and ALA are effective in many people and you would see any effect in a day or so. NAC Sustain is the product I think works best.

      All kinds of things can help aggression, it depends on the biological cause. In my son it is an L-type calcium channel blocker. Our reader Nancy found that a BCAA supplement works wonders.

      I think medical comorbidities often provide the clues.

      If money is no issue you could do genetic testing. GeneDX has been recommended by some readers and they have a special test looking at autism genes.

      Asperger's is different in terms of the scale of the biological issues. If you have normal IQ, normal motor skills and you can speak fluently, the issues are much more subtle that in classic autism. Some Aspies doe respond to the same therapies as those with Classic autism, for example Bumetanide, but some seem to find the answer in psychotropic drugs, which are not usually legal.

      I suggest you talk to some middle-aged Aspies. With the internet it is easy.

    2. The amantadine is wonderful for fatigue without making me feel over stimulated like amphetamine. Last year my neurologist offered to let me try amantadine or memantine and I picked the amantadine at the time for that reason. I will say when I first started it it rook me about a week to get used to how it affects my sense of time for like crossing the street i.e. I take 100mg twice a day, but my insurance only covers the 100 liquid release caplets, I've always been curious how I would do taking 50mg if my insurance covered the 100mg tablets. I still am going to reply in more detail I just have a hard time getting my thoughts out but I wanted to make sure I shared about how it affected my sense of time the first few days. I definitely recommend trying amantadine.

  3. Thank you both for your replies. She has over sensitive body,under responsive vestibular, attention issues,IQ on the 98th centile despite being brought down by a low spatial reasoning score. Poor gross and fine motor skills/dyspraxia. Hypermobility and dyslexia. Her speech and vocabulary are fine. High anxiety levels. I can't think of anything else.

    I will look at the website and genetic testing now. Thanks again.

  4. Hello Peter, Ling, and Friends!

    Hope everyone is doing well (and not in the middle of a snowstorm as I am …)

    I wanted to share a paper with everyone, and would appreciate any thoughts you may have on the subject. The paper can be found here:

    The paper is called "Vitexin reduces epilepsy after hypoxic ischemia in the neonatal brain via inhibition of NKCC1"

    In this paper, Vitexin appears to inhibit NKCC1, and is found in Passion Flower, Hawthorn, Chaste Berry.

    Has anyone had any experience with any supplements that include Vitexin?

    Thanks in advance,


    1. AJ, I think you mentioned Vitexin previously. I did actually buy some, but have never used it.

      Vitexin has been shown to have similar effects to estrogen. It is after all used for fertility related issues in women, but also in men (hence the Chaste Berry).

      Vitexin could be considered a kind of hormone replacement therapy for people who do not want to go to the doctor.

      It makes sense that vitexin affects NKCC1, but it has many other effects on a range of hormones.

      I think it is much safer to use bumetanide or azosemide for the NKCC1 effect, unless you want the hormonal effects. Changing the level of estrogen, prolactin etc will cause a cascade of other effects.

      Good luck clearing the snow at home, all I have to do is rake up the leaves.

    2. Hi Peter,

      Thanks so much for the insights into Vitexin! It always seems, in the world of biology, that a compound that affects a target of interest (e.g. target X) often seems to produce unintended consequences (e.g. in targets Y, Z, and alpha).

      I have been talking to a physician about Bumetanide, but there are such hesitations that it's unlikely this physician will trial it.

      I'll just go back to shoveling snow now :-)


    3. Isn't it odd that the authors of this paper suggest Vitexin for newborns if the hormonal effects are so many? But of course, it might only be for a short course.
      Given that Bumetanide can have ototxic effects in newborns, I doubt Vitexin will ever be tried in this group.

      We just had our first snow, but I'm still behind with my heaps of leaves in the garden. :-D


    4. AJ, there are MAPS doctors in the US prescribing Bumetanide, even Dr Frye. You could look for a MAPS doctor in Canada, or find one in the US. Either that, or pay a visit to Agnieszka in Poland.

    5. Hi Ling!

      With the snow we just got, I can't even see where my garden was ;-)

      The good news is that it hides all the leaves that were there that I hadn't dealt with yet …

      Hope all is well Ling!


  5. Hi Peter, thanks for the advice! I will look to see where the closest MAPS docs are to me. I'm actually not that far from the US border, if I can't find one close to where I'm at in Toronto.

    I just checked the weather in Poland … it's a veritable tropical destination compared to the cold snap we have here - I may consider it just to warm up :-) . My daughter is singing Christmas songs based on how much snow she is seeing … I feel like I'm on Hoth.

    I am actually moving slowly these days in terms of therapeutic options as I'm hoping to get some clarity on my daughter's mutation from a research team working on that gene, hopefully in the next couple of months. I'm hoping that once I have some more clarity, I'll be able to determine if affecting intracellular chloride levels are even relevant to my situation, before I even trial Bumetanide, but I've been trying to find a doc in the meantime just in case it would be relevant.

    I've also been thinking about contacting Servier to see if they would be open to extending the clinical trial of bumetanide to at least one site in Canada. Unlikely I know, but I'm always willing to try.

    Have a great day Peter!


    1. AJ, you made my day speaking of Poland as a tropical destination :-))) I haven't seen any sun for almost a week, it's freezing cold, raining every day and gets dark in the early afternoon. We are too far south to see aurora borealis and too far north to have locally produced wine - November is definitely to avoid at this latitude if you want to warm up ;-)

      Who knows, maybe the time will come for telemedicine in autism as in this story about longevity online clinic from the US. Coincidentally it’s about metformin as this blog post:

      Peter, you mention here cognitive improvement as helpful to learn life skills e.g. brushing teeth or tying shoe laces etc. For all of of them one needs also good motor skills and this is an issue in some autism, “grossly underestimated” according to this recent article:

      Clearly, there are persons with autism who would be totally aware how to brush the teeth and what for, but not able to do it because of motor planning issues.
      Just wonder if treatments improving motor skills could be listed as in the potential IQ enhancers list. Clemastine? And… ?

      Can't wait for the snow to hide all these leaves in the garden :-)

    2. Agnieszka, my IQ enhancers are:-

      Atorvastatin (but for FXS use Lovastatin, since there is evidence)
      Micro-dose Clonazepam

    3. Hi Agnieszka, I knew you would like the comment about Poland as a tropical destination ;-) My wife told me this morning that with the windchill it felts like -14C (although today's high will reach -3C). I just checked the weather in a major city in Poland and it said the high will be +8C.

      +8C would feel like a day in California to me now.

      By the way, I really like your comment about Telemedicine. It would be great if knowledgeable doctors around the world could be accessed via Telemedicine for ASD related prescriptions.

      Also, I went to our Developmental Pediatrician armed with the clinical trial results for Bumetanide and of course your document, and the doctor was very interested. Given the impact on kidneys, the doctor is still very hesitant but checking with other specialists to see if possible. So your document was very helpful in getting this far :-)

      Hope you have a wonderful day Agnieszka, and for just enough snow to hide the leaves but not enough to have to shovel the driveway





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