Showing posts with label Dementia. Show all posts
Showing posts with label Dementia. Show all posts

Monday 14 March 2022

Fenamates (Diclofenac, Ponstan etc): certainly for Alzheimer’s, maybe some Epilepsy, but Autism? I’m Impressed!


Some readers of this blog are interested in the potential of mefenamic acid (MFA), sold as Ponstan, to treat autism. There is a lack of evidence currently. 

On the other hand, the evidence looks pretty overwhelming in the case of this class of drug to treat Alzheimer’s, hence today’s post. If you have a case of epilepsy at home, you can follow up on that loose end I left.

I also introduce MFA as a therapy for sound sensitivity and Misophonia. It was pretty impressive in the case of Monty, aged 18 with ASD.


The highlights are:


·        Fenamate NSAIDs reduce the incidence of Alzheimer’s

·        Fenamate NSAIDs delay the progression of those already with Alzheimer’s

·        Acetaminophen/Paracetamol worsens the progression of Alzheimer’s

·        Low dose aspirin is chemoprotective, as well as reducing blood clots that cause heart attack and stroke, but offers no Alzheimer’s benefit

·        MFA/Ponstan is very effective in reducing Monty’s sound sensitivity


The caveats 

As is always the case, there are caveats.

It is well known that low dose aspirin can cause dangerous bleeding events in specific sub-populations.

A study of 6 million people in Denmark showed that older people taking the Fenamate Diclofenac has a slightly higher risk of heart problems than other NSAIDs. The risk is actually very low and symptoms in those affected generally appear within a month (and disappear on cessation).


Incidence of Alzheimer’s





The longer you live, the chance of developing Alzheimer’s rapidly increases. 

The signs are actual visible in a CT scan decades before the symptoms are evident.

Almost two-thirds of Americans with Alzheimer's are women.

Older Black Americans are about twice as likely to have Alzheimer's or other dementias as older Whites.

Of those with I/DD (Intellectual or Developmental Disability), it is people with Down Syndrome who are at major risk of early onset Alzheimer’s.  More than 50% will develop Alzheimer's. 


Non drug methods to protect against Alzheimer’s and other dementia 

In this blog we have encountered numerous dietary methods associated with reduced risk of all types of dementia and Alzheimer’s specifically.

·        Dietary nitrates (beetroot, spinach etc)

·        Betanin (the pigment in beetroot)

·        Ergothioneine (from mushrooms)

·        Spermidine (from wheatgerm and mushrooms)

·        Anthocyanin pigments from superfoods (bilberry, blueberry, purple sweet potato etc)


Maintaining normal blood pressure, blood glucose levels and cholesterol levels are big advantages. Normal body mass and regular exercise are also important.

Fenamates are a class of NSAID pain medication that many people have at home. In the US there are 10 million prescriptions a year of Diclofenac / Voltaren.

Another common Fenamate is Mefenamic Acid (MFA), commonly sold as Ponstan.  Ponstan is only expensive in North America. 

Most people’s reaction would be “Ah, yes those are pain medications, how could they help Alzheimer’s or other neurological conditions. Aren’t they the ones with those GI side effects?” 

NSAIDS deaden pain by blocking an enzyme called cyclooxygenase-2 (COX-2). Unfortunately, they also block to some extent a very similar enzyme called  cyclooxygenase-1 (COX-1). COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion.  Blocking COX-1 will cause GI side effects. Most people want to take an NSAID that is selective for COX-2.


Low dose Aspirin – the good COX-1 effect

There is a good effect from blocking COX-1, as from low dose aspirin (LDA), because it stops blood platelets sticking together and blocking blood flow.  LDA is also substantially chemoprotective and nobody has figured out why and it likely has nothing to do with COX1 or COX2. 

“Ishikawa et al. analyzed 51 randomized controlled trials (RCTs) and the cumulative evidence strongly supports the hypothesis that daily use of aspirin results in the prevention of cardiovascular disease (CVD), as well as a reduction in cancer-associated mortality [3].”


Anti-inflammatories in Alzheimer’s disease—potential therapy or spurious correlate? 

Epidemiological evidence suggests non-steroidal anti-inflammatory drugs reduce the risk of Alzheimer’s disease. However, clinical trials have found no evidence of non-steroidal anti-inflammatory drug efficacy. This incongruence may be due to the wrong non-steroidal anti-inflammatory drugs being tested in robust clinical trials or the epidemiological findings being caused by confounding factors. Therefore, this study used logistic regression and the innovative approach of negative binomial generalized linear mixed modelling to investigate both prevalence and cognitive decline, respectively, in the Alzheimer’s Disease Neuroimaging dataset for each commonly used non-steroidal anti-inflammatory drug and paracetamol. Use of most non-steroidal anti-inflammatories was associated with reduced Alzheimer’s disease prevalence yet no effect on cognitive decline was observed. Paracetamol had a similar effect on prevalence to these non-steroidal anti-inflammatory drugs suggesting this association is independent of the anti-inflammatory effects and that previous results may be due to spurious associations. Interestingly, diclofenac use was significantly associated with both reduce incidence and slower cognitive decline warranting further research into the potential therapeutic effects of diclofenac in Alzheimer’s disease.



Diclofenac Use Slows Cognitive Decline in Alzheimer Disease 

CHICAGO — While most common non-steroidal anti-inflammatory drugs (NSAIDs) do not significantly affect cognitive decline in patients with Alzheimer disease or mild cognitive impairment, research presented at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018, in Chicago, Illinois suggests that diclofenac actually reduces cognitive deterioration, while paracetamol accelerates decline. 

The study investigated cognitive decline associated with NSAID use in 1619 patients from the Alzheimer’s Disease Neuroimaging Initiative dataset. The Mini-Mental State Examination and the Alzheimer disease assessment scale were used to evaluate cognitive functioning. Additional variables that potentially explain cognitive decline were identified for the cohort including gender, apolipoprotein E genotype, level of education, vascular disorders, diabetes, and medication use. 


Study results showed that most common NSAIDs, including aspirin, ibuprofen, naproxen, and celecoxib did not alter cognitive degeneration in patients with mild cognitive impairment or Alzheimer disease. Diclofenac was the only NSAID that demonstrated a correlation with a slower rate of cognitive decline (ADAS χ2=4.0, P =.0455, MMSE χ2=4.8, P =.029). Conversely, paracetamol was correlated with accelerated cognitive deterioration (ADAS χ2=6.6, P =.010, MMSE χ2=8.4, P =.004), as well as apolipoprotein E ε4 genotype (ADAS χ2=316.0, P <.0001, MMSE χ2=191.0, P <.0001). 

Diclofenac’s correlation with slowed cognitive deterioration provides “exciting evidence for a potential disease modifying therapeutic,” the study authors wrote. If paracetamol’s deleterious effects are confirmed to be causative, it “would have massive ramifications for the recommended use of this prolific drug.”


One reason why paracetamol use might harm Alzheimer’s brains is the same reason it harms autistic brains; it depletes the level of the key antioxidant glutathione (GSH).  GSH will be in big demand in a damaged brain. 

As we will see later in this post, Fenamate class NSAIDs affect numerous ion channels, specifically Kv7.1, as a result some people with heart conditions will get side effects linked to arrhythmia and should therefore discontinue use.


Common painkiller linked to increased risk of major heart problems: Time to acknowledge potential health risk of diclofenac and reduce its use, say researchers -- ScienceDaily

Common painkiller linked to increased risk of major heart problems

Time to acknowledge potential health risk of diclofenac and reduce its use, say researchers 

The commonly used painkiller diclofenac is associated with an increased risk of major cardiovascular events, such as heart attack and stroke, compared with no use, paracetamol use, and use of other traditional painkillers, a new study finds.


The risk is actual quite low and is going to appear straight away, in terms of arrhythmia. If any drug or supplement makes you feel unwell, stop taking it and tell your doctor.


Which Fenamate for Alzheimer’s?

To decide which Fenamate is best for Alzheimer’s and indeed which might be helpful in some autism, it helps to ponder the various modes of action unrelated to COX-1 and COX-2. 

We have the NLRP3 inflammasome, which is suggested as the mechanism in Alzheimer’s.

Here we want to block inflammatory messenger like IL-1beta. In the chart below we see that Ibuprofen is useless, Diclofenac has an effect, Mefenamic acid is better, but Meclofenamic acid is the star.



Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer’s disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer’s disease therapeutics.


Fenamates and Ion Channels


A very broad range of ion channels are affected by Fenamates.

Researcher Knut Wittkowski focuses on the effect on potassium channels in his theory that Fenamates can treat autism and prevent non-verbal autism if given to toddlers.

Fenamates actually affect numerous ion channels.

·        Chloride channels

·        Non-selective cation channels

·        Potassium channels (Kv 7.1 , KCa 4.2, K2p 2.1, K2p 4.1, K2p 10.1)

·        Opens large conductance calcium-activated K+ channels (BKCa channels)

“Genetic variants in large conductance voltage and calcium sensitive potassium (BKCa) channels have associations with neurodevelopmental disorders such as autism spectrum disorder, fragile X syndrome, and intellectual disability… These findings support the relationship between BKCa channel impairment and social behavior. This demonstrates a need for future studies which further examine the contribution of BKCa channels to social behavior, particularly during critical periods of development.


·        Sodium channels

·        Blockage of acid-sensing ion channels (ASICs), which are implicated in numerous disorders and had their own post.


Fig. 2. Ion channels targeted by flufenamic acid. Flufenamic acid produces inhibition or activation of ion channels. Colored bars near ionic channel name correspond to the estimated EC50 for flufenamic effect. References are provided within the text.

 Having noted the above graphic, which actually applies to the closely related flufenamic acid, a logical question is to ask about the effect of Flufenamic acid on seizures. 

Flufenamic acid shows promise as an epilepsy drug

I am not looking for a seizure therapy, so I leave that loose end for someone who is.



The best initial defence against dementia is good diet and exercise. Sometimes that will not be enough, because the healthier you are, the longer you will live and so the threat from dementia increases. Some people have genes that predispose them to dementia.

Since most of us struggle to follow diets like those of ultra healthy people in Okinawa, or on a Greek island, it might be worthwhile adding beneficial functional foods (neutraceuticals) to your existing diet.

I drink a small amount of beetroot juice daily, which is not such a hard step to take. In addition to benefits to your heart and brain, another benefit has just been discovered; now it improves the oral microbiome :-


Research suggests changes in mouth bacteria after drinking beetroot juice may promote healthy ageing 

“Our findings suggest that adding nitrate-rich foods to the diet – in this case via beetroot juice – for just ten days can substantially alter the oral microbiome (mix of bacteria) for the better.”


Many older people take NSAIDs to treat painful conditions like arthritis, switching to a Fenamate NSAID would not be a difficult option and would give some protection from Alzheimer’s.

People already diagnosed with Alzheimer’s currently do not have any effective therapies. Drugs like memantine exist, but are not so effective.  If I was in that position, I would want to take a low dose of Mefenamic Acid, if that was unavailable, I would settle for Diclofenac.

Diclofenac (25mg to 100mg) is prescribed in much lower doses than Mefenamic Acid (250 to 500mg tablets). We see that the effect on the NLRP3 inflammasome is actually far greater from Mefenamic Acid than Diclofenac. If the Alzheimer’s effect is via inhibiting the NLRP3 inflammasome, then you might expect that only a fraction of a standard capsule of Mefenamic would be needed.  That would then really reduce any GI side effects via the unwanted effect on COX-1 or any chance of arrhythmia. 

The ketone BHB, like fenamate NSAIDs, inhibits the NLRP3 inflammasome.  Since in Alzheimer’s the brain loses the ability to transport enough glucose across the blood brain barrier, ketones can also be used as a supplementary fuel for the brain. In one of my old posts on BHB I remember the doctor treating her husband with early onset Alzheimer’s with large doses of ketones – with some success.


And Autism?

Is Knut right that the potassium channel modulation from Mefenamic Acid will benefit autism, or at least a sub-set of severe autism? We do not know.

Mefenamic Acid (MFA) has so many biologic effects, I very much doubt Alzheimer’s is the only neurological condition where it could be beneficial. 

I should add that MFA undoubtedly will have negative effects in some people, this is inevitable.

Stop the noise !!

We did have a problem recently with extreme sound sensitivity. Monty, aged 18 with ASD, has had increasing sound sensitivity (Misophonia) for a year, but the only real issue was with sounds at mealtimes.  Over a recent weekend the sensitivity increased so much he could not sleep and also drank unusually large amounts of water (this also connects to K+).

The next day at school he had a geography exam and he was completely dysfunctional. Monty’s assistant had prewarned the teacher and she agreed that he can sit the exam again next week.   

Fortunately, in the meantime the problem has been now been fixed (see below).

I was suggested to take to Monty to a Neurologist, but since there is no Dr Chez where we live, I did ignore that idea. In mainstream neurology sound sensitivity is just something you have got to learn to live with, perhaps with some Cognitive Behavioral Therapy (CBT) or just a pair of ear defenders, or those noise-cancelling headphones.

I did experiment years ago on the effect of an oral potassium supplement on reducing sound sensitivity, so I have long considered potassium ion channels a prime target.

Both hearing and the processing of the inputs is highly dependent on potassium channels, so I did return to MFA.  It has also been a topic in some recent email exchanges and I have long had some unopened packs of MFA at home.  The answer would be found in the kitchen cabinet and not in the neurology department

In bumetanide responders the Na-K-2Cl cotransporter (NKCC1) is over-expressed; it mediates the “coupled electroneutral movement of 1Na+, 1K+, and 2Cl ions across the plasma membrane of neurons”. This means that with each two chloride ions entering the neuron, come one sodium ion and one potassium ion.




In summary, bumetanide responders have too much chloride in their neurons, the bubble on the left, above.


Knut’s theory was put to me recently as “MFA works on reducing neuron excitation by opening K+ channels, emptying the cell, which in return fills up with Cl- “.

If this is the case, MFA would do the opposite of Bumetanide.

I actually think MFA’s effect is much more complex.

The original idea of Knut was to prevent severe non-verbal autism developing in toddlers, by blocking the progression of the disease. MFA was essentially a medium-term treatment for toddlers, until the critical periods in brain development were past.  It was not a treatment for teenagers, by then the damage would have been done.

I think changing the baseline level of K+ inside neurons is going to have many effects.  Changing the baseline level of Cl- has a profound impact on cognition.

Unfortunately, everything is interrelated and so nothing is simple.

I did try MFA to eradicate the extreme sound sensitivity. I was concerned it might reduce cognition, by raising intracellular chloride and undo the bumetanide effect.

The extreme sound sensitivity did disappear following a day or two of starting 250mg a day of MFA, but that may just have been a coincidence.  The more mild sound sensitivity, that we had all learned to live with for months, also vanished; I do not see how that could be a coincidence.  Mood also became very good, perhaps a bit uncontrollably happy.

The next question is what happens to sound sensitivity when I stop giving MFA.  Time will tell, but so far the benefits have been maintained.

Sound sensitivity/Misophonia is a classic feature of autism;  TV depictions often portray a lonely looking boy wearing ear defenders. For many with Asperger’s misophonia is their main troubling issue. None of these people are taking bumetanide.  Monty has taken Bumetanide for nearly 10 years and never needed ear defenders.

You, like Prof Ben-Ari, might wonder if bumetanide use might cause a problem with potassium and hence hearing.  There is indeed a known risk of ototoxicity, which is actually a rare but possible side effect of loop-diuretic use, particularly furosemide.

Fluid in the inner ear is dependent upon a rich supply of potassium, especially in that part of the ear that translates the noises we hear into electrical impulses the brain interprets as sound.




“Endolymph (in green) is limited to the scala media (= cochlear duct; 3), is very rich in potassium, secreted by the stria vascularis, and has a positive potential (+80mV) compared to perilymph.

Note that only the surface of the organ of Corti is bathed in endolymph (notably the stereocilia of the hair cells), whilst the main body of hair cells and support cells are bathed in perilymph.”


It is important to maintain a high level of potassium (K+) in the endolymph.

How the potassium gets there is a little bit complicated but it relies on:

·        The NKCC1 transporter

·        Potassium channel Kir4.1

·        Potassium channel KCNQ1 (Kv7.1) and in particular subunit KCNE1


Bumetanide blocks NKCC1 and so can potentially reduce potassium in the endolymph. Very high dose bumetanide would indeed risk ototoxicity.

We saw earlier in this post that Fenamates affect Kv7.1.

It is very poorly documented in the research, but Fenamates also affect Kir4.1.


The cochlea functions like a microphone. The auditory nerve then runs from the cochlea, hopefully bathed in potassium, to a station in the brainstem. From that station, neural impulses travel to the brain – specifically the temporal lobe, containing the primary auditory complex, where sound is attached meaning and we “hear”.


The auditory cortex is highlighted in pink and interacts with the other areas highlighted above


   Angular Gyrus   Supramarginal Gyrus   Broca's Area   Wernicke's Area 


By - self-made - reproduction of combined images Surfacegyri.JPG by Reid Offringa and Ventral-dorsal streams.svg by Selket, CC BY-SA 4.0,


The peripheral auditory system links the microphone/cochlea to the brain. The Primary Auditory Neurons begin in the cochlea and terminate in the Brainstem (in the Cochlear Nuclei). In these neurons potassium channels play a key role.  These channels include KNa1.1 and KNa1.2, which are regulated by intracellular Na+ and Cl, are found in a variety of neurons.

We assume that intracellular Cl is disturbed in bumetanide responsive autism.

Everything has to function to ensure normal hearing and with normal perception attached to that hearing.  Problems can arise in the cochlea (microphone) or in any of the above areas in the brain involved in transmitting or processing those signals.


Fenamates for some Aspie’s with Misophonia?

Misophonia has been covered in previous posts and we saw that therapies do exist in the research.  I think that there are multiple causes of sound sensitivity and likely also for those with Misophonia.

Low dose roflumilast was one interesting therapy, that works for some people but not others.  It does nothing for Monty regarding misophonia/sensory gating.

I wonder if some sound-troubled Aspies will respond to low dose MFA?


The top shelf

In our case, the answer to good health is usually found in the kitchen, but sometimes tucked away out of reach, up high at the back of a shelf, gathering dust, next to my stockpile of NAC.

There will be a dedicated post on sound issues in autism, which will draw everything together to include information from earlier posts.

and, not to forget, 

Danke vielmals Knut !

(Thanks to Knut!)

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.