Cerebral Folate Deficiency – increasing cerebral folate without increasing plasma/blood folate, via activating the reduced folate carrier (RFC)

 

Source: https://autism.fratnow.com/blog/folate-transport-systems-i-transmembrane-carriers/

Two readers of this blog have been telling me about the fundamental role of brain energy and metabolism in autism. Marco sent me a book called Brain Energy by a psychiatrist at the Harvard Medical School. He stumbled upon this subject when he encouraged a patient to lose weight using the ketogenic diet. As well as losing weight, the patient’s decades-long psychiatric disorders seemed to vanish. The author, Dr Palmer, now believes that many of his patients actually have metabolic disorders as the underlying basis of their psychiatric symptoms. 

Our reader Natasa is approaching with a similar idea, essentially that autism features a brain running on empty.

Today’s post is about increasing the level of folate within the brain, by targeting similar metabolic pathways to those that will boost “brain energy.”

Low levels of folate within the brain will cause varying degrees of neurological disorder.

There are three ways folate can cross into the brain.

1.     Folate receptor alpha (FRA)

2.     Proton-coupled folate transporter (PCFT)

3.     Reduced folate carrier (RFC)

Autoantibodies to the FRA have been linked to neurodevelopmental diseases, particularly cerebral folate deficiency, schizophrenia and autism. Recent studies have shown that these neurodevelopmental disorders can be treated with folinic acid (leucovorin).

Dr Frye, Professor Ramaekers and others are targeting the problem of low folate in the brain by supercharging the level of folate in the bloodstream and hoping more squeezes through the blood brain barrier.

In my previous post I mentioned that Agnieszka has pointed out the idea of using the supplement PQQ. This targets the third transport mechanism above, it is aiming to get more folate across via  the Reduced Folate Carrier (RFC).

Somebody recently wrote their PhD thesis on exactly this topic:- 

Regulation of Folate Transport at the Blood-Brain Barrier: A Novel Strategy for the Treatment of Childhood Neurological Disorders Associated with Cerebral Folate Deficiency

Camille Alam, Department of Pharmaceutical Sciences, University of Toronto 

Additionally, we provided in vitro and in vivo evidence that RFC expression and transport activity is inducible by another transcription factor, NRF-1. These findings demonstrate that augmenting RFC functional expression through interaction with specific transcription factors could constitute a novel strategy for enhancing brain folate delivery. Modulating folate uptake at the BBB may have clinical significance due to the lack of established optimal therapy for neurometabolic disorders caused by loss of FRα or PCFT function. 

What Camille is saying is that if folate transport mechanism number 1 and/or number 2 are not working, we can reinvigorate mechanism number 3.

So if you have Dr Frye’s folate receptor antibodies, or PCFT isn’t working then you might focus on Reduced Folate Carrier (RFC).

The good news is that we have lots of ways to target Reduced Folate Carrier (RFC).

We do not, it seems, have any clever ways to target PCFT. 

NRF-1 and PGC1-alpha

There is a lot in this blog about PGC1-alpha, because it is the master regulator for biogenesis of mitochondria.

All those people with impaired “brain energy” would love to activate PGC1-alpha.

NRF-1 is an activator of mitochondrial respiratory chain genes. NRF-1 specifically targets genes encoding subunits of the mitochondrial respiratory chain complexes, particularly complexes I, III, and IV. By binding to their promoters, NRF-1 directly stimulates their transcription, leading to increased synthesis of these critical protein components and enhanced oxidative phosphorylation (OXPHOS) capacity.

Synergy between NRF-1 and PGC-1alpha

PGC-1alpha acts as the upstream regulator. Various stimuli, such as exercise, cold exposure, and certain hormones, can trigger PGC-1alpha expression. Once activated, PGC-1alpha directly interacts with and co-activates NRF-1, enhancing its binding to target gene promoters and amplifying its transcriptional activity.

NRF-1 as the downstream effector.  NRF-1 fine-tunes the expression of specific mitochondrial genes, ensuring a balanced and efficient OXPHOS system. This synergy between PGC-1alpha and NRF-1 optimizes mitochondrial function and cellular energy production.

So for Natasa, trying to boost energy production in the brain and in the rest of the body, it would be ideal to have more NRF-1 and more PGC-1alpha

What has optimized mitochondrial function got to do with more folate in the brain?

It turns out that you can increase expression of Reduced Folate Carrier (RFC) via activating NRF-1 and/or PGC1alpha.

So what is good for your brain energy is likely to also be good for your brain folate.

Nuclear respiratory factor 1 (NRF-1) upregulates the expression and function of reduced folate carrier (RFC) at the blood-brain barrier

Folates are important for neurodevelopment and cognitive function. Folate transport across biological membranes is mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate transport primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems results in suboptimal folate levels in the cerebrospinal fluid (CSF) causing childhood neurological disorders. Our group has reported that upregulation of RFC at the blood-brain barrier (BBB) through interactions with specific transcription factors, that is, vitamin D receptor (VDR) could increase brain folate delivery. This study investigates the role of nuclear respiratory factor 1 (NRF-1) in the regulation of RFC at the BBB. Activation of NRF-1/PGC-1α signaling through treatment with its specific ligand, pyrroloquinoline quinone (PQQ), significantly induced RFC expression and transport activity in hCMEC/D3 cells. In contrast, transfection with NRF-1 or PGC-1α targeting siRNA downregulated RFC functional expression in the same cell system. Applying chromatin immunoprecipitation (ChIP) assay, we further demonstrated that PQQ treatment increased NRF-1 binding to putative NRF-1 binding sites within the SLC19A1 promoter, which encodes for RFC. Additionally, in vivo treatment of wild type mice with PQQ-induced RFC expression in isolated mouse brain capillaries. Together, these findings demonstrate that NRF-1/PGC-1α activation by PQQ upregulates RFC functional expression at the BBB and could potentially enhance brain folate uptake.

The hugely simple intervention mentioned above is to just take vitamin D. This has nothing to do with brain energy.

Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha

Folates are critical for brain development and function. Abnormalities in brain folate transport have been implicated in a number of childhood neurodevelopmental disorders, including cerebral folate deficiency syndrome, hereditary folate malabsorption, and autism spectrum disorders. These disorders have devastating effects in young children, and current therapeutic approaches are not sufficiently effective. In this study, we demonstrate that functional expression of the folate transporter, reduced folate carrier, at the blood–brain barrier and its upregulation by the vitamin D nuclear receptor can remarkably increase folate transport to the brain. These findings provide a strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by folate transport defects.

 Low vitamin D correlates with poor health, dementia, and death from all causes

Taking vitamin D has become popular in recent years.

A correlation does not guarantee causality.  It was thought that vitamin D might be the silver bullet to improved health in older people. It has not proved to be.

Low vitamin D also correlates with less time outdoors, doing some physical activity. Taking vitamin D does not mean you will live longer, but we know for sure that exercise improves many medical concerns that will improve healthy life expectancy.

The concern many people now have regarding skin cancer leads to some healthy active people having low vitamin D. Put on that sunscreen and your exposed skin will not be able to produce your vitamin D.

Vitamin D is important to health and is easy to maintain in the normal range, but it is just one element of good health. It might be one way to increase folate in the brain, for those who need it. 

 

Conclusion

How do you increase folate in the brain?

The obvious way is to put more folate in your blood, this is the standard therapy. You either take calcium folinate tablets or, very rarely, the more potent infusions.

If you have antibodies blocking transport via FRA, you could follow the hypothesis that these antibodies are from a reaction to cow’s milk and try going dairy-free. There is a complex relationship between milk and folate receptor alpha antibodies (FRAA), but direct evidence of milk causing FRAA production is limited.

Milk, particularly cow's milk, contains proteins similar to folate receptor alpha found in humans. Some individuals, mainly those with a genetic predisposition, could develop FRAA that cross-react with these milk proteins. This cross-reactivity would not necessarily mean the milk directly caused FRAA production but might trigger an existing immune response. Some studies, though not all, have found an association between higher milk consumption and increased FRAA levels.

If you want to increase folate transport via our third mechanism, Reduced Folate Carrier (RFC) you have many options:

The obvious first step is to take a vitamin D supplement to raise levels to the high end of normal. This can be done by taking a larger supplement just once a week, because vitamin D has a long half-life.

As you can see from the study below in children there is a correlation between low vitamin D and low folate in children.

 

Evaluation of correlation between vitamin D with vitamin B₁₂ and folate in children

The present study reported a positive correlation between vitamin D and vitamin B12 and folate levels. Regular measurement of these two micronutrient levels in children with vitamin D deficiency is important for public health.

Vitamin D is low in much of the population, even more so in wintertime. It seems particularly low in children with autism, perhaps because they are spending less time playing outside than other children.

Activate NRF-1 and/or PGC1alpha:

1.     Exercise, particularly endurance training

2.     PQQ supplement

3.     Perhaps resveratrol/pterostilbene

4.     Butyric acid / sodium butyrate

5.     The very safe old drug Metformin

6.     Other type 2 diabetes drugs like Pioglitazone

Metformin has been shown to raise IQ in Fragile-X by about 10 points and has a range of metabolic benefits and even cancer preventative effects. This common diabetes medication primarily targets AMPK, an energy sensor molecule upstream of PGC-1alpha. By activating AMPK, metformin indirectly stimulates PGC-1alpha and subsequently NRF1, leading to enhanced mitochondrial function.

Pioglitazone has been researched in autism and is my choice for peak risk spring/summer aggression and self-injury. Pioglitazone can potentially upregulate PGC-1alpha expression through several pathways:

•                    Pioglitazone activates AMPK, an important energy sensor molecule. AMPK can then stimulate PGC-1alpha expression through various signaling pathways.

•                    Pioglitazone activates PPAR-gamma and PPAR-gamma directly interacts with PGC-1alpha, potentially increasing its activity.

I think Metformin has a better safety profile than Pioglitazone and so better for every day use.

Butyric acid does have the potential to activate PGC-1alpha. Butyric acid is produced in the gut by fermentation. You need “good” bacteria and fiber. People with healthy diet naturally produce it. You can also buy it as a supplement (sodium butyrate) since it has numerous benefits – everything from gut health, bone health to a tight blood brain barrier.

According to a doctor I was talking to recently, nobody wants to hear that exercise is a key part of health. It is free and the side effects are generally all good ones. Endurance exercise will boost NRF1 and PGC1alpha. Many people with autism are overweight, often due to the psychiatric drugs they have been put on.

Sirtuin activators boost NRF1 and PGC1 alpha. There are drugs and foods which can do this, but a potent way is through exercise.

I hope Dr Frye is checking his patients’ vitamin D levels and supplementing to the safe upper limit.

Those taking I/V calcium folinate might want to look at the more potent ways to activate NRF1 and/or PGC1alpha.

 

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.

https://epiphanyasd.blogspot.com/search/label/metformin

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.

Diabetes Medicine MetforminMay Improve Cognition, Behavior Symptoms in Fragile X Syndrome Patients, Case Study Reports

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.

                                                              

Diabetes drug delivers multiple benefits forpeople with fragile X syndrome

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. 

Metformin as targeted treatment in fragile X syndrome 

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.

Results

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.

Conclusion

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 a metformin trial at the University of California at Davis MIND Institute.

A Trial of Metformin in Individuals with Fragile X Syndrome (Met)

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635566/

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.      
                                                           

Conclusion

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.

INTERVENTIONS:

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.

MAIN OUTCOMES AND MEASURES:

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.

RESULTS:

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).

CONCLUSIONS AND RELEVANCE:

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.