UA-45667900-1
Showing posts with label Roflumilast. Show all posts
Showing posts with label Roflumilast. Show all posts

Monday, 11 January 2021

2021 Autism PollyPill To Do List – Speech ↑ and Misophonia ↓

 

 A few ideas remain to be fine-tuned


Having started to develop my son’s polytherapy for autism back in December 2012, is there anything left to develop in 2021?

As we have seen, the biggest impact from interventions is when you start them very young, but improvement is possible at any age.

I was asked at the recent Synchrony autism conference what is next for the PolyPill?  and I replied that more spontaneous expressive language is my main target.  I have a good idea of what may help.

·        Calcium folinate, increased over 6 weeks to 45mg/day

·        Sulforaphane, with added Myrosinase in the form of Wasabi

I was contacted by a researcher from that Synchrony conference, suggesting that Low Level LED Therapy (LLLT) was worth trying to improve the use of speech.  It does seem to benefit people with many types of brain injury.  I did write a post on LLLT using lasers, not LEDs, in autism and there was a promising trial in Havana, which I shared with the researcher.

 

https://epiphanyasd.blogspot.com/2018/12/low-level-laser-therapy-lllt-for-autism.html

https://epiphanyasd.blogspot.com/2019/07/homeclinic-based-photobiomodulationlase.html

 

Many of the suggested modes of action of LLLT were in this graphic.


Click to enlarge the graphic

Another suggested mode of action for LLLT concerns improved drainage of lymph from the brain.  This is a known problem in some forms of dementia. Among alternative autism practitioners there are all kinds of manual lymphatic draining therapies.

  

PDE4 inhibitors 

Some readers are using PDE4 inhibitors as the anti-inflammatory component of their personal autism polytherapy.

The 3 “common” choices are: -

·        Pentoxifylline, cheap and even trialled a few decades ago in children with autism. It has a short half-life and is a non-selective PDE inhibitor.  It also has an interesting effect on HDAC, that can make chemotherapy work better.

·        Roflumilast, more expensive and normally used to treat exacerbations in COPD, but patented at a lower dose as a cognitive enhancer. It is more selective for PDE4 than Pentoxifylline and has a long half-life.

·      Ibudilast, common in Japan as an asthma therapy and now a potential treatment for MS (multiple sclerosis).  It is available in Germany, imported to order, with a prescription.

 

PDE inhibitors are not very selective and so some people get side effects.  The big one seems to be nausea. Side effects may well fade over time.

I did try Roflumilast at the supposedly cognitively enhancing dose of 100mcg, a couple of years ago, but it did cause nausea. The nausea may well fade away after a few weeks.  Roflumilast may also reduce the sensory gating problem common, in autism, but only at a dose of 100mcg, higher doses lost this effect.  All is in this old post below.

Impaired sensory gating is driven by HCN channels that need to be blocked.  The science shows us various ways this can be achieved, as I explained in the post below. You can target alpha-2A adrenergic receptors, reduce stress or reduce cAMP.

What is cAMP?  Look here: -

https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate

 

Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist

… in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker.

Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

This would explain why stress makes people’s sensory gating problems get worse. So, someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. 

Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.

While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.

One effect of a PDE4 inhibitor is that it reduces cAMP. So, a PDE4 inhibitor acts indirectly like an HCN blocker.

Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.

So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today.

 

HCN channels play a role in many neurological conditions.  It does get rather complicated, but if you successfully target these ion channels you are definitely at the cutting edge of science. 

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases 

The low dose Roflumilast might be a good choice for Aspies who get bothered by noises like clocks ticking and people chewing gum.

Pentoxifylline is very cheap, but the short half-life means you might need to take it three times a day.

100mcg of Roflumilast is 1/5th of a standard Daxas pill for COPD, which means crushing it and dividing in 5 parts.  This does also make it much cheaper, one pack would last you 5 months.

I will retry Roflumilast and also give Pentoxifylline a try. 

Based on the science, I think 100mcg of Roflumilast really should have a benefit in much autism.

I know other readers are using Pentoxifylline or Ibudilast.

All these PDE inhibitor drugs are normally used in adults. 

 

Misophonia

https://www.webmd.com/mental-health/what-is-misophonia#1

 

Misophonia is a disorder in which certain sounds trigger emotional or physiological responses that some might perceive as unreasonable given the circumstance. Those who have Misophonia might describe it as when a sound “drives you crazy.” Their reactions can range from anger and annoyance to panic and the need to flee.  The disorder is sometimes called selective sound sensitivity syndrome.

Individuals with Misophonia often report they are triggered by oral sounds  -- the noise someone makes when they eat, breathe, or even chew. Other adverse sounds include. keyboard or finger tapping or the sound of windshield wipers. Sometimes a small repetitive motion is the cause -- someone fidgets, jostles you, or wiggles their foot.

 

Impaired P50 gating

https://en.wikipedia.org/wiki/P50_(neuroscience)

 

In electroencephalography, the P50 is an event related potential occurring approximately 50 ms after the presentation of a stimulus, usually an auditory click.The P50 response is used to measure sensory gating, or the reduced neurophysiological response to redundant stimuli.

Research has found an abnormal P50 suppression in people with schizophrenia, making it an example of a biological marker for the disorder. Besides schizophrenia, abnormal P50 suppression has been found in patients with traumatic brain injuryrecreational drug use, and post-traumatic stress disorder.

 

It looks to me that:-

 

Misophonia = Impaired P50 gating  = Impaired sensory gating

 

Recent clinical trials using Roflumilast: -

 

Cognitive Effects of Roflumilast in MCI Patients (ROMEMA)

dose 50 mcg   100 mcg

 

Roflumilast and Cognition (EEGrofl) 

dose 100mcg, 300mcg, 1,000 mcg

 

Roflumilast: A potential drug for the treatment of cognitive impairment?

 Roflumilast is the one and perhaps the only drug which shows a dose dependent occupancy of PED-4 in primate models and at doses proven to be very safe in humans, has shown its efficacy in enhancing memory and cognition.

 

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients

This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 μg daily) with 14 days of washout between treatments.

Results

Verbal memory was significantly improved under 250 μg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03).

Conclusions

Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia.

 

Improvisation

I did recently write about Desmopressin nasal spray as a possible alternative to specially compounded vasopressin nasal spray.  I did actually order some, but what arrived was the tablet form of Desmopressin.

The advantage of Desmopressin over Vasopressin is that there already exists a nasal spray in your pharmacy. There is currently a worldwide availability issue. 

Fine tuning Social Behavior in Autism with an existing pediatric drug, Desmopressin?

Having recently been making Christmas Pudding and sweet mincemeat for mince pies, from raw ingredients and improvising for those not available, I think I can safely make my own Desmopressin nasal spray, and with the correct excipients. 

Due to Covid, we did not go to England at Christmas; setting Christmas Pudding on fire is something that Monty looks forward to.

Christmas pudding takes days to make and 8 hours to cook, then you leave it to mature.  You re-heat for Christmas lunch.

 


Sweet mincemeat is something that came to England with the returning crusaders.  Nowadays it is just made with dried fruit.  When the English established colonies in New England, they took the older version with them, which included actual meat.  Today in the US you have store-bought sweet mincemeat with ground beef in it, in the UK it has been meat-free for many decades. 



The fat in sweet mincemeat is suet.  In the UK and US, pre-packaged suet sold in supermarkets is dehydrated suet.

I had no idea what suet was, but I know it is not in my supermarket.  Suet is actually raw, hard fat of beef or mutton, found around the loins and kidneys.  Jewish people are not supposed to eat suet, but Muslim people apparently seek it out.  These days I think most is actually a vegetable substitute.  To follow the recipe, a friend helped out with some of this fat; I put a chunk of it in the freezer for a couple of hours and then grated it. You are supposed to coat with rice flour, if you want to store it for later use.

The recipe said 300g (10 oz) of suet but having grated half, I decided it was pretty disgusting and substituted butter for the remainder.

In the recipe are raisins, currants and sultanas, they are actually all slightly different.  In effect they are all dried grapes

 

Raisins, sultanas and currants

 

In the US, the term raisin is applied to both raisins and sultanas. To distinguish the two, sultanas are referred to as “golden” raisins.

Where we live, they are all just “dried grapes”.  The different types exist, but are called the same thing.

Candied peel and glace cherries were also a struggle to find, by this time I had decided to add dried blueberries and cranberries.

One day after the mincemeat jars were already full and maturing in the garage, candied peel and glace cherries turned up and got added.  There is a lot of brandy in the recipe and this is why you leave the jars to mature.

 



It was a lot of bother to make, but the resulting mince pies were really good.  The brandy carries the spices making it very fragrant, not at all like store-bought mince pies.

The Christmas pudding was set alight, in fact twice for good measure.

Compared to all that, how hard can it be to make desmopressin nasal spray?  It only has a handful of ingredients, after all. 


Sulforaphane

I first wrote about Sulforaphane from broccoli, back in 2014. Johns Hopkins have been researching this substance for decades.

What has happened to Sulforaphane for autism? Stuck as Complementary and Alternative Medicine (CAM) therapy forever?  Apparently so.

Sulforaphane has anti-cancer effects and is suggested for common cancers like that of the prostate.  A stable man-made version (an analog) was developed in the UK as drug to treat prostate cancer.  In France a modified broccoli-based OTC product is sold as another prostate therapy.

 

When it comes to autism, there have been a series of positive clinical trials.

Sulforaphane treatment for autism spectrum disorder: A systematic review

Autism Spectrum Disorder (ASD) is defined as a neurodevelopmental condition characterized by social communication impairment, delayed development, social function deficit, and repetitive behaviors. The Center for Disease Control reports an increase in ASD diagnosis rates every year. This systematic review evaluated the use of sulforaphane (SFN) therapy as a potential treatment option for individuals with ASD. PubMed.gov, PubMed Central, Natural Medicines, BoardVitals, Google Scholar and Medline were searched for studies measuring the effects of SFN on behavior and cognitive function. All five clinical trials included in this systematic review showed a significant positive correlation between SFN use and ASD behavior and cognitive function. The current evidence shows with minimal side effects observed, SFN appears to be a safe and effective treatment option for treating ASD.

 

The Johns Hopkins' researchers did spin off the idea to commercially exploit their findings.  The result is “True broc” from Brassica Protection Products.

 

https://truebroc.com/what-is-truebroc/ 

 

https://brassica.com/

 

Here you will find Avmacol and Thorne Crucera-SGS, among the products than include “True broc”.  

These products, along with Prostamol from France, are actually used in clinical trials.

The UK company Evgen is developing its stable analog of Sulforaphane for autism and other conditions.

https://evgen.com/technology/

I spoke to Evgen a few years ago and suggested their prostate drug might be used for autism.  You still cannot buy it, but there is a clinical trial for autism planned.

 

Do you need expensive broccoli supplements?

There are numerous cheap broccoli supplements and some moderately priced ones.

We know from the research that supplements generally are not reliable, because they often do not contain what is on the label.  This matters more with some products than others.  With broccoli products the big question is whether they really contain active myrosinase.  This is an enzyme that you need to make Sulforaphane when you eat broccoli.

Several years ago, when I started with Sulforaphane, I bought large tubs of Australian broccoli powder and one pack of Daikon radish powder.  Daikon radishes are rich in myrosinase and it is relative stable, so it can survive processing.  My idea was to start with just the broccoli powder and then, if not effective, add some Daikon radish powder for the extra myrosinase.  In the end I did not need to even open the Daikon radish powder.  A small scoop of this broccoli powder produced a profound effect, euphoria after minutes and then much more “speech”. Back then “speech” was more like babbling single words – but it was some kind of speech at least. 

Many people report broccoli powder improved speech, even parents of young Aspies report it. 

Some people found the effect on mood to be remarkable.

Long term users report that over time they have to increase the dose to maintain the effect.

It is important to note that for some people the benefit may not be from Sulforaphane, but rather from indole-3-carbinol (I3C).

 

Here I am quoting myself …

 

“PTEN is best known as a tumor suppressor affecting RAS-dependent cancer, like much prostate cancer. Activating PTEN is good for slowing cancer growth. As I mentioned in a recent comment to Roger, many substances are known to activate PTEN; a good example being I3C (indole-3-carbindol) which is found in those cruciferous vegetables (broccoli, Brussels sprouts, cabbage etc) that many people choose not to eat. PTEN is a well-known autism gene.” 

The research has now caught up: - 

Study hints at dietary chemical as therapy for type of autism

A compound derived from cruciferous vegetables, such as broccoli and kale, might limit the impact of certain mutations in a top autism gene, a new study suggests.

The compound, called indole-3-carbinol, or I3C, acts on the gene PTEN, a tumor suppressor. 

This does raise questions about the prostate cancer research.  A sulforaphane analog drug contains no indole-3-carbinol (I3C).

  

Does Broccomax “work” 

The easy to buy product is Broccomax.  In the research they do not seem to like it, but it does not include the True Broc product from the Johns Hopkins spin-off.

Anecdotally, Broccomax does “work” for autism, but less so than some expensive products.

My Australian broccoli powder is no longer made, but it was not expensive and it did “work”.

 

Spice up Broccoli with Wasabi?

In the original research from decades ago, the Johns Hopkins researchers combined Daikon radish sprouts with broccoli sprouts, the Daikon radish sprouts where there to provide myrosinase.  The product had to kept deep frozen.

Daikon radish is widely available and is a good source of myrosinase.

I was re-reading old research and noted one researcher advocating putting Wasabi on your broccoli – the spicier the better apparently. Wasabi is Japanese horseradish and is widely available.  If it comes on a large bottle is likely fake wasabi - yes like they fake saffron, they fake wasabi.

Is it crazy to add wasabi to your broccoli capsules?

Look at what is in the expensive Avmacol supplement that they only sell in North America.

 

 


In the research they found that adding just 0.25% Daikon to frozen broccoli “brought it back to life” and sulforaphane was found in the person eating it. 

If you are using gelatine capsules with broccoli powder you can open them and, using a pointed knife, add a small amount of wasabi, re-seal and then swallow.  There is no taste or smell of wasabi.

It is bit fiddly to do this, but you soon master doing it.

 

Calcium Folinate (Leucovorin)

 

There is a lot in this blog already about Calcium Folinate.  It should give some benefit to the 75% of autism who have a problem with folate transport across the blood brain barrier. 

One of the most prominent effects in responders is improved speech. Just look at the tittle of the clinical trial

 

Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder


The only issue with Calcium Folinate (Leucovorin) are the side effects, but Professor Ramaekers assures me that if you gradually increase the dose over several weeks, there should not be any.

The summer before Covid, at 45mg a day of Calcium Folinate, my son had much more expressive language and it was also more complex language.  The problem was aggression.

 

Conclusion

As you can see the 2021 to do list is mainly tying up the loose ends remaining from previous ideas, so I anticipate success.

Broccoli powder does still have an effect, but much milder than a few years ago.  Does wasabi increase the effect?  This is very subjective, having bought the little jar of Wasabi, I will continue to adding it to two capsules of Broccomax before breakfast.

Calcium Folinate did increase speech significantly at the large dose (3 x 15mg a day) in my original trial.  At the lower dose of 15mg the effect is present, but is mild, and short-lived for the first few days.   I will very gradually increase from a starting dose of 15 mg a day and see if it possible to avoid the negative effects.

I do like the idea of the tiny dose of Roflumilast.  It has multiple potential benefits:-

1.     Improve sensory gating and reduce Misophonia

2.     Improve cognition

3.     Potentially reduce NKCC1/KCC2 expression and so make bumetanide more effective.

Can this be achieved without nausea? I think it is likely a matter of perseverance.  In COPD the starting dose of roflumilast is half the maintenance dose, but the likely “autism dose” of 100mcg in an adult is less than half the COPD starting dose of 250mcg. 

The research already tells us the effective dosage (for 1 & 2), 100mcg in an adult, and importantly that the effect is lost at higher dosage; indeed, the recent trial in Mild Cognitive Impairment (MCI) included a dose as low as 50mcg.

You would have to find the therapeutic window.  You are changing the intracellular level of cAMP, which will have numerous effects, not just on HCN channels, but also on things like pCREB and BDNF.

I think 80mcg will be a good place to start.

There may, or may not be, an equivalent dose of Pentoxifylline/Ibudilast that gives a similar effect.  Ideally you would want all 3 effects.

A dose higher than 100mcg might have a beneficial anti-inflammatory effect and so help reduce NKCC1/KCC2 expression which increases (3) but at the loss of (1) and (2).

It would be interesting to know if Maja’s daughter has/had Misophonia and what has been the effect of her Pentoxifylline use.

The next question is how to reliably measure such small doses of Roflumilast.  This drug does not dissolve in water, but is highly soluble in ethanol.  You have the choice of cutting a pill containing 500mcg into 5-6 pieces (fortunately, it is a large pill), or just crushing the pill and then using microscales to fill new capsules, or make a tincture.  The tincture should be the most accurate.  Tinctures are widely used for OTC remedies like propolis.  A tincture has the advantage that you can easily vary the dose. In phase 1, where I just try it on myself, I have opted for the tincture. One tablet dissolves in 2ml of vodka (dilute ethanol) to make a paste, but was much more fluid in 3 ml (the 3rd ml added probably could be just water).  One half of an old propolis pipette contains 100 mcg duly dissolved in 0.6 ml of vodka. It tastes exactly like the original propolis tincture, because all you really notice is the ethanol. Most commercial propolis tincture is made with alcohol and uses a much more concentrated ethanol than you will find in vodka. 

I was asked by an autism Grandad at the 2019 Thinking Autism conference how his Grandson could be helped.  The young man is highly intelligent, but has a severe problem with sound sensitivity.  His family paid extra money for him to sit his final school exams in a room with no other students, but the invigilator was opening up candy to chew all through the exams and so the boy flunked the exams.   This young man has Misophonia and I bet would exhibit impaired P50 gating if given an EEG. Before exam time, he needs to block some of the HCN channels in his brain and reduce stress/anxiety.  He might well benefit from Roflumilast 100 mcg and Propranolol 20mg and then sail through his exams. 

I actually think that many people reading this post likely have Misophonia, that is if they are a relative of someone with polygenic autism.  In the literature Misophonia is claimed to affect more women than men, but I doubt that is actually true.  If you have autism, your doctor is highly unlikely to add a diagnosis of Misophonia. 

Is Desmopressin going to be helpful?  I had put Vasopressin down as a potential therapy more for Aspies, but our reader whose young child was prescribed Desmopressin nasal spray by her neurologist, noted a broad range of substantial improvements. Desmopressin is water soluble, so no vodka required.





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.

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 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.      
                                                           
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.