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Showing posts with label Choline. Show all posts
Showing posts with label Choline. Show all posts

Sunday 6 October 2013

Autism - Drugs and Supplements that actually do work

Following requests for more information about supplements and drugs that really do seem to help with autistic behaviours, I have updated my "Top Tips" page.  Here is the updated information for anyone who is interested.

You will find links to the science behind all these ideas in various posts on my blog.  Many of these are "off label" applications, since there are no treatments yet  licensed for autism.

From comments received, it is clear people want "supplements" because they are available without prescription.  The rules vary widely from country to country.  A supplement in the US may be a drug in the UK and vica versa.  Or even a drug in UK is a supplement in Germany.  Just do some research on the internet.
 
Since I am not a doctor, this is not medical advice.  Since your doctor does not read the autism research, he/she will probably not be able to help you.



Anti-oxidants

Science established some time ago that oxidative stress plays a central role in autism.

There is one widely available antioxidant that is highly effective. It is called NAC  (N-Acetyl Cysteine) and is available without prescription via the internet (from Amazon for example) or many pharmacies.

The result is very dose dependent.  Some people take time to adjust to it, due to mild stomach irritation.  Most supplements come in 600mg capsules.  Two capsules has an effect, but the effect becomes larger as you increase to about 3g per day (i.e. 5 capsules per day).  You should observe a great reduction in obsessive behaviours within a few days.  Then new good behaviours should emerge quite rapidly.  Speech increases.

To read about this on the blog, go to the list of labels and click on GSH.


Neuroprotection and anti-inflammatory

The research is conclusive that there is chronic neuroinflammation in autism.  The anti-oxidant will contribute to managing this, but an anti-inflammatory agent that can reach the brain will give additional benefit.

This blog has highlighted research to show that widely used drugs called Statins have a secondary effect that reduces neuroinflammation.

The Statin I choose is Atorvastatin, but Simvastatin also looks a good choice.  In the UK Simvastatin is available without prescription.

I use 10mg Atorvastatin.  The behavioural improvement was visible within two days.  New behaviours involving initiative emerge.

To read about this just click on statins in the list of labels.


GABA Neurotransmitter

Research going on for 10 years in France has shown that the widely used diuretic Bumetanide reduces the level of chloride in the brain.  The high level of chloride causes the brain neurotransmitter GABA to malfunction in autism and babies with neonatal seizures.

The effect of taking 1mg of Bumetanide has a dramatic behavioural effect.  It improves the child's ability to control himself.  He appears more "present" and not in his own world, this results in more interaction with his peers and an improvement in mood and a general increase in happiness.  Speech increases.

To read about this just click on bumetanide in the list of labels.


Autsim flare-ups  -  over activated mast cell response to allergens

Violent episodes may sometimes be provoked by an allergic reaction caused by so-called, mast cells.  What in a typical child might just cause a runny nose or sneezing, may cause violent/aggressive behaviour in a child with ASD.

A cheap over the counter drug drug called Claritin, acts as an anti-histamine H1 antagonist, it will subdue the allergic reaction within a few tens of minutes.

Many people do not respond to a particular anti-histamine, if one does not work just try a different one.  Your pharmacist can suggest an alternative (levoceterizine for example).  The brand names vary by country.

If the child complains about creepy feelings on his/her legs this would be an indicator or this type of allergic reaction.

There are other serious behavioural causes of self injury, but if the child is normally well behaved and under self control, sudden outbursts may be being triggered by mast cells.  Read all about mast cell research here.


Lower Serotonin Levels 


High serotonin levels are a known biomarker of autism;  lowering them does indeed appear to reduce autistic behaviours.   
You can do this via diet.  Avoid food known to raise serotonin, for example bananas and caffeine.  A low carbohydrate, high protein diet is known to lower serotonin levels.  The Atkins (induction phase) diet and the Ketogenic diet are also known to lower serotonin levels.  You will know if it is working because lowering serotonin increases appetite, your child should put on weight.
The easier way is with a serotonin antagonist like Periactin, often prescribed in the US to underweight children.  Periactin is a first generation antihistamine drug, so it will cause drowsiness.  It is known to be antiserotonergeric.  It is available OTC in some countries.

Read the post on Serotonin here.


Increase acetylcholine levels
The story about acetylcholine is quite complex, and the full post about it is here.
To increase acetylcholine there are various options.  The drug options shown to be effective work by affecting the enzyme acetylcholinesterase.  The two drugs shown to be effective in autism are Galantamine and Donepzil.  These are prescription drugs.
The same effect is possible using a nicotine patch, or even potentially by using nicotine gum.  One quarter of a 7mg patch applied for 6-8 hours is suggested by one US doctor.
The other method, that is sometimes combined with Donepzil, is to give the dietary supplement choline, which is widely available.
 

High potassium diet reduces sensory overload

If your child with ASD, like most, has a problem with sensory issues like sound, light, smell etc, there is a dietary solution.  Increase potassium in his/her diet - eat more bananas, oranges, kiwis, potatoes etc.  You can also use potassium + magnesium supplements.  If you live in the US, beware of these supplements, they are very weak.  A banana has 500mg of potassium,  US supplements contains up to 100mg, UK supplements are up to 200mg.  Magnesium plays a role as well, it is needed to maintain potassium levels.  I use a cheap French supplement with 500mg Potassium and 150 mg Magnesium, taken half AM and half PM.  Potassium supplements can irritate the stomach, but they do modify autistic behaviours for the better.
Potassium ion channels (like Kir 4.1) play a role in the brain in both ASD and epilepsy.  It is very complicated and still not fully understood, but it WORKS! 
 
 

Thursday 3 October 2013

Biomarkers in Autism : The Cholinergic system – In need of caffeine & nicotine or maybe just choline

Strange as it may sound, but if you have ASD a strong cup of coffee and a cigarette may actually do you some good.  Following on from my earlier post about Serotonin, showing that LSD was seen as an effective therapy in the 1960s, you might be wondering where my blog is taking us.  I just follow the science, wherever it takes us.

First of all what is the Cholinergeric system.

Cholinergic system (a summary from Wikipedia)
Cholinergic typically refers to acetylcholine in the neurological sense.  The parasympathetic nervous system, which uses acetylcholine almost exclusively to send its messages, is said to be almost entirely cholinergic. Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes are also cholinergic

In neuroscience and related fields, the term cholinergic is used in the following related contexts:
  • A substance (or ligand) is cholinergic if it is capable of producing, altering, or releasing acetylcholine ("indirect-acting") or mimicking its behaviour at one or more of the body's acetylcholine receptor types ("direct-acting").
  • A receptor is cholinergic if it uses acetylcholine as its neurotransmitter.[2]
  • A synapse is cholinergic if it uses acetylcholine as its neurotransmitter.

Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS). It acts on both the peripheral nervous system (PNS) and central nervous system (CNS) and is the only neurotransmitter used in the motor division of the somatic nervous system.

In the central nervous system, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system, which tends to cause anti-excitatory actions.
Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be plausibly associated with the memory deficits associated with Alzheimer's disease.

Synthesis and degradation


Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing Ach.

Receptors


There are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). They are named for the ligands used to activate the receptors.

Nicotinic


Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and calcium ions. They are stimulated by nicotine and acetylcholine. They are of two main types, muscle-type and neuronal-type. The former can be selectively blocked by curare and the latter by hexamethonium. The main location of nicotinic AChRs is on muscle end plates, on autonomic ganglia (both sympathetic and parasympathetic), and in the CNS.[32]

Muscarinic


Muscarinic receptors are metabotropic, and affect neurons over a longer time frame. They are stimulated by muscarine and acetylcholine, and blocked by atropine. Muscarinic receptors are found in both the central nervous system and the peripheral nervous system, in heart, lungs, upper GI tract and sweat glands. Extracts from the plant Deadly night shade included this compound (atropine), and the blocking of the muscarinic AChRs increases pupil size as used for attractiveness in many European cultures in the past

--- end of wikipedia ---
 
The Research Showing Abnormality in ASD
The following study was carried out in the UK in 2002 on post mortem brain tissue from “Brain banks” in the US.  It is extensively referred to in the later research.




 






An earlier paper on the same subject:-



CONCLUSIONS: These neurochemical abnormalities implicate the cholinergic system in developmental disorders such as autism and suggest the potential for intervention based on cholinergic receptor modulation.

If the low level of cortical nicotinic receptors is consistently observed and clinically relevant, therapeutic strategies could include receptor agonists, such as nicotine, which has already been applied in Tourette’s disorder with amelioration of symptoms. Such treatment could also be disease modifying.
 

Other studies on autistic brain samples have shown diminished acetylcholine and nicotinic receptor activity.

Implications 10 years on remain the same
A recent study by neuroscientists at Ohio State University, concludes that neuronal nicotinic acetylcholine receptor (nAChR) alterations are biomarkers for ASD and that specific nAChRs subtypes are likely to be useful therapeutic targets for the treatment of core deficits. They claim a case can be made for the use of  α7 nAChRs to reduce neuroinflammation in the brain in those ASD individuals with such clinical pathology. The ultimate hope is that these agents, when administered early in development, by their presumed ability to modulate a number of different neurotransmitter systems and associated signaling pathways, could help correct core deficits associated with ASD.

Interventions

Just by spending 5 minutes on Wikipedia, you can find logical interventions that could have been tested since 2002.  Some have indeed been tested, others have not.  Here below is a copy-paste from Wikipedia, with interesting drugs highlighted.

 

Reversibel acetylcholinesterase inhibitor (often abbreviated AChEI)


Compounds which function as reversible competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. These include:


Natural Compounds



ACh receptor agonists/antagonists


Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand. Agonists increase the level of receptor activation, antagonists reduce it.

Drugs acting on the cholinergic system


Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it.

ACh and its receptors
Drug
Nm
Nn
M1
M2
M3
+
+
+
+
+
+
+
+/-
-
+
-
+
+
+
-
-
-
+
-
-
-

Direct acting


These are drugs that mimic acetylcholine on the receptor. In low doses, they stimulate the receptors, in high doses they numb them due to depolarisation block.



------- end of Wikipedia ---------
 
Evidence based approach
The web is full of commentators telling you to only pay attention to evidence-based treatments.  This sound great in principle, but it assumes there are copious amounts of well-constructed clinical trials.  Moreover, is assumes that there is just one type of autism, or that clinical trials are sophisticatedly constructed to test individual sub-types, one at a time (which they are not).

So, in reality, the evidence is generally poor quality and so applying a pure evidence-based approach will leave you exactly back where you started.
I have gathered together what I think is a remarkable amount of evidence from multiple imperfect trials and anecdotal case studies.


Use Of Donepzil
Following on two earlier trials, Chez et Al carried out a double-blind study  of Donepezil hydrochloride, an acetylcholinesterase inhibitor  to confirm those findings. 

 

 The trial concluded:-

Expressive and receptive speech gains, as well as decreases in severity of overall autistic behavior, were documented after 6-weeks for the treatment group. These improvements were statistically significant when compared to placebo, and were clinically meaningful as assessed over time. Donepezil hydrochloride appears to improve expressive and receptive language as well as overall autistic features, consistent with the hypothesis of acetylcholinergic enhancement

 Here is a more recent case study from India


A woman consulted psychiatric Out-Patient Department (OPD) for her 5-year and 2-month-old son presenting with typical autistic symptoms like social, behavioural, and communicational ineptitudeness. Subsequent treatment with Donepezil resulted in marked improvement in the aforementioned symptomatology. Recent studies in autistic child have shown diminished acetylcholine and nicotinic receptor activity, thus an acetylcholinergic enhancer, Donepezil, likely accounts for improvement in autistic symptoms. Evidently, the case report consolidates Donepezil role as a potentially useful agent in the treatment of cognitive and behavioural symptoms observed in this disorder.

 Mecamylamine
There was a recent trial of Mecamylamine, with mixed results, but the researcher is already planning a follow trial of a similar drug called varenicline, that was previously suggested by other researchers.

RESULTS:

Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense.

CONCLUSION:

Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline.

Varenicline is a drug developed to help people to stop smoking.  It is widely used and looks set to be trialed in autism


Galantamine
Galantamine was successfully trialed and I am surprised we do not hear more about it.  In fact, it was developed in the Soviet Union in the 1950s and is now used for Alzheimer's.  It is based on snowdrop flowers.  It is available as a drug and as a supplement, depending on where you live.

RESULTS:

Patients showed a significant reduction in parent-rated irritability and social withdrawal on the ABC as well as significant improvements in emotional lability and inattention on the Conners' Parent Rating Scale--Revised. Similarly, clinician ratings showed reductions in the anger subscale of the Children's Psychiatric Rating Scale. Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. Overall, galantamine was well-tolerated, with no significant adverse effects apart from headaches in one patient.

CONCLUSION:

In this open trial, galantamine was well-tolerated and appeared to be beneficial for the treatment of interfering behaviors in children with autism, particularly aggression, behavioral dyscontrol, and inattention. Further controlled trials are warranted


The missing evidence
You will have noticed caffeine and nicotine in the title of this post.  You may have noted that back in 2001/2 the original researchers suggested the logical next step was to trial nicotine patches.

All I can find is one case report in ADHD, which to me is just ASD-lite.


If you look in internet forums you will see that DAN doctors in the US are using nicotine patches.  You will also find people giving small doses of caffeine.
Having reviewed “the evidence” I think it is entirely logical to trial SMALL doses of nicotine and caffeine.  The research indeed tells us that only SMALL does may have the desired effect.
One report I read was a DAN Doctor giving her own child a quarter of 7mg nicotine patch.  By my research, that equals the nicotine of a single cigarette.
You will also see older kids with HFA (high functioning autism) writing on the web how they feel it easier to (pretend to) be more NT (neuro-typical) after drinking coffee and/or smoking. (Maybe they just look more NT, or maybe there is some truth in it).  They do not talk about alcohol.
The other “obvious” thing that has not been trialed is acetylcholine or choline itself.  It is known to be deficient in autism.  It is sometimes included in multivitamin pills in small amounts. Choline is widely available as a supplement.  It is also used for its nootropic properties and there are claims it reduces neuroinflammation.  It is used in depression, memory loss, Alzheimer’s and schizophrenia  It also lower cholesterol. Most surprisingly, choline is prescribed to control asthma, a comorbidity of ASD.  
Choline is used by people trying to boost their brainpower by combining it with other nootropic drugs.  Their favourite drug appear to be Piracetam, which is the same drug used for ASD in Ukraine and subject of a clinical trial in Iran, that I wrote about recently.

It is remarkable how many drugs I am writing about are either (ab)used by body builders or now IQ builders.

Conclusion
This post has really surprised me.  Firstly, there more drugs that look like they actually do work in autism (Donepezil and Galantamine).  There is an interesting phase 4 trial underway using Donepzil + Choline. Phase 4 is the final phase.

Nicotine may set alarm bells ringing, but if you check it out, you will see that very small amounts are apparently harmless.  Thanks to smokers, there exists a perfect transdermal delivery system.  Just why nobody trials it in autism (Glaxo produce Nicorette patches) is inexplicable.
Small amounts of coffee are given to even young children in many strong coffee drinking countries (like the Balkans). Coca Cola and even Ice Tea are caffeine-rich.

Choline is probably the simplest, cheapest and safest intervention;  but that does not mean it is will be effective.  Nobody has made a controlled trial with it, probably because there is no money in it.
For a change in my posts, it looks like there is something for everyone.