Medicine - More Art than Science

Today's post is only indirectly about autism, it is more to do with what expectations are realistic from medical science in 2013.

I come from a family full of doctors and two engineers.  As one of the engineers, I know that engineering is a true science, and I had assumed that so was medicine.  In engineering the answers are either right or wrong, maybe or sometimes is not acceptable.  If you build 100 aeroplanes, full of maybe millions of components, you expect them work (ie not crash) everyday for 30 years.  An acceptable failure is much less than 1%, over the entire life of the planes.  So the science needs to be fully understood to the tiniest detail.

The more I am reading about medical science, the more clear it becomes how little is really understood and how trial and error is behind many breakthroughs.  Many drugs, particularly in neuroscience, work for reasons not fully understood; or there are several proposed methods of action, perhaps one of which is correct.  This really is not science.

Once you start thinking about medicine as an art rather than a science, things become clearer.  It also means that the old fashioned approach of 20-50 years ago might actually be more appropriate, than that of today.    

This also means that medicine is more about probability.  So, some new hi-tech anti-cancer drug may work in 60% of patients, but if you are one of the 40%, why suffer those horrible side effects? or indeed pay for it.  Or, for your allergy medicine, the doctor may prescribe you say, Claritin, but he probably does not tell you that in X% of patients it will not work.  Perhaps he should say, here are four antihistamines try them all and choose the two that work best, then just alternate between them.

I have been reading about thyroid hormones.  I am amazed by all the nonsense written about them, including in mass market books by experts.  The question is actually very simple, there is a prohormone called T4 with a long half-life and an active hormone called T3 with a much shorter half-life.  To optimally treat hypothyroidism you just need balance the dosage and frequency of T3 and T4 and you need to know that T3 is needed throughout the body and for it to be produced locally from T4, requires special enzymes (D1, D2, D3) to be present in sufficient quantities.  As a result, some people may need to be given T3 in addition to (or instead of) T4.   How complicated is that?

So how does this apply to autism?  Well, it means that perhaps we should not be critical of the "trial and error" approach of some US autism doctors.  "Trial and error" does need to have boundaries and safety is clearly the most important issue.  It also means that it is totally "normal" to find therapies that work in one group and yet are ineffective in another.  It means that applying complex statistical analysis, from sciences like engineering, to evaluate tiny clinical trials in autism is really a waste of time.  Not surprisingly, none of these trials stand up to scrutiny later.  Those scrutinising these mini studies are making the same mistake I did, thinking medicine is a "hard" science.  Maybe it will be in 500 years, but not in 2013.

Much can be learnt from Monty, age 10 with ASD, whose piano teacher tells me  "if a pill works, keep taking it". Hundreds of millions of people have benefited from taking statins, but as I learnt, 99% for the wrong reason.












 

Cytokine Theory of Disease & the Vagus Nerve

If you are a regular reader of this blog you will know that the key to controlling autism is reducing oxidative stress and neuroinflammation.  One of the key drivers of the on-going neuroinflammation are signalling molecules called cytokines; if you can limit the release of harmful cytokines you can reduce neuroinflammation.  This appears to be easier said than done.  I learnt that some statins limit the release of pro-inflammatory cytokines and neuroscientists in the US are researching their use, but not yet in autism.  I did some home research and found a positive effect within 24 hours.

It turns out there is an entire field of neuroscience relating to cytokines as a mediator of disease and this is all channelled through the Vagus nerve.  There is an eminent  neuroscientist, Kevin Tracey, who dominates this field; he is credited with discovering that vagus nerve stimulation inhibits inflammation by suppressing pro-inflammatory cytokine production.   Tracey is also an inventor, he is seeking to apply the science and has an interesting start-up company.  So I have found a kindred spirit and if you read his papers, you will find that often missing element, a sense of humour.

Tracy has even written a book, which explains his discoveries.

Fatal Sequence: The Killer Within

For those scientists among you, a very readable paper is:- 

Physiology and immunology of the cholinergic  Anti-inflammatory pathway

For those in a hurry, here is summary

The cytokine theory of disease is a concept that cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease.

One example is the case of TNF, a cytokine implicated as a necessary and sufficient mediator of lethal septic shock. Administration of TNF to healthy humans reproduces the metabolic, immunological, and pathological manifestations of the disease and the gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock. Other pathophysiological activities ascribed to TNF are the capacity to cause fever and localized inflammation. Clinical successes in the 1990s using drugs that specifically inhibit TNF for patients with inflammatory bowel disease or rheumatoid arthritis directly implicated a pathogenic role of this cytokine in other diseases and validated in humans the fundamental premise of the cytokine theory of disease.

 

 

The cholinergic anti-inflammatory pathway

Tracey reasoned that, since the CNS coordinates major physiological responses via innervated circuits, it might also use neural input to control a potentially deadly cytokine response. In classical physiological systems, the sensory projections of the autonomic nervous system provide input to brain networks about essential bodily functions. These elicit a coordinated neural output from the CNS to maintain homeostasis for parameters as varied as heart rate, blood pressure, digestion, body temperature, organ perfusion, and blood glucose levels. Accordingly, it seemed possible to posit the existence of a comparable mechanism to control cytokine release that could, at least in theory, function as an extremely fast, reflex-like anti-inflammatory pathway controlled by brain networks.  Stimulation of vagus nerve signals was shown to significantly inhibit TNF release in animals receiving lethal amounts of endotoxin. Subsequent work established that vagus nerve signaling inhibits cytokine activities and improves disease endpoints in experimental models of sepsis, schemia/reperfusion, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis. The cellular molecular mechanism for inhibition of cytokine synthesis is attributable to acetylcholine (ACh), the major vagus nerve neurotransmitter. Macrophages and other cytokine-producing cells express acetylcholine receptors (AChRs), which transduce an intracellular signal that inhibits cytokine synthesis. The best characterized of these cholinergic receptors that suppress cytokines is the α7 subunit of the nicotinic AChR (α7 nAChR).

 

 

It takes nerve to restrain cytokines: anatomy of an innervated cytokine system

Recent studies of the physiology, functional anatomy, and cellular molecular mechanisms of the cholinergic anti-inflammatory pathway indicate that the principal components for cytokine suppression by the vagus nerve converge in the spleen. Endotoxin localizes to macrophages primarily in the spleen and liver, thereby activating an immediate early cytokine response. The spleen is the major source of both hepatic and systemic TNF during endotoxemia; it releases newly synthesized TNF into the splenic vein, which drains into the liver, and from there, TNF crosses into the systemic circulation.

 Vagus nerve stimulation, or administration of α7 nAChR agonists, inhibits not only TNF but also IL-1, IL-6, IL-8, and high mobility group box 1 (HMGB1)

 

Preclinical efficacy of experimental therapeutics

Preclinical studies are in progress to determine whether it may be possible to develop therapeutics based upon either devices that stimulate vagus nerve activity or drugs that activate the cholinergic anti-inflammatory pathway to suppress cytokine damage. A significant number of studies indicate that the cholinergic anti-inflammatory pathway is a robust regulator of cytokine-mediated damage in local and systemic experimental disease.

The role of exercise

Exercise reduces levels of TNF and other cytokines, confers protection against cardiovascular disease and type 2 diabetes, increases vagus nerve activity, and confers protection against the development of atherosclerosis. It is possible that the mechanism of these exercise effects is at least in part attributable to exercise-induced increases in cholinergic anti-inflammatory pathway activity. Obesity, on the other hand, is characterized by diminished vagus nerve output and elevated cytokine levels, which have been implicated in mediating insulin resistance and atherosclerosis. Since weight loss and exercise are each associated with increasing vagus nerve activity, one can consider whether enhanced activity in the cholinergic anti-inflammatory pathway might decrease cytokine production and reduce the damage and metabolic derangements mediated by chronic, low-grade systemic inflammation that is characteristic of the metabolic syndrome

His conclusion:-

“It is bemusing to think that one of the fundamental premises of the ancient Greeks was that dietary manipulation controlled humoral balances. This concept is now, at least in principle, supported by new evidence of a direct link between dietary composition and the regulation of cytokines by the cholinergic anti-inflammatory pathway. Modern clinical studies have advocated supplementing diet with fish oil, soy oil, olive oil, and other fats to significantly increase vagus nerve activity, reduce inflammatory markers, and improve disease severity in inflammatory bowel disease, rheumatoid arthritis, and cardiovascular disease. These clinical anti-inflammatory responses may be linked to the fat-induced stimulation of the cholinergic anti-inflammatory pathway, as is the case in rats. And now it appears that a major source of systemic TNF during lethal challenges is the spleen, the source of Galen’s black bile. One can’t help but wonder: How did the ancient Greeks know?”

 

Anti-inflammatory activities of vagus nerve stimulation

The discovery by Tracey that vagus nerve stimulation inhibits inflammation by suppressing pro-inflammatory cytokine production has led to significant interest in the potential to use this approach for treating inflammatory diseases ranging from arthritis to colitis, ischemia, myocardial infarction, and congestive heart failure. Action potentials transmitted in the vagus nerve activate the efferent arm of the Inflammatory Reflex, the neural circuit that converges on the spleen to inhibit the production of TNF and other pro-inflammatory cytokines by macrophages there. This efferent arc is also known as the Cholinergic anti-inflammatory pathway Because this strategy targets the release of TNF and other pro-inflammatory cytokines, it may be possible to use vagus nerve stimulation instead of anti-inflammatory antibodies (e.g., Remicade or Enbrel) to treat inflammation. SetPoint Medical, Inc. is an early-stage medical device company, set up by Tracey, developing an implantable  neurostimulation platform for the treatment of inflammatory diseases.

Remicade and Enbrel are ultra-expensive drugs, costing about $20,000 per year.  Not surprisingly, some US autism doctors are wondering what they would do in autism.

My Conclusion

I was wondering if Kevin Tracey might be related to Jeff Tracy, in which case, can Brains please make Monty, aged 10 with ASD,  a vagus nerve stimulation device, preferably with a built-in nuclear power pack.  (I refer to a cult British TV series from the 1960s called Thunderbirds, a favourite of both Monty and his big brother, Ted.)  

 

 

IBS, IBD and Autism, leading to Cholinergic Signaling and the Vagus Nerve

This post is all about those stomach problems typical of many kids with ASD and some of their neuro-typical close relatives. Since Monty, aged 10 with ASD, does not have any of these problems, it is not something I have looked into earlier.  As you will see later in this post, by understanding the underlying science, we can move another step towards inhibiting systemic inflammation, which affects all people with ASD.
 

Irritable bowel syndrome (IBS) and Inflammatory Bowel Disease (IBD),

First of all we need to differentiate two common conditions with very similar symptoms.  IBS is the less serious condition, though it causes lots of discomfort.
 

Irritable Bowel syndrome - IBS

Irritable bowel syndrome (IBS) sufferers show no sign of disease or abnormalities when the colon is examined.

IBS does not produce the destructive inflammation found in IBD. It does not result in permanent harm to the intestines, intestinal bleeding, or the harmful complications often occurring with IBD. People with IBS are not at higher risk for colon cancer, nor are they more likely to develop IBD or other gastrointestinal diseases

The exact cause of IBS is unknown.   The most common theory is that IBS is a disorder of the interaction between the brain and the gastrointestinal tract, although there may also be abnormalities in the gut flora and immune system.

Inflammatory Bowel Disease -  IBD

Inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis

Crohn’s disease has a strong genetic component and is far more prevalent among smokers.  The usual onset is between 15 and 30 years old.

Ulcerative colitis is an auto-immune disease with no known cause.  The symptoms are very similar to Crohn’s disease, but there are some stark differences.  Ulcerative colitis is far less prevalent among smokers

Autistic Colitis / Ulcerative Colitis

The Inflammatory Bowel Disease (IBD) that seems to be relevant in Autism is ulcerative colitis, so much so that Wakefield and Krigsman sought to name a sub-type Autistic Enterocolitis.  Due to all the furore about vaccinations and autism, the research of these two gastroenterologists has been blacklisted.

Dr Krigsman has an informative website and has published some interesting research.

If you spend all day looking via the endoscope  at children with ASD, you are bound to notice a thing or two.  Ignoring what Krigsman observes is bizarre.

In case you are wondering what he does, he is going through the mouth to do an Upper Endoscopy; for the Colonoscopy he goes in from below.  He does both procedures under general anaesthetic.  That will be painless; I once had an endoscopy under general anaesthetic and you have no bad effects.  I had the misfortune to have another one without any anaesthetic, which was one of the most unpleasant experiences of my life.

Ulcerative colitis looks like a nasty condition but Krigsman finds it is generally treatable with some combination of anti-inflammatory medication, antimicrobials, probiotics, digestive enzymes and dietary restriction.

One thing he does not mention is nicotine, more of that later.

GERD

Gastroesophageal reflux disease (GERD) is a very common disease.  The acid within the stomach rises up into the esophagus and in doing so, damages its lining.

Most children will outgrow their reflux by their first birthday. However, a small but significant number of them will not outgrow the condition. This is particularly true when a family history of GERD is present.   It is estimated that 15% of adults of adults are affected by GERD.

Krigsman find that in kids with ASD and their siblings, GERD is relatively common.

 

Mechanisms linking IBS and IBD to Autism

I have already written about the link between food allergies, autism and behaviour.  In those posts it was histamine released from mast cells (along with cytokines and other nasties) that was the culprit.  The treatments included antihistamines and mast cell stabilizers (Ketotifen, Intal etc).  I would presume this would fall into the IBS category.

When it comes to IBD, things get interesting.

In 1936 the Nobel Prize for Physiology was awarded to Sir Henry Dale and Otto Loewi.  One had identified the neurotransmitter acetylcholine and the other had shown how the vagus nerve releases acetylcholine to control heartbeat.

It later became apparent how important the vagus nerve is.  The vagus nerve is a modulator of inflammation throughout the body.  Acetylcholine, the principle neurotransmitter released by the vagus nerve, can exert its anti-inflammatory effect via binding to nicotinic acetylcholine receptors (nAChRs), which are expressed on macrophages and other immune cells.

 
In a recent post I showed that autistic brain samples have diminished acetylcholine and nicotinic receptor activity.  I showed how this could be corrected either by drugs that mimic acetylcholine (eg nicotine or acetylcholine) or with an acetylcholinesterase inhibitor (Galantamine or Donepezil).

I found it very interesting that IBD can be successfully treated by mild smoking (3 cigarettes a day) or with nicotine patches. 

This then connects various comorbidities in a very useful way and opens up therapeutic directions.  The vagus nerve is also key to epilepsy.  Vagus nerve stimulation is currently used to treat epilepsy and depression.

Experimentally, vagus nerve stimulation is already used in autism.  

Vagus nerve stimulation therapy inpatients with autism spectrum disorder and intractable epilepsy: results fromthe vagus nerve stimulation therapy patient outcome registry.

CONCLUSIONS:

Patients with ASD and intractable epilepsy respond as favorably as all other patients receiving VNS therapy. In addition, they may experience a number of QOL improvements, some of which exceed those classically observed following placement of a VNS device.

 

Kevin J. Tracey

A neurosurgeon and inventor, Kevin Tracey, is the man behind the inflammatory reflex.  The inflammatory reflex is a neural circuit that regulates the immune response to injury and invasion. All reflexes have an afferent and efferent arc. The Inflammatory reflex has a sensory, afferent arc, which is activated by cytokines, and a motor, or efferent arc, which transmits action potentials in the vagus nerve to suppress cytokine production. Increased signaling in the efferent arc inhibits inflammation and prevents organ damage.

We will be looking at his research and the Cholinergic anti-inflammatory pathway, in later posts

 

Epilepsy, Autism & EEGs

It is widely known that autism and epilepsy are comorbid with each other. Statistics are not very consistent, but it appears that up to 35% of people with autism will develop epilepsy and something like 30% of people with epilepsy already have autism.

My interest in epilepsy is currently just as a comorbidity, since Monty, aged 10 with ASD, has not exhibited any signs of it.  I will refer back to epilepsy in later posts when I attempt to “validate” potential autism interventions.  My logic is that if something has a positive effect across the majority of comorbidities, then I may be on to something.  For example, I found it insightful to read in a small study that nicotine patches reduced the incidence of epileptic attacks by 50%.

I recently came across an excellent, highly readable, paper that I think all parents interested in ASD should read.  It is written by an Israeli lady who is also doing some other very thoughtful research into treating autism.  The research itself is a retrospective study of EEG (Electroencephalography) tests on 56 children done in the US.

Autism and epilepsy: Cause,consequence, comorbidity, or coincidence?

EEG testing is known to be very insightful, but due to cost and availability, is rarely used in autism.  Some children, diagnosed with autism, turn out to have something different.

 Here are some highlights:

·        About 10% of children given a diagnosis of autism are found to have either a paroxysmal EEG pattern, as seen in acquired epileptic aphasia (Landau–Kleffner syndrome), or electrical status epilepticus during sleep, as seen in some children with childhood disintegrative disorder. 

·        None of the children who presented with ‘‘unlikely symptoms,’’ such as febrile convulsions, breath holding spells, and rage episodes, were diagnosed with epilepsy  

·        As many as 40% of the total group with autism had epilepsy, which was symptomatic in most children. Half of the children presented with convulsions, and they all had abnormal electroencephalograms (EEG) and were diagnosed with epilepsy.  

·        About one-quarter of the children presented with staring episodes, half of whom had epilepsy. 

·        None of the children with episodes of rage or breath holding spells had epilepsy 

o   This is the opposite of what many experts assume 

·       Our results, which indicate that clinical suspicion for epilepsy should be high if there is a history of convulsion and staring episodes, are in agreement with other studies showing that nearly all autistic children with seizures also exhibit epileptiform activity on electroencephalograms

 

A short film

Here is a parent-made film, showing the EEG procedure.

Conclusion

If you live in an area where EEGs are on offer, (California seems to be one good place to live) then it looks like a very smart test to have done.  If you were thinking your child’s tantrums and raging were indicative of future epilepsy, you can breathe again. 

 

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! 

 

 

Parental Placebo Effect in Autism

I have not met that many parents of kids with ASD; from those that I have met it, is clear that often the therapies applied are limited by the more skeptical parent.  There really are no therapies that everyone agrees on.

So it is no surprise that sometimes my wife doubts the value of the therapies I am sharing in this blog.  She would far rather have a homeopathic wonder cure, than use drugs or ABA.  I saw today as an opportunity.  Monty, aged 10 with ASD, had been up half of the night with a virus and his Mum said "don't give him any of your medicines"; "OK" I replied.

By 2pm Monty was in an increasingly bad mood, frustrated,  exhibiting obsessive repetitive behaviours and showing warning signs of mild self injury.

So I mixed him up a Peter cocktail (1.2g NAC, 10 mg atorvastatin and 1mg of bumetanide) in orange juice.  Within 10 minutes things started to change.  Facial expression switched from anger to contented and, most telling of all, he sat at the piano and started to play.  I could not have hoped for a better result. 

After an hour I asked Mum, if she noticed the transformation.  Yes she had and agreed it was remarkable.


Placebo Effect

It is clear that the more involved the parent becomes, the greater is the risk of seeing what you want to see, rather than what is there.  This why nobody generally listens to parents and indeed why doctors are not supposed to treat their children.

It is always good to have a reality check.

I can now move forward to my serotonin and acetylcholine interventions, in the knowledge that previous interventions have past their critical test.

Nicotine Patches - Autism, Alzheimer's and MCI

Following on from my last, rather science-heavy post, in which I became convinced of the possible value of nicotine patches in autism, I found that in the field of Alzheimer’s, their therapeutic value has already been established.

Autism is indeed not Alzheimer’s, but studies on brain samples in both diseases  have shown the same diminished acetylcholine and nicotinic receptor activity.  Also, note that the two Alzheimer’s drugs Donepezil and Galantamine, that are acetylcholinesterase inhibitors, were successfully trialed in autism.  I had proposed that nicotine patches might do the same job and hopefully without the side effects.

Alzheimer’s research is well funded.  You will below how the research is very professional.

 

Paul Newhouse, Clinical Neuroscience Research Unit, Vanderbilt University

Dr Newhouse has already been looking at the effect of nicotine on Alzheimer’s and MCI (Mild Cognitive Impairment) for many years.  Only in 2012 though did he publish his phase 1 clinical trial of nicotine patches in non-smokers with MCI.

"The trial involved 67 non-smokers with MCI, which is considered an intermediate between normal aging and dementia. People with MCI are more likely to develop Alzheimers's disease. 

Half of the patients wore a skin patch that delivered 15 milligrams of nicotine per day; the other half wore a placebo patch. The study was double-blinded, meaning both the patients and the researchers were unaware who was getting the drug.

After six months, patients who wore the nicotine patch regained 46 percent of their age-adjusted "normal performance" on long-term memory tests, whereas patients in the placebo group worsened by 26 percent."

It looks like even he was surprised at just how good the results were.  The improvement was profound and the patches were well tolerated.  Later stage trials will now follow.

Nicotine treatment of mild cognitive impairment

A 6-month double-blind pilot clinical trial

 

Here is the Abstract:- 

Objective: To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI).

Methods: Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings.

Results: Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent.

Conclusion: This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies.

Classification of evidence: This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI.

Here is a link to the full paper

 

Here is a lengthy Power Point presentation of his findings.

 

Conclusion

It is now clear that nicotine patches are effective in people with diminished acetylcholine and nicotinic receptor activity (which includes Alzheimer’s and Autism) and seem well tolerated by non-smokers.  As I pointed out in the last post, only a SMALL dose will work, a large dose will have the opposite effect. Dr Newhouse has actually tested this effect (see his presentation) and makes similar comments.  In the coming years, I am confident he will establish an excellent therapy for MCI and Alzheimer’s.  For Autism, I think it will remain a case of improvisation.  Note that in the trial they started with a low dose and built up to the 15mg patch over 21 days.  This dose was for adults.

Newhouse also suggests that nicotine may work better than the drug alternatives and might make a permanent (beneficial) change in subjects.  This was also suggested by other researchers in my previous post.

The patches can be cut like Sellotape/Scotch tape and they certainly do have an effect.  I know, because I am testing half a 15 mg patch right now.

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.

Nicotinicreceptor abnormalities in the cerebellar cortex in autism

 

An earlier paper on the same subject:-

Cholinergic Activity in Autism: Abnormalities in the Cerebral Cortex and Basal Forebrain

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:

• Some organophosphates not listed under "Irreversible" below
• Delta9-tetrahydrocannabinol (THC)
• Carbamates
• Physostigmine
• Neostigmine
• Pyridostigmine
• Ambenonium
• Demarcarium
• Rivastigmine
• Phenanthrene derivatives
• Galantamine
• Caffeine – noncompetitive (also an Adenosine receptor antagonist)^[8]
• Piperidines
• Donepezil, also known as E2020
• Tacrine, also known as tetrahydroaminoacridine (THA')
• Edrophonium
• Huperzine A^[9][10]
• Ladostigil
• Ungeremine^[11]
• Lactucopicrin

Natural Compounds

• Huperzine A
• Galantamine
• Onchidal
• Coumarins
• Celastrus paniculatus

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
ACh, Charbacol, AChEi (Physostigmine, Galantamine, Neostigmine, Pyridostigmine)	+	+	+	+	+
Nicotine, Varenicline, Cotinine	+	+
Succinylcholine	+/-
Tubocurarine, Atracurium, Cisatracurium, Rocuronium, Vecuronium, Pancuronium	-
Epibatidine, DMPP, Decamethonium		+
Trimethaphan, Mecamylamine, Bupropion, Dextromethorphan, Hexamethonium		-
Muscarine, Methacholine, Oxotremorine, Bethanechol, Pilocarpine			+	+	+
Atropine, Tolterodine, Oxybutynin			-	-	-
Vedaclidine, Talsaclidine, Xanomeline, Ipratropium			+
Pirenzepine, Telenzepine			-
Methoctramin				-
Darifenacin, 4-DAMP, Darifenacin, Solifenacin					-

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.

Acetyl l-carnitine[33] Acetylcholine itself Bethanechol Carbachol

Cevimeline Muscarine Nicotine

Pilocarpine Suberylcholine Suxamethonium

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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. 

 

Donepezil hydrochloride: a double-blind study in autistic children

 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

Role of Donepezil in Autism: Its conduciveness in Psychopharmacotherapy

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.

Placebo-controlled pilot trial of mecamylamine for treatment of autism spectrum disorders.

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

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

Varenicline in Autistic Disorder: Hypothesis and Case Report of Single-Patient Crossover

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.

A prospective, open-label trial of galantamine in autistic disorder.

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.

Transdermal Nicotine in Adult ADHD With Depression and Anxiety

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.