Pregnenolone - an effective OTC anti-inflammatory therapy for autism?

Pregnenolone is the true mother hormone, being derived from cholesterol and the precursor of all steroid hormones. 

It is a potent anti-inflammatory agent.  It is  also claimed that supplementing with Pregnenolone will increase IGF-1, which I found interesting, given my very recent post on IGF-1 therapy in autism.  

In the late 1940’s and 1950’s successful studies were carried out into the use of Pregnenolone in the inflammatory condition of arthritis. 

As we found in recent posts regarding the vagus nerve, all inflammatory conditions (autism included) share much in common.  A treatment that is effective against neuroinflammation in one condition should be tested in the others.

Interest was high in Pregnenolone because it was cheap and free of troubling side effects.  Alternative steroid treatments, for example with Prednisone, can have major side effects.

In an earlier post I referred to the successful use of the steroid Prednisone in ASD in the US.  Wider adoption, and the lack of clinical trials, are held back by the fear of side effects.

Promoting Speech in a 7 year old Non-verbal Child with Autism

"... Dr Michael Chez, of the Pediatric Neurology and Autism Neurodevelopmental Program, Sutter Neuroscience Institute in Sacramento California.  He wrote a paper I have already referred to in this blog called:-

Immune Therapy in Autism: Historical Experience and Future Directions with Immunomodulatory Therapy

In that paper he talks of his knowledge of the effects of prednisone on children with autism and he mentions the dosage used.

Treatment was usually prescribed with daily prednisone doses of 2 mg/kg/day for 3 to 6 months. Limitations to therapy were usually Cushingoid side effects. As in other chronic conditions requiring steroids, pulse dosing was tried with steroids in the form of prednisone or prednisolone at 5 to 10 mg/kg twice per week.

Long-term success with no dependence or minimal Cushingoid effects has been noted in several hundred patients treated in this manner (Chez, unpublished data, personal communication).

In all, 17 of 32 patients showed response to prednisone after 2 to 4 months of treatment (53%). Improvements were seen on EEG and in language skills of the patients. Other steroid treatment series of regressed language in autistic spectrum patients diagnosed with LKS variant showed improved language with pulse-dose steroids."

 Pregnenolone Studies

Pregnenolone in the Treatment of Rheumatoid Arthritis

Pregnenolone in Rheumatoid Arthritis

If effect, Pregnenolone seems to be a weaker, but much safer, alternative to Prednisone.  Some people with arthritis currently take it. 

Pregnenolone is indeed already one of hundreds of fringe treatments for autism.  There are some very good reasons why it should be effective. 

Stanford University are currently running a clinical trial of Pregnenolone on adults with autism. It is the same researcher that worked on their study on NAC in children with autism.  It is nice to know that the adults with ASD have not been forgotten; after all, children have a habit of growing up.

A Study of Pregnenolone in the Treatment of Individuals With Autism

Conclusion

The next time I receive a question on this blog asking for a potentially effective OTC anti-neuroinflammatory “supplement” for autism, I will know what to suggest trying.

The Vagus Nerve and Autism

It is good to know that there are some brilliant minds out there, willing to cross disciplines.  A case in point is Professor Stephen Porges, a neuroscientist with particular interests in understanding the neurobiology of social behavior.  He is a Professor in the Department of Psychiatry and the Director of the Brain-Body Center in the College of Medicine at the University of Illinois at Chicago.  He has an equally clever wife who is a world leader in the role of neuropeptides oxytocin and vasopressin in social cognition.
You would want to think twice before inviting this couple round for dinner, unless you had spent the day before boning up on your science. 

Porges is best known for his Polyvagal Theory.  The Wikipedia article does not really do justice to the theory.  Here are two highly cited papers:-

The polyvagal theory: phylogenetic substrates of a social nervous system (2001)

The Polyvagal Theory: phylogenetic contributions to social behavior (2003)

He has only written one paper on autism, it is certainly not a light read but it shows a brilliant mind.

The vagus: A mediator of behavioural and visceral features associated with autism 

This paper is actually a chapter in a book and can be accessed via Google Books.

His paper explains odd autistic behaviours in terms of the functioning of the vagus nerve.  For example, the neural mechanism for making eye contact is shared with those needed to listen to the human voice.  So if you struggle to make eye contact, you will struggle to listen to what somebody is saying to you.  We can infer that if your ABA program trains you to make eye contact, you will likely become a better listener in the process.  Also, don’t talk to somebody unless you are facing them.

He comments on the regulation of the gut, the vagus and the immune system, vagal regulation of the HPA axis, all with reference to ASD.

Having read his paper you really will need no more convincing to go tune up your child’s vagus nerve. 

Tuning up the Vagus Nerve

Unlike Professor Porges, I like to simplify things so you do not read them more than once.  Clearly Kevin Tracey and Porges are the experts on the vagus nerve, but they do not go as far as telling you what you really want to know – how to improve its function using today's technology.  Fortunately, there is plenty of research on the Cholinergic System, of which the vagus nerve is part.  The following paper is a good example:-

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

You may recall from my earlier post Biomarkers in Autism: The Cholinergic system, that there are two types of cholinergeric receptors, nicotinic and muscarinic.  This paper is telling us how in autism these receptors are fewer in number than normal and the ones that are there, are not working (binding) as they should.

So this goes some way to perhaps explain why so many odd behaviours can be tracked back to the autistic vagus nerve; it is damaged.

In his paper, Porges is basically telling you to go try a vagus nerve stimulator, of the kind that already exists for epilepsy (see photo above) and Kevin Tracey is developing for arthritis (another inflammatory condition).  Right now this is not very feasible, but chemical stimulation of the vagus nerve does not look beyond the wit of man, using currently available technology.


 

It’s a Small World – IGF-1 and NNZ-2566 in Autism

You may or may not believe in fate, but some strange things have been happening related to Australia, growth hormones and TBI.

Last week I took Monty, aged 10 with ASD, to have his IGF-1 (insulin-like growth factor) measured.  At the time, this had nothing to do with autism, rather just what the Endocrinologist had requested.  Then I start doing my research on hormones and autism and found, surprisingly, there is an ongoing clinical trial in autism using IGF-1.  Then I start looking again at TBI (Traumatic Brain Injury), which I see as having much in common with ASD.  I looked for similarities in hormone disruptions found in TBI and ASD; I found there are many and they are mainly related to GH (growth hormone) and IGF-1.  The problem with IGF-1 therapy is that it is intravenous; I had told the Endocrinologist that I was not going to measure IGF-1, because I was not very keen on giving Monty intravenous drugs.  In the end, I did the test anyway and I am glad I did.

As I researched TBI, I saw a great deal of interest in using GH as a therapy and the US military is providing a great deal of funding to develop therapies.

Today the postman brings me my first post from Australia in several years.  It contains some children books for Monty (Thank you Lisa).

Now I come across NNZ-2566;  it is a synthetic analogue of a naturally occurring neurotropic peptide derived from IGF-1.   NNZ-2566 is being developed both in intravenous and oral formulations for a range of acute and chronic conditions including TBI, Fragile X and Retts syndrome.  NNZ-2566 exhibits a wide range of important effects including inhibiting neuroinflammation, normalizing the role of microglia and correcting deficits in synaptic function.  NNZ-2566 is being developed guess where? Australia, by Neuren Pharmaceuticals.

Just 10 days ago the company made the following announcement:-

Melbourne, Australia, 18 October 2013: Neuren Pharmaceuticals (ASX: NEU) announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for Neuren’s programme to develop NNZ-2566 for Fragile X Syndrome. Fast Track designation is designed to expedite the development and review of important new medicines that are intended to treat serious diseases and meet unmet medical needs.

A different group of researchers are poised to begin clinical trials of IGF-1 in children with autism early next year. Because IGF-1 is already approved in the United States for use in children with short stature, the U.S. Food and Drug Administration is allowing the researchers to proceed directly to clinical trials for its use as an autism treatment.

What a lot of coincidences.

For those scientists among you, here are more details.

First of all it has been shown that in autism there are elevated levels of growth hormones.  Here is an American study.

Elevated levels of growth-related hormones in autism and autism spectrum disorder

 The Australians quote research from Finland that looks to me to contradict the above paper.  One difference is that the US researchers were testing blood and the Finns were testing spinal fluid.  What is clear is that in autism IGF-1 is not normal.

Neurotrophic Factors in the Pathogenesis of Rett Syndrome

Abstract

Rett syndrome is characterized by disruption of a period of vigorous brain growth with synapse development. Neurotrophic factors are important regulators of neuronal growth, differentiation, and survival during early brain development. The aims of this study were to study the role of neurotrophic factors in Rett syndrome, specifically whether Rett syndrome has abnormal levels of specific neurotrophic factors in serum and cerebrospinal fluid and whether the changes differ from other neuropediatric patients, for example, those with infantile autism. Four neurotrophic factors were measured: nerve growth factor, brain-derived neurotrophic factor, glial cell line—derived neurotrophic factor, and insulin-like growth factor 1 from the frozen cerebrospinal fluid and from serum (except glial cell line—derived neurotrophic factor) by enzyme-linked immunosorbent assay and cerebrospinal fluid glutamate and aspartate by high-performance liquid chromatography (HPLC) method in patients with Rett syndrome. Insulin-like growth factor 1 was measured from the cerebrospinal fluid of patients with infantile autism. We found low concentrations of cerebrospinal fluid nerve growth factor in patients with Rett syndrome compared with control patients. The serum levels and other cerebrospinal fluid neurotrophic factor levels of the patients did not differ from the controls. Patients with Rett syndrome had high cerebrospinal fluid glutamate levels. Patients with infantile autism had low cerebrospinal fluid insulin-like growth factor 1 levels. Nerve growth factor acts especially on cholinergic neurons of the basal forebrain, whereas insulin-like growth factor 1 acts on cerebellar neurons. In Rett syndrome, the forebrain is more severely affected than the other cortical areas. In autism, many studies show hippocampal or cerebellar pathology. Our findings are in agreement with the different morphologic and neurochemical findings (brain growth, affected brain areas, neurotransmitter metabolism) in the two syndromes. Impairment in dendritic development in Rett syndrome could be the consequence of cholinergic deficiency and of neurotrophic factor/glutamate imbalance. Cholinergic gene expression might be influenced by the Rett syndrome gene directly or via the neurotrophic factor system.

 Then we have research showing GH/IGF-1 has secondary functions beyond those in the text books.  Lots of nice words like neuroprotective, regenerative etc.

Role of the Growth Hormone/Insulin-Like GrowthFactor 1 Axis in Neurogenesis

Abstract

The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1 affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis. Recently, GH therapy has also been shown to induce cell genesis in the adult brain. The profile of effects by GH therapy may be somewhat different than that of IGF-1. In addition, GH secretagogues (GHS) also have neuroprotective and cell regenerative effects per se in the brain. Finally, transgenic disruptions in GH signaling pathways affect neuron and astrocyte cell numbers during development and during adulthood. Altogether, data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell genesis and neurogenesis in the adult brain. Theoretically these substances could be used to enhance recovery after brain injuries. However, further experiments with specific animal models for brain injuries are needed before clinical trials can be started. 

For those of you that like mice studies:

Growth factor improves autism symptoms in mice

Now back down under to let the Aussies make their case:

The Case for IGF-1 and IGF-1 (1-3) Glypromate in Autism

Courtesy of our friends “down under” you can read a presentation explaining the likely merits of both IGF-1 and its “terminal tripeptide” IGF-1 (1-3) as therapeutic agents in autism.  The clever Aussies have gone one better and produced NNZ-2566.  It is an analog of and IGF-1 (1-3).  This means it has that the molecule has been very slightly modified.  In this case this has been done to allow it to be orally available (i.e. not by injection) and to better cross the blood brain barrier (BBB). 

NNZ-2566 rationale for use in Autism Spectrum Disorders

Mount Sinai Hospital Clinical trial of IGF-1

Mount Sinai Hospital is a leading US teaching hospital in New York; they are carrying out a trial of IGF-1 in autism.  They are starting with a sub type with a genetic deficiency called SHANK3, but they will then look at the benefit in other types of ASD. 

http://clinicaltrials.gov/ct2/show/NCT01525901 

"In an important test of one of the first drugs to target core symptoms of autism, researchers at Mount Sinai School of Medicine are undertaking a pilot clinical trial to evaluate insulin-like growth factor (IGF-1) in children who have SHANK3 deficiency (also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome), a known cause of autism spectrum disorder (ASD).

The seven-month study, which begins this month, will be conducted under the leadership of the Seaver Autism Center Clinical Director Alex Kolevzon, MD, and will utilize a double-blind, placebo-controlled crossover design in children ages 5 to 17 years old with SHANK3 deletions or mutations. Patients will receive three months of treatment with active medication or placebo, separated by a four-week washout period. Future trials are planned to explore the utility of IGF-1 in ASD without SHANK3 deficiency."

 

Conclusion

For a change, my conclusion is that further study is needed (by me).  Probably all the hormonal disruptions in autism need to be looked at together (serotonin, T3 etc) before any wild conclusions are drawn.


 

Monty’s First Joke

Today at 6.30 in the morning something very unexpected happened;  Monty, aged 10 with ASD, made his first joke.  For a boy of few words this is quite a big step.

“I hit my head and now I can see birdies”

Elder brother Ted, when he finally arose, was impressed. It was very much his kind of humour, making a joke about your own weaknesses.

Regular readers will know that we are currently investigating the role of the vagus nerve in autism; all I can say is that nobody mentioned that the vagus nerve also mediates your sense of humour.  It may just be a happy coincidence, but this happened within 24 hours of our latest little experiment.  


 

Epsom salts, Autism and Hypokalemic Sensory Overload

Early on in this blog I wrote about a supposedly rare condition, where somebody suffers from sensory overload, usually from sound, but it could be light or even smell.  That condition has fancy sounding name, Hypokalemic Sensory Overload.  The cure is very simple, just to give oral potassium and within 20 minutes there is a full recovery.  Here is one research study.

 

I felt it odd that nobody had compared this to sensory overload in autism.  I did my own experiment at home and found to my surprise that sensory overload in autism could also be treated with oral potassium.

In the last few weeks I received two very thoughtful comments on this blog, from adult sufferers who have found the same remedy as I have.  So at least I am no longer in a minority of one.

The interesting thing about potassium in the human body is that it relies on another electrolyte, magnesium.  Without sufficient magnesium, the body cannot maintain an adequate level of potassium.  This is why supplements normally contain both potassium and magnesium.  A problem with both potassium and magnesium is that they very easily upset the stomach, indeed some laxatives are based on magnesium.

Epsom salts

I have noted that the long list of autism interventions used in the US, frequently includes having a bath in Epsom salts.  Epsom salts are named after a town near London, England, from which they were originally mined.  Epsom salts are just magnesium sulphate (MgSO4).

In the “biomedical” community it is proposed that magnesium does great things for autism and/or sulphur does.

The sulphur part at least has a scientific explanation.  It was long ago shown that there is an apparent abnormality in the sulphur metabolism in autism. 

In effect there is greater loss than normal of sulphur in the urine, resulting in lower plasma levels than in typical people.

So people are dipping their kids in Epsom salts on that basis that either the magnesium or the sulphur will do some good, not sure of which.

Interestingly, on the web, I found one mother writing about the Epsom salts baths she gives her child; she says she know when it is time for another one, where her child starts to cover her ears (sound sensory overload).

Trans-dermal Magnesium

Since magnesium supplements are in-effect laxatives, other ways have been sought to administer this electrolyte.  There are several transdermal creams and sprays that do indeed seem to work, but they can irritate the skin.  Interestingly, also on the web, some autistic adults talk about using such supplements and benefiting. 
 

Making the Connection

Well I hope this is all obvious to you, at least one of the things that is going on is an ion channel disease, the result of which is sensory overload in autism.  By chance, some people have stumbled upon magnesium supplementation as a therapy.  The extra magnesium is making whatever potassium there is in that person’s diet more effective, and hence reducing their symptoms.  Since the condition is actually Hypokalemic Sensory Overload, they would do even better to add some extra potassium as well.

The sulphur part may, or may not be, a red herring.  Sadly there are many of them in autism.

Conclusion

I have completed this part of my autism investigation.  If you want to treat autistic sensory overload, that seems to affect almost all people with ASD and most with ADHD, the options are:-

1.     Reduce the body’s daily loss of potassium and magnesium, with a potassium sparing diuretic, like Spironolactone

2.     Increase consumption of potassium and magnesium in diet.  Bananas, oranges and kiwis are rich in potassium, for example.

3.     Use small doses of oral potassium and magnesium supplements throughout the day

4.     Use expensive transdermal magnesium treatments.  Nobody seems to make a potassium version.

5.     Take a soak in the bath with an added cup of Epsom salts.

There should be a second reason to try option (1).  For entirely unrelated reasons, this drug is proposed to help in autism due to its secondary anti-inflammatory and hormonal effects.
Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders

 I have to say that, having done my field research, I will be sticking with (2), (3) and the occasional (5)

 

Hormonal Remedy for Brain Injuries

Autism is a non-traumatic type of brain injury; the kind you typically see in the Emergency Room is TBI (Traumatic Brain Injury), after a car crash or, in the US, a shooting.

TBIs are very common and frequently fatal; when not fatal they often produce grave ongoing physical and psychological consequences, some of which may be life-long.  As a result there is a great deal of research into understanding TBIs and how to best treat them.

In this blog we have already mentioned that statins are being used to successfully treat TBI.  As I discovered, they have an impact in autism as well.

My renewed interest in TBI is two fold:-

1. Does TBI cause ongoing hormonal changes in the brain? (as does ASD)
2. Are there hormone therapies for TBI? (there are experimental ones for ASD)

The answer is yes and yes.

After a TBI there frequently are hormonal changes and they have even been given a name.

Post TBI Hormonal Deficiency Syndrome

The most frequently affected hormones are reported to be growth hormone (GH) and insulin-like growth factor (IGF-1).  This is interesting because these same hormones appear to be affected in autism.

There is a hormone therapy for TBI and it is currently undergoing a third stage clinical trial at 67 hospitals across the US. 

Progesterone for the Treatment of Traumatic Brain Injury (ProTECT III)

You can read all about the study with the above link.  If you are curious as to how Progesterone can reduce neuroinflammation and be neuroprotective, here is another paper:-
Progesterone as a neuroprotective factor in traumatic and ischemic brain injury

Regular readers of this blog will know that I like charts.  Here is a neat summary of how progesterone helps in TBI.

Progesterone is indeed a female hormone, but it is also present in small amounts in the male brain.  It is a fringe therapy for ADD and ADHD with the hormone given transdermally.

In TBI, progesterone is being given intravenously in the ER, as soon as possible after the accident.

In autism we are working many years after the brain injury occurred, but that should not stop us looking further.  The same applies to statins.


 

Endocrinology & Autism - the Final Frontier

When I started this blog 85 posts ago, I could not even spell endocrinology, let alone know how important it might be in my quest to figure out autism and how best to manage it.  Endocrinology is all about the biosynthesis, storage, chemistry, biochemical and physiological function of hormones and with the cells of the endocrine glands and tissues that secrete them.

What does that have to do with autism?

Well, 85 posts later, I think I can safely tell you that while oxidative stress and neuroinflammation in the damaged autistic brain are the two drivers of autism, most of the behavioural consequences are likely mediated by you child's endocrine system. 

Like me, you can try as hard as you like to minimize oxidative stress and neuroinflammation and this will take you a long way; but the ultimate goal would be to give the endocrine system a little help to switch from autistic homeostasis towards neurotypical homeostasis.  Is this really possible?  A year ago I would have said this was pure fantasy; now I am not so sure.

There are numerous well documented hormonal imbalances in autism, only some of which have been investigated and none very thoroughly. 

Medicine is full of "-ologies" and you would have thought autism had most to do with Neurology, but I have a feeling that Endocrinology will give me the final piece of the puzzle that I am looking for.

For this next stage in my investigation I will be taking advice from an Endocrinologist.








 

Piracetam for Autism, Comrades

Piracetam was first synthesized in 1964 by a Romanian scientist called Corneliu Giurgea, who was highly unusual.  He was educated in then communist Romania, followed by research in Russia and then at the University of Rochester in the US, before ending up in Belgium, eventually as the Head of Research at drug firm UCB and being a Professor at a Belgian university.  How this was possible under the strict form of communism followed in Romania,  I do not really understand.

Anyway, Giurgea was clearly very resourceful and he decided to invent a new class of drugs, to be called Nootropic.

He stated that Nootropic drugs should have the following characteristics:

1.     They should enhance learning and memory.

2.     They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).

3.     They should protect the brain against various physical or chemical injuries.

4.     They should increase the efficacy of the tonic cortical/subcortical control mechanisms.

5.     They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity.

Piracetam was soon followed by other drugs developed by competitors.

This class of drug seems never to have been licensed in the US, but was used widely in the Soviet Union, Eastern Europe and some western European countries.

As seems all too common in medicine, nobody knows for sure how Piracetam works.  There are many proposed mechanisms and I was attracted by one of them.

Autism in Ukraine

The internet does give the impression of giving you all the answers.  Often it gives you far too much information, much of it of dubious quality.  In reality, you are only seeing what is written in English, and although it is the international language of science and medicine, you will never see the majority of Russian, Japanese and Chinese knowledge/research.  Medical practice varies widely between Western medicine and the others.

In Japan for example, the MMR vaccination has been banned since 1993 and Prozac, the anti-depressant prescribed in huge quantities in the US, is a banned substance.  

So it was not a surprise to find only passing references to apparently widespread use of Piracetam for autism in the Ukraine, going back for decades.  I have no doubt if you could access the Russian research you would find studies on this.

Side Effects

There is no shortage of drugs prescribed in the US for autism, such as Ritalin, Prozac and Risperidone.  I have no doubt that they have some very good qualities; however they all have very real side effects, some of which are permanent.  Giurgea was very wise to only consider drugs with very few side effects and low toxicity.

In the 50 years since he synthesized Piracetam, one thing everyone seems to agree on, is that either it has no side effects, or it has very minor side effects.

Does Piracetam work?

In the 1970s there were numerous studies on Piracetam in a wide range of neurological conditions.  Today Piracetam is extensively used “off label” as a treatment for many of those conditions.  Does Piracetam work in autism?

I guess the doctors in the Ukraine must think it works.  Dr Akhondzadeh, a researcher into autism, ADHD, and other mental health conditions in Iran, found it to be effective.  Kelly Dorfman of the Development Delay Resources in Pittsburgh thinks it is effective for learning disabilities and dyspraxia, but less so for autism.

Olga Bogdashina, President of the Autism Society of Ukraine, notes that piracetam is widely used as an autism treatment in the Ukraine. Having conducted her own small-scale study, she found that piracetam improved the attention spans and mental capabilities in the majority of participating children. She also says that her autistic son became more sociable and flexible and less aggressive on the supplement. She does warn that during the initial phase of treatment, hyperactivity and tantrums may increase. However, researcher Stephen Fowkes notes that these side effects are only common with high doses, and asserts that they are rare with standard doses (both cited in “Letters to the Editor, Autism Research Review International, 1996).

I thought Bogdashina’s name was familiar.  I read her book on sensory issues in autism.  It is a good read, but it does not really tell you what to do.

Piracetam’s claimed possible methods of action

·        It is NOT a sedative or a stimulant

·        Piracetam is a positive allosteric modulator of the AMPA receptor.

^·         It is hypothesized to act on ion channels or ion carriers; thus leading to increased neuron excitability

^·         GABA brain metabolism and GABA receptors are not affected by piracetam.

^·         Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors, which are implicated in memory processes

·        Furthermore, piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes.

·        Piracetam is thought to increase cell membrane permeability

·        Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na⁺, K⁺).

·        It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brains.

·        Piracetam, while in the brain, appears to increase the synthesis of cytochrome b5, which is a part of the electron transport mechanism in mitochondria.

·        But in the brain, it also increases the permeability of the mitochondria of some intermediaries of the Krebs cycle.

In 2005 there was an interesting review carried out in Poland; it is very readable.

Piracetam - An old drug with novel properties? 

"Piracetam is generally reported to have minimal or no side effects. It is interesting to note, however,  that piracetam is occasionally reported side effects of anxiety, insomnia, agitation, irritability  and tremor are identical to the symptoms of excessive acetylcholine/glutamate neuroactivity. In spite of these effects, piracetam is generally not considered to be a significant agonist or inhibitor of the synaptic action of most   neurotransmitters. The piracetam-type nootropic drugs might exert their

effect on some species of molecules present in the plasma membrane. It would seem that they act as potentiators of an already present activity, rather than possessing any neurotransmitter-like activity of  their own."

It would seem to me that we have come back to the vagus nerve and the Cholinergic system

http://epiphanyasd.blogspot.com/2013/10/biomarkers-in-autism-cholinergic-system.html

I learnt in that post that there are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR).  Mostly it seems to be the nicotinic type that is targeted by medical science, but piracetam has an effect on the other type of receptor.  This would explain excessive use of piracetam causing symptoms of too much acetylcholine.

If this is indeed the case, that would add yet another method of “correcting” the known biomarker of autism that is “diminished acetylcholine and nicotinic receptor activity”.  Of all the methods I have so far investigated, this might actually be the safest;  it is certainly inexpensive.

Effect on Comorbidities

My method of separating fact from fiction in autism now includes looking at the effect of therapies on the principal comorbidities of autism.  Most genuinely effective drugs seem to work across many comorbidities.  Epilepsy is the most prevalent comorbidity.
 

Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo

"CONCLUSIONS—This study provides further evidence that piracetam is an effective and safe medication in patients with Unverricht-Lundborg disease. In addition, it shows that a dose of 24 g is highly beneficial, more effective than lower doses and that a dose-effect relation exists. There is considerable variation in optimal individual dosage. "

Note:  Unverricht–Lundborg disease is the most common form of an uncommon group of epilepsy called the progressive myoclonus epilepsies.

Conclusion

Piracetam seems to be a safe supplement/drug that improves mood and reduces aggression (and SIBs).  I thought it was worthwhile testing and indeed I was not disappointed.  The dosage suggested is 50-100 mg/kg, but the optimal dose seems to vary by child.  If you follow my vagus nerve/neuroinflammation/ cholinergic way of thinking, then Piracetam would be acting (via acetylcholine) to reduce pro-inflammatory cytokines and hence reduce inflammation in the autistic brain.  This would mean that Piracetam would be a useful tool to control autism flare-ups, be they triggered by pollen allergy, intestinal inflammation, or even stress.  I shall use it as such.

As for why Piracetam seems more effective in the Ukraine than in Pittsburgh - that I can answer.  Much of what passes as autism in Pittsburgh, would be completely ignored in Kiev.  It would not be diagnosed as autism; only if it is disabling would it be called autism.  If you have "autism-lite", the symptoms are mild and you probably do not need Piracetam and it would likely have little effect.   The same would apply for the majority of ADHD/ADD cases, outside of the US they would not be diagnosed as such.

If you are on Ritalin for your severe ADHD, you might want to try Piracetam.  If you Google ADHD and Piracetam, you will find adults using Piracetam to avoid the side effects of Ritalin.

If your child suffers from SIBs (self-injurious behaviours) then Piracetam, along with nicotine patches, would be well worth investigating.