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Monday 18 March 2013

Glutathione (GSH) Part II - N-Acetylcysteine (NAC)

Please take a look at Part I before reading this post.  Remember this is a blog, not medical research or medical advice.  Always read the full clinical study and then go talk to your paediatrician.
 

Here is the final part of my current research into GSH which, you will be pleased to learn, leads to where it should; a successful clinical trial.  This time it is not in France, the trial will be in Palo Alto, California, home of Stanford University.

You will recall, that while researching one evening in February, I had rather stumbled upon the subject of GSH.  In Part I you learned all about GSH, Redox and came across a funny type of stinky chemical called a thiol.  I asked you to make a note of one particular thiol called Cysteine.

 

1.     Brain region-specific glutathione redox imbalance in autism

 We now go inside the autistic brain.  Last year some very smart Americans did some research measuring GSH and GSH Redox  (the ratio of GSH/GSSG) in different regions of the brain of autistic subjects.  You will probably prefer not to know how they managed to do this.

 They were able to prove that in certain parts of the brain, GSH Redox was decreased by more than half in the autistic subjects, compared to typical subjects of the same age.  That means GSH was low and GSSG was high.  By consequence, the autistic brains had a much higher level of oxidative stress (always a bad thing) than the other subjects.

They suggested that this might leads directly to the neurodevelopmental abnormalities in autism.


 

2.    Regulation of cellular glutathione

So now I was on a roll, I had found a serious biological abnormality in autism, but would it lead me to another Epiphany? Highly unlikely I thought, but onwards I went.

The next step was to find out a bit more about GSH

This part is both interesting and rather complicated, so I am going to give you just the highlights.


  • Glutathione synthesis and metabolism
The way GSH is synthesized in the body seems well understood in the literature.  While hoping to simplify this text I do need to point out I just noticed another odd coincidence that I have to follow up on later (NADP/NADPH the actual chemical required for the GSH Redox chemical reaction to take place also has other known functions in human biology NADPH is used for processes such as lipid synthesis, cholesterol synthesis and fatty acid elongation.  I have another parallel investigation into omega 3 and autism, where I have learnt that in autistic children  there is a proven lipid metabolism disorder that causes high cholesterol and low omega3/omega6 ratio.  So have to add NADP/NADPH to my list of things to investigate).

GSH is all over your body - brain, lungs, liver, kidneys and in all these places some of it gets converted to GSSH.  But on balance, if your body is in good shape GSH should be greater than 99% and GSSH less than 1%.  If not, bad stuff will happen.

There are five known ways to increase the level of GSH (a good thing to do):-

1.    Enhancement of uptake of cystine

2.    Reduction of cystine to cysteine  (add a reducing agent such as NAC)

3.    Provision of alternative sources of cyst(e)ine

4.    Provide a GSH precursor (γ-Glutamylcysteine) directly

5.    Add GSH directly (intravenously, not by eating it)

 
3.    Clinical trial of glutathione supplementation in autism spectrum disorders

I came across a study from 2011 when some well-meaning folk wanted to test GSH supplementation in autism.  Now the problem is that they neglected to spend 4 hours on Google Scholar before they started.  Now, if you think I am beginning to sound smug, well you are entirely correct.  It seems Peter, doing research in the spare room, knows more about something than some white coated researchers.

They just had to look on Wikipedia to learn that “Raising GSH levels through direct supplementation of glutathione is difficult.  Research suggests that glutathione taken orally is not well absorbed across the gastrointestinal tract”  They quote research from 1992, so it must be widely known by 2011.

The study used oral GSH and a commercial transdermal GSH preparation called KIRKMAN Reduced L-Glutathione Lotion (50 g will set you back  EUR 45)

 But at least the idea behind the trial was good.

 

4.     Glutathione precursors to raise GSH levels in plasma (N-acetylcysteine, whey protein)

Going back to hard science, you quickly find that there are already well established methods to successfully raise GSH levels, via the administration of certain supplements.

 ·         Whey protein, as used by body builders, but not so cheap

 ·         N-acetylcysteine, otherwise known as NAC and pretty cheap.

 
So I follow up both and later opted for NAC.


5.     N-acetylcysteine (NAC)  in the Emergency Room and  Psychiatry

NAC has been used as a precursor to GSH for more than 30 years.  It is the standard Emergency Room treatment in the case of paracetamol overdose.

It turns out that NAC is another little wonder.  It is already used in obsessive compulsive disorder, schizophrenia, trichotillomania (a new one to me) and bipolar disorder.  It is even used in HIV therapy.

But no mention of Autism.

NAC is available as a drug or as a supplement without prescription.


6.    A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism

Finally, the bit you have been waiting for.  When I found this clinical trial at the end of  my 4 hour Googling session, I would have fallen off my chair, had I not been lying down at the time.

A eureka moment perhaps;  I found a clinical trial testing just what I wanted to test -  a serious study of NAC on the behaviour of kids with autism.  This study was carried out by Antonio Hardan at Stanford University, California.

Enough said.


  

 
If you want the full version they expect you to pay $31.50.

Well that was a productive 4 hours, but it set me back another $31.50.

Sadly, finding all the references again and writing my two posts on GSH has taken another 4 hours.

That was of course a few weeks ago.  The rest is history.  I suggest that you turn on your speakers., and click the link below.

 

 
1965 was an important year.  One of them was that this song was produced and is apparently  #89 in  Rolling Stones list of the 500 greatest songs of all time.

13 comments:

  1. This is fascinating. Like you, my husband and I spend hours and hours reading research about autism because our son has it (high-functioning...quite bright and creative..) This is so interesting. Do you have any updated information about NAC? Is anyone else trying it in studies?

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    Replies
    1. Many people use NAC and other antioxidants (ALA, carnosine etc) and find it helps autism. These are all cheap and available widely so there is no money to be made and no incentive for large expensive trials.

      Delete
  2. Peter, Im not sure if you are aware of this but I know theres a couple of long term users of NAC on your blog (I believe your son also?).

    Long-Time Treatment by Low-Dose N-Acetyl-L-Cysteine Enhances Proinflammatory Cytokine Expressions in LPS-Stimulated Macrophages
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913600/

    I wonder if it might be more wise to use NAC in autism once every 3-4 days maybe instead of daily. Also the addition of simple glycine has been showing to increase GSH production even further. Ill post this about glycine (I was allready aware of it though):

    Dietary Glycine Is Rate-Limiting for Glutathione Synthesis and May Have Broad Potential for Health Protection
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855430/

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    Replies
    1. Aspie 1983, the study shows that low dose NAC and high NAC had the opposite effect, in the model they studied.

      "In our study, we found that low-dose NAC treatments for long-time increased expressions of IL-1β and IL-6 in LPS stimulated RAW264.7 cells, whereas high-dose NAC treatments decreased their expressions. Taken together with the previous reports mentioned above, our results suggested that the NAC-induced GSH/GSSG balance might regulate proinflammatory cytokine expressions in LPS-stimulated RAW264.7 cells. Furthermore, we also found that different concentrations of NAC induced opposite consequences in phosphorylation levels of several kinases, including ERK1/2, AKT and JNKs, suggesting that the GSH/GSSG balance might be associated with these kinase activities. Notably, we have shown that different concentrations of NAC cause opposite effects on phosphorylation of AKT, which was an upstream signal molecule of both NF-κB and AP-1"


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    2. Peter they never mentioned long term high dose, they just said high dose (not sure if acute or chronic... the study is rather vague).

      Also what would be considered a 'low dose' in a human model, it is hard to pin down. There have been multiple other studies regarding negative effects of NAC (nearly all long term studies), it seems to work best acute but chronic dosing seems to flip a switch somehow in most studies even producing adverse effects.

      Delete
  3. Something to keep in mind though is that glycine also has an effect on NMDA receptors (co-agonist from what I remember) and thus should potentiate signalling, substances that effect glycine signalling is researched in shizophrenia (think sarcosine, d-serine).

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    1. Glycine is a co-agonist at extrasynaptic NMDA receptors, which probably isn't what we want. D-serine works at the same receptor at synaptic sites.

      Aspie1983, have you ever tried Bacopa?

      /Ling

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    2. Hi Ling,

      Nope I have not, however I have been digging up extensive information about, it seems to influence SERT (yes the serotonin transporter), I have 2 short alleles, this means my body is constantly flooded with serotonin as the transporters function is to remove the serotonin (this is also why SSRI's bomb the brain with serotonin as they inhibit the transporter).

      The problem in my own case which I dont get is that that Aspergers is associated with decreased 5ht2a binding in the cortex (this is the core feature of its social problems and has been studied with brain scans in people with Aspergers), however lowering total serotonin would also mean less 5ht2a activity (stuff such as MDMA has its pro-oxytocin effects not only through 5ht1a but also 5ht2a, in fact blocking 5ht2a has been shown to nearly fully abolish the therapeutical effects of MDMA in PTSD studies and such).

      As you might know (I currently posted this) I have been doing psilocybin microdosing (yes the psychedelic), it has a unique mechanism of action and its effects are somewhat opposing even to that of SSRI's, namely INCREASED amygdala reactivity the day after psilocybin administration. This opposes the action of SSRI's which dull the amygdala.

      Here is a very informative video of how it works (dont worry its only a small short bit too watch):

      https://www.youtube.com/watch?v=F5_b3eQR3Fc Start watching at 19:15

      So far my experience with it is that I seem more sensitive to both positive and negative emotions, which is what I want. Being blind to negativity can also be a curse, being unable to recognize fear for example can put one in a dangerous situation.

      And people with aspergers also seem to have problem with fear acquisition, yet fear conditioning seems intact.

      Back to bacopa, most studies say that it seems to block 5ht2a, my experience with 5ht2a blockers is horrendous (think extreme aggression on metergoline which is a 5ht2a/5ht1a antagonist, theres a couple more meds that I have tried that block 5ht2a and all give me a horrendous experience).

      What I found striking (and im getting my blood drawn for this soon) is that herbs (damiana and vitex), dramatically increase my empathy and emotional wellbeing. The overlap? They are herbs that both increase progesterone (yes progesterone is also needed for males).

      Progesterone (and estrogen) increases 5ht2a activity in the cortex (this is exactly where my problem is I believe) and also regulates serotonin activity in the amygdala.

      Also the experiences I have read about bacopa is that most users say it aggrevates anhedonia when used long term, since my apathy is finally getting less due biogaia gastrus (also complete normalization of stools) and psilocybin, the last thing I want to touch is anything that could worsen it.

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    3. Do I understand it correctly that you are always at the verge of serotonin syndrome then?

      Bacopa modulates 5HT1a, 5HT2a, 5HT2c, 5HT3a and 5HT6, but in many cases it has a "normalizing" effect in conditions where the expression of these receptors have gone awry, like epilepsy.

      This review was impressively dense with neuropharmacological effects of Bacopa, so if anyone want to learn more:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746283/

      /Ling

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  4. Keep in mind also that both asd and autism actually seem more about improper NMDA signalling, once again people only think NMDA as either excitotoxicity or hallucinations (nmda agonism and antagonism respectively). Theres lots of medications that potentiate signalling and at the same time are neuroprotective.

    Remember Peter talking about sodium benzoate? This this is a D-amino acid oxidase inhibitor, guess what this will do? Yes this will increase D-Aspartic Acid (this is like the main ligand for NMDA activation) concentrations in the brain.

    Another example is D-cycloserine:

    The NMDA Agonist D-Cycloserine Facilitates Fear Memory Consolidation in Humans
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2638747/

    A randomized, placebo-controlled trial of D-cycloserine for the enhancement of social skills training in autism spectrum disorders.
    https://www.ncbi.nlm.nih.gov/pubmed/26770664

    A trial of D-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder.
    https://www.ncbi.nlm.nih.gov/pubmed/24824660

    d-Cycloserine enhances durability of social skills training in autism spectrum disorder
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264460/

    N AcetylCysteine, another example:

    Glutathione is an endogenous ligand of rat brain N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors.
    https://www.ncbi.nlm.nih.gov/pubmed/9251108

    It seems to suppress the activity of ligands of the glutamate binding site yet enhances binding of the MK-801 agonist (on NMDA receptors).

    Also PQQ I have had a good experience with which is odd since this actually lowers glutathione and also modulates the NMDA redox site.

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    Replies
    1. Thanks! I had not seen that link on D-Cycloserine use in children before.
      I still think that D-serine _might_ be the better of the two...

      /Ling

      Delete
  5. Hi,

    I have been reading up about GSH and about 10 days started my 9 year old (classical Autism) on NAC (600 mg/day). It is early to say but along with theanine (300 mg/day) seems to be helping with reducing irritability. while reading on GSH and NAC, came across continualg/glyteine to increase GSH. Was wondering if you have tried this or reserached this and if it is a better option for Autism where there could be chronic GSH deficiency. Sorry if this comment is duplicate (tried earlier but dont know where that comment went)

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  6. Gamma Glutamylcysteine does raise the level of GSH, just like NAC.

    The producer suggests that if you have a Glyteine deficiency, NAC will not help you and only their product will.

    Equally, if you have a selenium deficiency none of these supplements will help you.

    Ideally, someone will compare the effect in humans. So you can compare the effect and indeed cost.

    It is marketed as Continual G with pictures of healthy people who clearly do not need it. In healthy people if you artificially increase antioxidants, the body just reacts and produces less of its own, leaving you no better off.

    Your 600mg dose of NAC is low, many people use a dose 4 times higher.

    Continual G cost more than $100 a month. We have no idea what the NAC equivalent is. Is it just 600mg ?

    ReplyDelete

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