Friday, June 1, 2012

Glutathione: We Loves It (NAC and Autism)

I love twitter.  And I'm nearing 10,000 tweets, which is probably diagnostic of something.  But twitter is a great way to find articles and studies and things of interest tweeted by others with similar interests.  And twitter is how I found this new study from Biological Psychiatry, A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism.  Everyone go follow Cognitie.  He's obviously intelligent and good-looking to boot, with lots of cool links and whatnot.

N-acetylcysteine is a supplement I've covered before, in Problems?  I Have a NAC for That.

(Phoenix:  Armistice.  Right click to open in new tab)

A healthy brain is all about balance.  One one side we have glutamate, which is the major excitatory neurotransmitter in the central nervous system.  Think of glutamate as a charioteer with a whip forcing the horses in your noggin to GO GO GO.  We're glad we have glutamate.  Without glutamate we'd be dead.  But the problem is, glutamate doesn't always know when to stop.  That's why we have GABA, the major inhibitory neurotransmitter in the central nervous system.  GABA is the groom who takes those horses out to pasture to munch on the green grass and rubs the horses down with a nice brush.  In the right balance, you have a winning horse.  With too much excitatory action you get a worn-out old nag.

In autistic spectrum disorders, there are a number of lines of evidence pointing to problems with the excitatory/inhibitory balance in the brain.  There seem to be increases in expression of RNA for genes in the glutamate pathway, and there are certain genes having to do with the glutamate system that increase the risk for having autism.  Glutamate is actually the precursor for GABA, and the enzyme that catalyzes the transformation from one to the other is glutamic acid decarboxylase.  Both reduced levels of this enzyme and increased levels of glutamate have been reported in areas of the brain and spinal fluid in some children with autism.

In addition, as I noted in a previous blog post, autism symptoms may be a result of redox imbalance.  That is, throughout the body, we have oxidants and antioxidants.  We oxidize things to burn them in order to make energy, but we are left with "reactive oxygen species" as part of the burning process.  Antioxidants go around and sop up the reactive oxygen species to prevent them from damaging and destabilizing proteins and fats and whatnot.  Reactive oxygen species run amok can damage neurons and cause major brain problems.

We're used to thinking of "antioxidants" as vitamins such as C and E.  However, the major antioxidants in the body are actually superoxide dismutase, catalase, and glutathione.  The glutathione is one of the ways where NAC comes in, because as a supplement it is the best way to replenish gluathione in the liver and the rest of the body.*

(Animal Kingdom: Strange Attractor )

In the brain, the cysteine from N-acetylcysteine activates a glutamate-cysteine antiporter (a type of transporter in and out of a cell that exchanges cysteine for glutamate).  Shoving glutamate into the extracellular space in the brain leads to downregulation of glutamate transmission in the central nervous system.  So if you have too much glutamate whipping the brain, NAC seems like a mighty useful supplement to take.  Therefore, if autism spectrum disorders (and other neurologic and psychiatric disorders) are a result of an excitatory:inhibitory imbalance, with overabundant excitation, NAC will bring the players more into balance.

At the same time, if autism spectrum disorders (and other neurologic and psychiatric disorders) are a result of redox imbalance, with reactive oxygen species terrorizing the delicate neurons, NAC will help the body make plenty of glutathione to help clean up those bad boys.

There's no single cause of austim, but NAC might be a way to kill several birds with one stone, as it were.  AND, in the brain the two pathways (excitatory:inhibitory and redox) come together, as glutathione can displace glutamate at its receptor.  Another win for NAC, it would seem.**

And, as noted in the excellent editorial in the same issue of Biological Psychiatry, Translating the Rosetta Stone of N-Acetylcysteine, these multiple effects may be why NAC has been shown to be efficacious in trials of so many psychiatric disorders.  In the first paper I linked above, a small pilot trial, symptoms of irritability in autism were much improved in 5 kids, minimally improved in 6 kids, no change in 2, and one child got worse (though after the trial and on no NAC the subject had the same symptoms which were eventually found to be due to constipation).  In the placebo group, two were much improved, five were minimally improved, five had no change, one was minimally worse, and one was much worse.  Postive trials for NAC have also been reported for certain symptoms of schizophrenia, bipolar depression, cocaine craving, smoking cessation, trichotillomania, and gambling. What is also fairly remarkable is a lack of negative studies (established agents for all of these conditions have many negative studies.)

We still don't know if NAC is entirely safe (I wrote some theoretical problems with long-term use in my original blog article), and dietary supplements that aren't pharmaceutical grade might not be as reliable in dose, active ingredient, etc. as prescription medication.  On the other hand, we know that prescription medicines aren't entirely safe, and in many cases, we know they have very considerable risks.
It would be nice to have some replication of these studies.  As it stands, however, NAC has more of an evidence-base for use trichotillomania than any standard pharmaceutical.

Out of all the supplements, the ones that impress me the most are NAC and magnesium.  NAC sure isn't "evolutionary psychiatry," but in this modern world of stress, poor sleep, and inflammatory food, beefing up the glutathione and taming the glutamate seems like a reasonable approach, particularly if you are having devastating symptoms (as in severe autistic disorders).

*Glutathione itself is poorly absorbed as a supplement, and is too large a molecule to be easily absorbed into the cells.  Cysteine is the rate-limiting component of the reactions taking glutamate + cysteine to eventually make glutathione.  Cysteine itself is not easily absorbed, but the acetylated form, N-acetylcysteine, is.  Therefore, if you take n-acetylcysteine, you supply both a necessary precursor for glutathione and a nifty way to mop up excess glutamate.  Win-win on that front.

**and another eek! for acetaminophen

49 comments:

  1. Dr. Harry Demopolous developed a formulation of reduced (L-gamma-glutamylcysteinyl glycine)that has been available for over 20 years and is stable, non-toxic, and bioavailable. www.glutathionescience.com

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    1. But it won't likely activate the glutamate antiporter, nor would it help mop up glutamate by combining with it to turn it into GABA. CNS-wise cysteine is more interesting than glutathione, imo

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  2. http://www.glutathionescience.com/glutathione_science_029.htm

    art de vany says this GSH is absorbed.

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  3. Emily,

    In placing NAC up at the top of the paleo supplement hierarchy with magnesium, are you suggesting it is generally useful in cases outside of psychiatric disorders?

    What about other substances that can boost glutathione but may not have the potential side-effects of NAC like ALA, cordyceps, milk thistle?

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    1. ALA, milk thistle look good for the liver to me but I'm not sure if they will be quite as dramatic in the CNS as NAC. Other antioxidants that have been examined in autism (vitamin C for example) have had mixed results. Other glutamate blockers or NMDA antagonists (such as d-cycloserine, amantadine, and memantine) have had mixed results or have been ineffective. And I've seen memantine cause some pretty spectacular psychosis in demented patients (anecdotally).

      And I'm not suggesting everyone chug some NAC by any means (though I am very fond of the idea of putting magnesium back in the water, as it were ;-) The long-lived healthy folks in the blue zones don't take NAC. I'm fond of the idea of NAC in these devastating illnesses with no cures and caustic symptom relievers (such as antipsychotics) because it seems a decent balance of risks and benefits (and keeping in mind that NAC is still an experimental treatment.) I'm also fond of the idea of taking some NAC with tylenol if you need it for pain relief. That seems like a low risk, possibly high reward maneuver to me but as far as I know, not tested.

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    2. Emily,

      Your account of people suffering from psychosis as a result of an NMDA antagonist really disturbs me. I believe I would benefit from lowering my glutamate, but after reading about the "dissociative anesthetic Ketamine" (which I guess is an NMDA antagonist) and now even these other prescribes NMDA antagonists, it makes me nervous to supplement with Magnesium for my OCD.

      My fear is based on the fact that I have had a few circumstances in my life, once smoking weed, and another time after taking a caffeine pill where I felt I was pretty close to psychotic. I had panic attacks during those times, but it felt like more than that as well. As you can tell I fear losing my sanity from taking the wrong thing. My question is, is it the NMDA antagonist property that causes this psychosis? Is there reason to worry about all NMDA antagonists as they all may have this "dissociative" property about them (even magnesium in high doses)? Why is it that Schizophrenics could benefit from glutamate inhibition yet suffer psychosis from the NMDA inhibition (from ketamine, or Memantine apparently as well) that allows the inhibition?
      Please fill me in if you know anything about this! Your post completely turned me away from Memantine as I feel I am a sensitive individual and need a 100 percent garuntee that I won't have problems with what I take.

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    3. Peter, dissociatives like Ketamine induce psychosis for a number of reasons that extend beyond their effect on NMDA antagonism. They also block NMDA competitively, meaning that they lower NMDA below healthy levels. NMDA antagonists like Memantine and Magnesium will only lower NMDA levels that are overactive.

      Also keep in mind that dissociative type NMDA antagonists will actually raise Glutamatergic transmission. They do so through a unique pathway, but also indirectly by inhibiting NMDA so profoundly that the body in turn tries to increase Glutamate to balance it out.

      In other words, if you need a reliable NMDA antagonist that will not cause the same issues as Ketamine, then Magnesium fits the bill.

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  4. very interesting post. NAC also seems to be recommended for people with the MTHFR polymorphism, and is incorporated into the medication Cerefolin. Any suggestions as to how NAC can benefit this population of people?

    Thanks
    David

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    1. Hmmm. No idea. May be part of the whole holy grail thing linking diabesity to bipolar disorder, etc (keeping in mind that obese mothers are more likely to have autistic kids, it seems, as well). Will have to look into that.

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    2. Emily, do you not know about the MTHFR as it relates to GSH and Austism? And all other methylation issues? I am finding out that I have 2 copies of MTHFR A1298C, so I started NAC..but then I found out I have CBS, which is causing trouble at the top end of the methylation pathway in the sulfuric pathway...meaning I have to avoid sulfur supps and foods for awhile to clear that first before addressing the MTHFR...I'm surprised you didn't mention this? Many autistics have these issues too.

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  5. "Glutathione itself is poorly absorbed as a supplement"

    Random question, do you know whether the delivery mechanism (oral vs transdermal vs other) can make a difference in how glutathione is absorbed?

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    1. I've heard people like TD formulations better, but I have no idea. Again, glutathione itself may not be as important as a ready pool of constituents to make glutathione when and where it is needed. Making glutamate into GABA or glutathione may be part of why NAC is effective. It mops up the excess oxidants and excitatory neurotransmitters simultaneously.

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  6. Here's something related by Chris Masterjohn: http://www.westonaprice.org/blogs/cmasterjohn/2012/04/07/glutathione-101-part-1-cysteine-misbehaves-but-glutathione-saves/

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    1. and the funny thing about that blog is that enormous doses of cysteine are used to *replete* glutathione in the case of tylenol overdose, way higher than any of the supplemental doses, and it can mean the difference between life and death. Interesting.

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    2. Minor addendum: You mention the vomiting gigs in the ER in your PT article - intravenous NAC doses seem to be favoured in Europe, because they cause much less sickness.

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    3. They vomit because it is like eating sulfur. It's absolutely disgusting. Between the charcoal icies, the NG tubes, and (if tylenol) the NAC, ODers have a pretty unpleasant ER experience. The pill formulations can be made so they do not have the taste or smell, though I'm told some formulations are more successful at this mask than others. I'm not sure why IV NAC has not caught on as much in the US. Perhaps cost or tradition.

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    4. Tradition probably; after all, having to repeat the treatment because the last dose landed on the floor isn't cheap either...
      A bit like St John's Wort: You'll find it next to the Magnesium tablets here; no big deal.

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  7. Nice post.

    Since I've had for a long time (since I can remember) a somatoform disorder that creates physical disconfort associated with anxiety and depression (it's more or less under control with medication), do you think NAC and magnesium can help? Because basically nothing seems to help a lot, be it therapy, diet, exercise, medication (maybe the best but sometimes has some problematic secundary effects)...

    Thanks I would really appreciate if you could comment on this

    Gonçalo from Portugal

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    1. Health anxiety/somatoform has many similarities to OCD and has been studied as such. There is an ongoing trial of NAC for OCD at Yale. That's all I know.

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  8. I love your article about NAC. I am using it in my practice for resensitise the endorphin receptor (MOR). Together with magnesium sulphate (dermale) it is a wonderfull way to help people with autisme and ADHD. Thank you :)

    LF (Belgium)

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  9. Now glutamic acid decarboxylase uses our old friend manganese, plus B6.
    I started taking NAC for Hep C, found it better than ALA, and rather quickly and painlessly gave up multiple drug habits (not my intention). I think the NAC made this possible, nay, inevitable. I don't take it now.

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  10. Why do you say "eek" to acetaminophen?

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    1. acetaminophen very quickly demolishes glutathione stores in the body. Definitely in the liver, definitely in the airways, probably in the brain and kidneys and everywhere else.

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  11. NAC prevents cocaine relapse:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661026/

    Glutamate and compulsion in addictions:
    http://psychiatryonline.org/article.aspx?articleid=177693

    Acetyl-carnitine in methadone withdrawal (ALCAR is a GABA agonist)
    http://journals.lww.com/clinicalneuropharm/Abstract/2009/01000/Acetyl_L_Carnitine_in_the_Management_of_Pain.8.aspx

    Milk Thistle as effective as fluoxetine for OCD:
    http://www.naturafoundation.co.uk/?objectID=4031&page=1

    Niacinamide/nicotinamide a GABA (or benzodiazepine) receptor enhancer:
    http://www.sciencedirect.com/science/article/pii/0091305780902361

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  12. I have suffered from severe trichotillomania (compulsive hair-pulling) since age 17. At age 25 I read about a new study that showed more than 50% of trich patients stopped or reduced hair-pulling on moderately high daily doses of NAC (1200mg/day or more). Trich is notoriously hard to treat with anything whether chemical or cognitive or behavioral treament, so more than 50% is a watershed. It takes several weeks of building it up in your system to get the benefits, and it doesn't cure trich alone, but I'm pulling so much less now that I've been taking daily NAC for a couple years. (I take 1800mg in three 600mg doses, with meals.) I can't say enough how much NAC has helped me.

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  13. George, about glutamic acid decarboxylase and manganese - are you thinking of this paper? http://www.ncbi.nlm.nih.gov/pubmed/7264641
    The authors fed manganese to rats for two years expecting it to be toxic, and to their astonishment, they stopped ageing. Their GAD was just as high as in young rats.

    I ask this because I've never come across a report of GAD being activated by Mn. If you have, could you tell me please?

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    1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950338/
      This says GAD is not activated at low levels of Mn.
      Mn for GAD I remember from an old textbook; but Mn is required for glutamate synthesis and GABA degredation as well, so is equal-opportunity.

      Thiamine might be important for glutamate as well - I think this is how Korsakoff's syndrome works (and alcoholic anmesia?)

      "Such decreases in KGDH (ketoglutare dehydrogenase) may explain previous findings of region-selective changes in energy metabolism and of decreased synthesis of glucose-derived neurotransmitters (acetylcholine, GABA, glutamate) in pyrithiamine-treated rat brain. "
      http://www.springerlink.com/content/m112756033343422/

      Now, these are all Mn-dependent neurotransmitters; so is thiamine deficiency also a factor in manganese toxicity and/or deficiency?
      Glutamate and GABA are glucose-derived

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    2. That said, I can't find any reference to MN in GAD online. B6 yes. So maybe the older reference was wrong, or the MN requirement came from glutamate.

      Only this:
      http://www.moyak.com/papers/manganese-enzyme-mineral.html

      Manganese is a cofactor for enzymes involved in hydrolysis, phosphorylation, decarboxylation, and transamination. It also promotes activities of transferases such as glycosyltransferase, and of glutamine synthetase and superoxide dismutase. Manganese helps in the production of enzymes used for metabolism of proteins and fat. It supports the immune system, blood sugar balance and is involved in the production of cellular energy, reproduction and bone growth.

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  14. Autism: The Eusocial Hominid Hypothesis

    ASDs (autism spectrum disorders) are hypothesized as one of many adaptive human cognitive variations that have been maintained in modern populations via multiple genetic and epigenetic mechanisms. Introgression from "archaic" hominids (adapted for less demanding social environments) is conjectured as the source of initial intraspecific heterogeneity because strict inclusive fitness does not adequately model the evolution of distinct, copy-number sensitive phenotypes within a freely reproducing population.

    Evidence is given of divergent encephalization and brain organization in the Neanderthal (including a ~1520 cc cranial capacity, larger than that of modern humans) to explain the origin of the autism subgroup characterized by abnormal brain growth.

    Autism and immune dysfunction are frequently comorbid. This supports an admixture model in light of the recent discovery that MHC alleles (genes linked to immune function, mate selection, neuronal "pruning," etc.) found in most modern human populations come from "archaic" hominids.

    Mitochondrial dysfunction, differential fetal androgen exposure, lung abnormalities, and hypomethylation/CNV due to hybridization are also presented as evidence.

    A short video introduction

    The full 2-hour video presentation

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  15. http://www.ncbi.nlm.nih.gov/pubmed/18466343
    *Ketogenic diet increases mitochondrial glutathione

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  16. Astaxanthin might help with glutamate induced excitotoxicity too (PMID 20828541).

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  17. Nice article. Emily- any advice on dosage, timing in the day, with food?

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  18. I am interested in trying my son on some NAC but I got lost when you talked about something tasting like sulpher, and overdosing on NAC or was it Tylenol. Bottom line is there Sulfer in NAC? Does Magnesium Citrate work or is there another type of magnesium you recommend? What can you tell me about NADH? Thank you your help.

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  19. Very interesting information about NAC.

    ASEA has been shown to increase blood levels of glutathione 800% and SOD 500%. ASEA also increases catalase.

    It provides redox signaling molecules of stabilized sodium and stabilized chloride - something that was thought to be impossible.

    I take NAC as well as ASEA since the NAC might make the glutathione last even longer.

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    1. I am sorry to sound uneducated but what do the acronyms ASEA and SOD stand for please?

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  20. I took 15 days of Levofloxacine, from an antibiotic group called fluoroquinolones, 500mg(one pill per day) for an infection.I was already taking a benzodiazepine called Clonazepam(0.25mg per day) for anxiety and 0.25mg was working just perfect.
    When i started taking Levofloxacine i felt very very anxious,couldnt sleep, had EXTREME panic attacks like 2-3 times a day and i had increased my Clonazepam dose 4 time to 1mg per day(and the benefits from 1mg now are weaker than they were on 0.25 mg prior taking Levofloxacine).
    Its been one month since i took the last pill of Levofloxacine and i feel the same.I had to call the ambulance 3 times.Im acting very strange, im very afraid, im staying in my car almost all day and feel so psychotic.I never felt this way in my life. I read this is due to Levofloxacine binding to GABA/A receptors in the brain but is this going to go away? It's already been a month...


    Wikipedia:
    Fluoroquinolone antibiotics have been noted by Ashton and confirmed elsewhere as increasing the incidence of a serious CNS toxicity from 1 to 4% in the general population, for benzodiazepine-dependent population or in those undergoing withdrawal from them. This is probably the result of their GABA antagonistic effects as they have been found to competitively displace benzodiazepines from benzodiazepine receptor sites. This antagonism can precipitate acute withdrawal symptoms, that can persist for weeks or months before subsiding. The symptoms include depression, anxiety, psychosis, paranoia, severe insomnia, parathesia, tinnitus, hypersensitivity to light and sound, tremors, status epilepticus, suicidal thoughts and suicide attempt. Fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal. NSAIDs have some mild GABA antagonistic properties and animal research indicate that some may even displace benzodiazepines from their binding site. However, NSAIDs taken in combination with fluoroquinolones cause a very significant increase in GABA antagonism, GABA toxicity, seizures, and other severe adverse effects.

    Will this GABA antagonism go away so i can be back on my normal klonopin dosage?

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  21. My son (now 8) has been on NAC for over a year (600mg 3x a day). He has ADHD and Aspergers. NAC has been a life-saver. He used to have uncontrollable rages lasting hours every day that made him so sad because he couldn't help it. Therapies did not help. Homeopathic medicines didn't work. Omegas didn't help. Then we went to prescription medications...trying 6 different ones over the coarse of two years. Some would work but only for a short bit and they all had side effects. Then I did a bunch of research and decided to try NAC. After 3 days he stopped having rages. He still has occasional tantrums but they last a few minutes not hours. He still sees a psychiatrist who agrees it has helped immensely. The only other medication he is on is a low dose of clonidine for hyperactivity.

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    1. Forgot to mention he has MTHFR and growth hormone deficiency as well. Have never found any other child with similar issues.

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  22. Hello,Oltean Sergiu.
    I can relate to your experience, A panic attack is always a scary experience but one triggered by a med is the worst. I had panic attacks triggered by two anti depressants taken at the same time wellbutrin in morning & Efexxor At night.
    I had low energy & my doctor gave me these prescriptions saying I might be depressed. I called the ambulance one night because i was weak & full of fear with tremors. I cannot even describe the terror, the horror of these panic attacks. My life took a spin. I was then put on xanax which helped. but it took almost a year for me to return to a 90% recovery. I feel it was never going to go away. I have faith in God and he helped me though it. In this time of need Jesus Christ proved to be true & real. I can say he is real not by what i read, heard or rationalized, but by the miracle he performed in my life. My body / brain was so sensitive that even supplements as simple as a Pro biotic would spin me into a horrible panic, worse if i took a calming herb like passion flower or B- vitamin complex supplement, one time I drank some aloe vera juice & panic attack! Crazy! I could not understand it. Anything with nutritional value affected me. Weird! I could not treat it with anything natural. Your brain chemistry can really take some time to recover. I was so afraid i would get addicted to Xanax, afraid i would not recover, afraid i get sick & had to take a anti biotic (like one you took) or other med, that would put me over the edge. I developed ulcers. I then let go & left it up to God, I received comfort in prayer, reading the bible, listening & trusting in him and his promises. I would only listen to up lifting music , talk , tv. Thank God he got me through this. A year later I am 95% better and doing some public speaking, something I could never do prior. God is awesome! At times I might feel anxious at times but its part of recovery. So if your are prone to anxiety / panic attacks be careful what you take. Towards the end, the reason for my low energy was my adrenals & testosterone were low. What! My fault for not getting second opinion before I took those meds.Have patience! God is good!

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  23. I'd Like to share my experience about NAC I started taking it just as a supplement 1 tab a day after 4days of taking NAC i certainly felt the difference eye sight from 20/30 to 20/15 feeling happy and good. After 2 weeks of feeling out of this world, TINNITUS hits me like a ton of brick. I have now been suffering the worse case of ringing in my ear for 1 month and i think the soul culprit was the NAC. just sharing

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  24. Um you could prob find anything in SOME children with autism. This sounds more like astrology than science

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  25. I started taking NAC as an experiment to treat my trichotillomania, but stopped because I suspected it was giving me stomach trouble and didn't have any noticeable improvements on my trich. Now, 8 months later, I'm still having stomach issues. I've been diagnosed with Irritable bowel syndrome (IBS) and my symptoms seem to be abnormally high sensory input from the gastric system (e.g. I feel gas, movements, nausea and other input from my stomach stronger than I should). This also includes constipation at times. Cannabis, paradoxically, also seems to potentiate these symptoms. You said that one kid in the study you mentioned got worse, and was later diagnosed with constipation. Could these things somehow be related?

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  26. Look into ASEA. It increases glutathione 800% by increasing the redox signalling molecules, according to research. Taken orally, it contains no drugs.

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  27. Hi Emily,

    Do you think RiboCeine by Max International (D-Ribose L-Cysteine), which is supposed to be more effective at boosting glutathione would also have the same NMDA antagonist properties?

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  28. http://www.metametrix.com/files/learning-center/articles/hypohomocysteinemia.pdf


    Doesn't this suggest that taking less folic acid and B12 would lead to higher innate glutathione levels?

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  29. Hi,
    I am using Nac together with alpha stim and so far it is effective to cure anxiety.However taking too much seems to make you hyper;
    Interesting article here;
    https://www.openminds.com/market-intelligence/executive-briefings/peeesumner.htm
    Could I mix it safely with L theanine?

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  30. Do you know a good place to purchase N-acetylcysteine that you find to be a reputable source?

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  31. I am trying to get to the bottom of the question: if someone has poor sulfuration pathways, will NAC be an issue for them at all? Thanks.

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