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