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N-acetyl cysteine (NAC)
(updated 11/2009)

Bottom line: here is a potential new tool for the treatment of bipolar depression. We have only a single research study to go on, but that was a well-designed placebo-controlled trial.^Berk And the stuff is cheap. And it is only chemical step away from a normal body molecule, so there is some reason to think that at normal doses t might turn out to be safe -- it's not entirely foreign. However, don't get too excited yet. Let's see how this turns out in a year or two.

In the meantime, it's something I'm beginning to explore using in treatment. Just beginning.  The research study came out in Sept 2008...

• What is n-acetyl cysteine?
• Who can benefit?
• How does it work? 
• How safe is it?
• How is it used? (doses and such)

What is n-acetyl cysteine?
Short Answer:  it is an easy way to deliver an amino acid called cysteine, which otherwise does not easily reach brain cells. Cysteine has two potential ways of working. In some research studies, it was used for one reason but may have actually worked through the other!  

At this point, it's not clear exactly how the stuff is helping, when it does; but it seems clearly more than a placebo. 

Who can benefit? 
This simple molecule has been studied and shown to be better than a placebo for the treatment of

• bipolar depression^Berk  
• compulsive hair-pulling ("trichotillomania")^Grant 
• cocaine craving^LaRowe
• cigarette smoking (decrease use but not craving)^Knackstead 

and preliminary evidence (not studied yet against placebo, or in humans) for

• compulsive nail-biting^Berk
• reversing the brain changes induced by cocaine (in rats, anyway)^{Moussawi, Madayag}

How does it work? 

Long Answer (this gets really complicated. These are my working notes. Skip on down the page unless you're really interested!) Mechanism #2 is starting to look to me like the important one. 

Mechanism 1. Cysteine is an important ingredient, the limiting one in fact, for the creation of glutathione. Glutathione is an "anti-oxidant", one of the primary ones. These molecules clean up chemical debris in cells, to oversimplify quite a bit.  Research suggests that people with depression have too little glutathione.  Using NAC is really just a way to try to raise the glutathione levels.

Glutathione (GSH, L-gamma-glutamyl-L-cysteinylglycine) is the predominant anti-oxidant in the cytoplasm of cells. Virtually all cells require glutathione for viability and function. Glutathione is synthesized from three amino acids in a two-step process, beginning with the combination of glutamic acid & cysteine and ending with the addition of glycine. The liver & lungs are the primary sites of glutathione synthesis. Glycine & glutamic acid are plentiful in cells, so it is the availability of cysteine that controls the reaction rate.

Mechanism 2.  Another amino acid, glutamate, acts as a neurotransmitter (serotonin is another neurotransmitter you are probably more familiar with). Too much glutamate activity is not good, and that may be part of the problem in mood and anxiety disorders. Well, it turns out that cysteine can lower the amount of glutamate stimulation getting through to some neurons.  It does so through a close relationship with glutamate, in in which it affects the balance between the two amino acids in brain neurons (I know, that was really vague. But this "co-transport" story is even more complicated, and I cannot really explain it well, yet). Changing cysteine levels can change this cysteine/glutamate balance -- to the good, it appears, for people with mood and anxiety problems. 

How safe is it?
A review of safety issues was recently published (2009). 

Bottom line: oral acetylcysteine looks pretty safe when used in the doses studied for mood and compulsive behaviors.  Nothing is completely safe, of course; there are "rare" cases of severe allergic reactions with the oral approach used here, but no deaths (how rare? not clear, but looks extremely rare). However, it may affect blood coagulation. If you're taking it, make sure to tell your doctor, especially any surgeon or anesthesiologist heading in your direction. 

There are reports of depleting Vit C and trace minerals. I haven't run these reports to ground. If anybody finds the source, please let me know (jimp@psycheducation.org). Likewise warnings re: contraindicated in kidney disease. 

In reading the 2009 reference above, it's really hard to sort out oral from intravenous NAC, but it sure looks like nearly all the trouble occurred with the IV form. That means we're still a bit in the dark regarding safety of the oral form, as the focus has been on the IV form for years. Ongoing oral NAC is a completely new idea. 

How is it used? (doses and such)
The Australian research team studying bipolar depression^Berk used 1 gram twice a day, in addition to whatever else patients were taking. In other words, this was an "add-on" study, not a test of NAC by itself. One fellow has already written me saying he's convinced that adding NAC has helped him (thanks for the heads up, Sean).  He's taking 600 in the morning and 1200 in the evening. Says it doesn't smell good but doesn't taste too bad. He buys it for about $12 / month using a GNC brand. 

I just looked around and found an average internet cost, for 1800 grams daily, around $15 per month with shipping if you're crafty about the available deals. 

However, it is also available by prescription, as a generic, so for many people that's more like $5 a month (although the actual cost to the medical care system is $67 in my local pharmacy), but unfortunately this version is a liquid that must be mixed twice a day in a strong-tasting liquid, e.g. orange juice or diet soda, because it smells and tastes bad.