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N-acetyl cysteine (NAC)
(updated 1/2010)

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 one chemical step away from a normal body molecule, so there is some reason to think that at normal doses it 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?
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

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

Other health claims
Some other possible benefits less relevant to mental health:  NAC has been claimed or shown to lower the rates of viral infections, treat fluid in the ear, lower heart disease risk by lowering homocysteine, improve insulin sensitivity, decrease infections in lung diseases, and help prevent kidney stones. (references, such as they exist for these claims)

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. 

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 not a completely new idea, though.  A 6 month study in diabetes reported no concerns about long-term risk.Martina  NAC has also been used as ongoing treatment for cystic fibrosis. One study looked specifically at the safety of using 2.8 grams per day for 12 weeks; no major concerns emerged in this research.Dauletbayev 2009 Of course a much longer study would be helpful. 

There are reports of depleting Vit C and trace minerals, and warnings about NAC being contraindicated in established kidney disease. None of these concern seem to be substantiated in the literature I've reviewed on safety, but I could have missed something.  The Epocrates database for medications does not list kidney issues as a contraindication. See more on trace metals, including copper, at the bottom of this page if you're concerned. 

How is it used? (doses and such)
The Australian research team studying bipolar depressionBerk 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. 

 [Update 2/2010: best deal I can find lately -- Puritan.com, 5 bottles of 600 mg capsules, #120 each bottle (so each bottle contains a month's worth), for $50 and free shipping. That's $10/month. See their NAC page and look for the 5 bottle deal (Buy 2, get 3 free) at the bottom]

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. 

 

Ultra-fine-tooth-comb details on safety (not for the average reader, in my view):

Copper
The drugs.com page on NAC lists a potential to deplete copper over time. No reference. Where did this idea come from?  Searching PUB MED,  acetylcysteine copper, one has to go back over 100 references to 1990 for the first reference to trace mineral depletion. When this was investigated experimentally, looking for increased excretion in patients taking NAC,  no increase was found.Hjortso The authors concluded that no supplementation with trace medals was required when NAC was used in an ongoing treatment.

Why did they even look? The only other remotely relevant reference I can find is three years earlier (search PUB MED acetylcysteine trace metals). In this earlier study, the question was whether a "chelation effect" (grabbing metal ions and pulling them out of the body, for the treatment of metal overexposure) was any greater for lead or mercury or other heavy metals.Ottenwalder

In other words, NAC has been studied for use as a means of treating heavy metal exposure. If it works to pull those metals out, maybe with long-term use it could pull out other body metals, like copper or zinc (which our bodies contain in very small amounts)? 

Looks like this was the logic of another practitioner, who provides more references generally but none on this question (i.e. logical concern, no data; Monroe St. Clinic). How reassured should we be by the "no increased excretion under normal circumstances" Hjortso paper? Not clear yet.