Problems? I Have a NAC for That

In the comments of the Depression and Leaky Gut post, Tony Mach mentioned an interesting amino acid called N-acetylcysteine (we'll shorten that to NAC) and put up a link to the Wikipedia page "describing its wonders." I'd heard of NAC before, of course, as the punishment/savior for people who show up in the ER having overdosed on that most disgusting of things to overdose on, acetaminophen (Tylenol, or paracetamol). If you decide to down a whole bottle (or far, far less with alcohol - even the upper limits of a normal daily dose can damage your liver when combined with alcohol), you might feel sick immediately, but then perhaps recover and think nothing of it - until a few days later, when the accumulated killing of hepatocytes and rotten liver make you very very ill, and nothing short of a liver transplant will save you. Failing that, you die a rather horrible death. Livers are vital, we have no substitutes, no bypass machines, mechanical livers, or liver-like dialysis machines. Apparently there are 56,000 ER visits a year from tylenol overdoses in the US, and 100 deaths.

Well, if someone shows up with a tylenol OD to the ER, you get a level 4 or more hours post-ingestion, and plot the level and hours post-ingestion on a handy graph. Above the dark line on the graph? Welcome to the world of N-acetylcyteine, a disgusting compound typically administered with fruit juice, but still makes some people vomit. You give a loading dose of 150mg/kg followed by 70 mg/kg for 17 more doses. If you can't keep down the dose, it has to be repeated. During this time is when the psychiatrist is typically called to the ER to figure out whether it is safe to let the person go, or if it was a serious suicide attempt in need of further intervention. It is surprisingly easy to overdose on tylenol accidently, as acetaminophen is in a zillion over the counter medicines, plus perscription painkillers percocet and vicodin, etc. 4000 mg a day is the upper limit of "safe" (without alcohol) - you can get acute liver failure with as little as 7800 mg if you are unlucky.

The treatment is as simple as it is magical - possible fuliminant liver failure on one side, skipping out of the hospital doing just fine on the other. And the treatment has everything to do with the body's master antioxidant, glutathione. Seems that a metabolite of tylenol, NAPQI, kills liver cells like gangbusters. Glutathione can bind to it and render it harmless, but once you run out of glutathione, the leftover NAPQI does its nasty job. That's where N-acetylcysteine (NAC) comes in - it is a ready precursor to glutathione, so your liver can have a bountiful supply to fight off the NAPQI.

Well, have a look at the Wikipedia article. NAC is not only the treatment for mucus build-up in cystic fibrosis, but also acetaminophen overdose, perhaps to reduce the kidney toxicity of contrast dye (though that doesn't seem to be holding up), in interstitial lung disease, and investigationally in reduction of noise-induced hearing loss, lessening the destruction of pancreatic beta cells, curing a hangover, and decreasing symptoms of the flu. But of course I don't care about all that. As a specialist I am required by medical convention to stick to the brain and keep my little nose out of other parts of the body... but NAC has some interesting properties in the noggin as well.

As usual it all goes back to glutamate, the excitatory neurotransmitter of doom. In short, having too much glutamate around is to your neurons rather like whipping your horse to go and go and go until you kill it. Horses and brains need time at pasture, chilling out and eating appropriate foods, and sometimes a nice rubdown and brushing. Well, NAC seems to be able to get into some tricky areas of the brain and do some amazing management of glutamate. Over the past few years, a number of intriguing studies have come out using NAC alone or as adjunct treatment for some difficult psychiatric conditions. Some of these were decent multicenter randomized controlled trials. The real deal.

These tricky conditions? Trichotillomania (compulsive hair-pulling, which is both common and exceptionally difficult to treat - several decades of research has come up with nothing as effective as the NAC trial!). Schizophrenia. Bipolar Depression (another very difficult and disabling condition that doesn't respond particularly well to therapy or medicine). And there is an ongoing study on OCD. The studies vary between 2000-4800mg daily of the capsules (I'm assuming these are better tolerated than the emergency room drink), and in most of the studies, there were more adverse events and side effects in the placebo arm than in the treatment arm. Many of the studies were as long as 6 months, which is a lifetime for randomized controlled clinical trials, and all of the studies had positive effects. That is pretty astounding, considering how pharmaceutical companies have no doubt spent millions and millions chasing down bipolar depression, for example, without much to show for it (there's quetiapine, fluoxetine, and olanzapine+fluoxetine with modest effects). Another cute little study used NAC to reduce cocaine cravings - again, something for which there is really no effective FDA-approved medical treatment.

Why would a precursor for the master antioxidant have anything to do with glutamate in the brain? The mechanism is sort of hysterically complicated, so I'll quote the trichotillomania paper for fun:

[NAC] is a hepatoprotective antioxidant that is converted to cysteine, a substrate for the glutamate-cysteine antiporter. This antiporter allows for the uptake of cysteine, which causes the reverse transport of glutamate into the extracellular space, which stimulates inhibitory metabotropic glutamate receptors and, thereby, reduces synaptic release of glutamate. The restoration of the extracellular glutamate concentration in the nucleus accumbens seems to block reinstitution of compulsive behaviors.

Translating the sciencespeak: NAC helps excess (and toxic) glutamate stop being at the wrong place at the wrong time. It helps us put that brain out to pasture for some rest and recovery.

What are the downsides of NAC? I can think of two problems that might be biggies - first off, NAC is a mucolytic that thins mucus by cutting disulfide bonds. I suspect that might raise risks - one wouldn't want too little mucus. Mucus is important. Paul Jaminet mentions this issue and links a study here. Also, cutting disulfide bridges within the body is what that inflammatory baddie homocysteine is supposed to do, leading to crispy collagen and inelastic elastin in the arteries (which would possibly first show up as high blood pressure).

Of course, no hunter gatherer was chugging 2 grams of NAC daily. It's not evolutionary psychiatry. But it does seem to have the potential to replicate, perhaps with some downsides, the natural brain glutamate situation of a lower-stress life with plenty of appropriate minerals and micronutrients. Hey, maybe even absence of tons of carbs on top of an inflammatory rodent diet. Or some ketosis. We live a modern life - some brains are already tracking in the wrong direction. It would certainly be worth studying NAC further so we have more information, and, in my view, in intractable or otherwise untreatable conditions that significantly impair functioning, giving it a try.