Welcome to my blog, a place to explore and learn about the experience of running a psychiatric practice. I post about things that I find useful to know or think about. So, enjoy, and let me know what you think.

Friday, May 6, 2016


I've been hearing a lot about N-Acetylcysteine (NAC) in the treatment of psychiatric disorders, so I thought it would be worth looking into.

A 2015 systematic review in Neuroscience and Biobehavioral Reviews has the following abstract:

N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.

I'm not sure how they drew their conclusions. They have a rating system called, Grade of Recommendation (GOR), from A-best, to D-worst, and N-no studies identified. They also state, at least for some disorders, whether they recommend NAC for treatment, from Yes to No, with Mixed in between.

They found only 1 GOR of A, for Bipolar disorder, and even that they recommended as Mixed.

The B/Mixed were:

Depressive Disorder
Impulse Control-Trichotillomania


-In one study of NAC in treating and preventing symptoms during the maintenance phase of Bipolar Disorder, when compared to placebo, the NAC group demonstrated a significant improvement on the Montgomery–Asberg Depression Scale (MADRS), Bipolar Depression Rating Scale (BDRS).

-Cannabis-dependent adolescents and young adults given NAC and counseling had significantly fewer positive urine cannabinoid tests than those given placebo and counseling.

-There may or may not have been a reduction in cravings for Cocaine.

-Children with Autism had less irritability.

-A large randomized controlled trial in individuals with major depressive disorder (MDD) and MADRS score ≥ 18 showed improvement in multiple outcome measures – in the NAC group when compared to placebo add on treatment to usual treatment for 12 weeks.

-In a medium sized trial, significant improvements were found on the Massachusetts General Hospital Hair Pulling Scale, the Psychiatric Institute Trichotillomania Scale and the CGI in participants who received NAC as compared to the placebo group.

- I can't figure out from the paper what NAC did for patients with Schizophrenia.

Everything else was worse.

However, NAC was pretty well-tolerated, with no serious side effects, so it's probably worth a try in conditions not responding well to other treatments. At least, I think that's their conclusion. Also, other than the IV form used in acetaminophen overdose, and the Sub-Q form used in ALS studies, NAC is sold over the counter as an oral medication, with doses ranging from 2-2.4g/day.

Posited mechanisms of action for NAC include effects on:

Oxidative Stress
Mitochondrial Dysfunction
Inflammatory Mediators
Glutamate Neurotransmission
Long Term Neuroadaptation
Dopamine Neurotransmission
Serotonergic Neurotransmission

Check out this visual:


To get into a little more clinical nitty-gritty, there are a number of trials posted on clinicaltrials.gov, most without results.

One that did have results looked at NAC in alcohol dependence, with the primary outcome  measure Alcohol consumption in percentage of heavy drinking days:

No statistical analysis was provided.

Another was NAC in pediatric trichotillomania:

Again, no statistical analysis.

However, when I plug the raw data into 1 Boring Old Man's table,  (see also DIY Study Evaluation) I get:

The trichotillomania study had a p value of 0.185, a Cohen's D effect size of 0.433, and a 95% CI of -0.202 to 1.068 (In case it's too hard to read). So there's no statistically significant difference.

The Alcohol study's data was weird, with no calculable p value, and negative Cohen's D's, so then I tried change in means, which was negative, and that got p=0.533; Cohen's D=0.190; CI (-0.403-0.782). I'm not sure if that's a legitimate calculation on my part.

Basically, the numbers are bad, and I only decided to include the spreadsheet as practice at evaluating a study.

So now I ask myself, "Would I prescribe or recommend NAC?" Based on this post, I'd have to say maybe. I'd probably stick to the conditions I listed above. Maybe I'd use it as an add-on for depressive symptoms in between bipolar episodes, or in unipolar depressed patients stable on medication but with some residual symptoms. I might suggest it to patients trying to stop using cannabis or cocaine. I don't treat children, but I think if I did, I'd feel more comfortable prescribing NAC for irritability than risperdal. If I ever had a patient with trichotillomania, I'd be willing to try it. And maybe as an adjunct for anxiety or something in schizophrenia.

The bottom line is probably that it won't hurt, and it might help.

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