NAC for Schizophrenia
Dec 26, 2015
Jacob Schor ND, FABNO
Several recent studies suggest that n-acetyl-cysteine (NAC) taken orally may provide benefit to people suffering from schizophrenia. One of these studies, Rapado-Castro et al, published in March 2015 reported intriguing findings. The longer a patient has suffered from schizophrenia, the more NAC appears to help them. Data analyzed in this paper actually came from a randomized clinical trial that was published in 2008. This time the data was analyzed to see if duration of illness influenced degree of benefit.
In the initial 2008 study 121 participants were randomized in a double fashion to 24 weeks (placebo=62; NAC=59). Participants had been previously diagnosed with schizophrenia. Participants took 500 mg of NAC per day, 200 mcg of selenium per day, or 500 IU of Vitamin E per day. The subjects treated with NAC improved more than placebo-treated subjects over the study period. Effect sizes at end point were consistent with moderate benefits.
This new Rapado-Castro paper found a significant interaction between duration of the illness and response to treatment. The longer a patient had been ill, the stronger the positive response to the NAC, that is, the better NAC worked.
These changes were not what the investigators had predicted. Their assumption was that NAC impact would be greater in patients with more recent disease onset. The results were the opposite, the longer the history of illness, the greater the response.
The response was much greater in those participants with a 20 or more history of illness than in participants with a shorter history. NAC may be more useful in those with more chronic disease than acute illness. [I realize I’m repeating this over and over. These results are so surprising I think I need to repeat myself so this sinks in.]
About 1.1% of the general population suffers from schizophrenia  but it is long known that schizophrenia runs in families. Risk of the disease increases to 10% of people who have a first-degree relative with schizophrenia and for an identical twin of a person with schizophrenia, the risk increases to 40-65%. 
NAC is derived from the amino acid cysteine and is widely available over-the-counter as a nutritional supplement promoted for its antioxidant properties. NAC is well tolerated and safe; it has been widely used internationally for decades.  NAC is used to antidote acetaminophen overdose and has been approved for this purpose by the FDA since 1985, given either orally or by IV.
NAC is also used as a mucolytic agent in chronic obstructive pulmonary disease  and cystic fibrosis , to protect the kidneys from damage from the contrast-agents used in imaging studies  and as a preventive agent for atrial fibrillation. NAC can be used to prevent and treat seasonal influenza virus infection.
There has been growing evidence over the past ten years that NAC is also useful in treating psychiatric and neurological disorders; it appears to moderate pathophysiological processes that are involved in a range of psychiatric and neurological disorders, including oxidative stress, neurogenesis and apoptosis, mitochondrial dysfunction, neuroinflammation and dysregulation of glutamate and dopamine.  NAC reverses the neuroadaptation and metaplasticity induced by cocaine addiction. The neuroadaptation theory of addiction suggests that exposure to drugs of abuse induces adaptive molecular and cellular changes in the brain that mediate addiction-related memories. Compared to other types of memories, addiction-related memories develop fast and last extremely long; the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. 
In the last few years numerous reports have been published on using NAC to treat a range of psychiatric or neurological conditions including schizophrenia, bipolar disorder, skin picking, trichotillomania, obsessive-compulsive disorder, autism and addiction to nicotine, cannabis, cocaine, methamphetamine, gambling  as well as epilepsy, amyotrophic lateral sclerosis, neuropathy and traumatic brain injury.
In a systematic review of NAC use in psychiatry and neurology published in August 2015, Deepmala et al evaluated and graded the level of evidence for the use of NAC in treating psychiatric and neurological disorders as it stood at the time. For now Deepmala’s paper and in particular the summary tables should stand as our go to reference in these matters. The amount of NAC used in these trials was usually from 2.0 to 2.4 grams of NAC per day administered orally divided into two doses.
For those of us trained in naturopathic medicine back when NAC was used solely as a mucolytic agent, this new range of applications is quite fascinating.
This current paper by Rapado-Castro now suggests NAC may be of even greater utility after long-term psychiatric debility. This is even more fascinating as NAC may provide benefit in conditions that we once might have thought too long standing and too deeply ingrained to be ameliorated.
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