successful completion of the questions at the end of this paper has been approved for continuing education by the bddt-n; 1.0 credit nutritional medicine and by the cnpbc; one ce hour.
Colin MacLeod, ND
Kinesis Health Associates
164-166 Ochterloney St.
Dartmouth, Nova Scotia, Canada
NAC at high oral or intravenous doses is the gold standard treatment for acetaminophen toxicity. NAC antidotes acetaminophen poisoning by repleting glutathione stores and as a result mitigates liver damage. NAC exerts its therapeutic action through glutathione repletion, as well as glutamate modulation and mucous thinning in treating other health conditions. Recently data has surfaced supporting NAC as an effective treatment for a variety of health conditions, including non-acetaminophen-induced acute liver failure, COPD, flu prevention, idiopathic pulmonary fibrosis, acute renal failure due to contrast media, schizophrenia, bipolar disorder, autism, grooming disorders, obsessive compulsive disorder, addiction and angina. Adverse effects of NAC by the oral route are mild at low doses and exclusively gastrointestinal, while IV NAC can lead to anaphylactic reactions, including pruritus, rash, tachycardia, hypotension, bronchospasm and syncope. Care should be taken with concomitant treatment with nitrates and NAC, due to NAC’s potentiating effect on nitrates. It is evident from the published data that NAC is a safe and valuable clinical tool, useful for treating a wide variety of health conditions. 
Introduction
Although widely accepted as the primary antidote to acetaminophen overdose and as a mucolytic agent, N-acetyl-cysteine (NAC) has a variety of clinical applications, some of which have only recently come to light. Cysteine is a non-essential amino acid that is found mostly in animal products. NAC is essentially cysteine with an acetyl group attached. This acetyl group limits digestive degradation and promotes absorption. NAC powder has a white colour and dissolves clear to slightly purple in water. NAC has a sulphur-like odour and unpleasant taste which makes high oral doses challenging to administer.
Standard Dosing
NAC is commonly available without prescription in 500mg or 600mg capsules. NAC is also available at 200mg/ml solution for oral and intravenous use in the treatment of acetaminophen overdose and as a mucolytic in pulmonary conditions with excessive mucous. Dosing of NAC is condition specific and has been best established in the treatment of acetaminophen toxicity.
In the treatment of acetaminophen toxicity in adults, the oral dose of NAC is 1,330 mg/kg (93,100 mg in 70 kg individual) in 18 doses spread over three days: a loading dose of 140 mg/kg followed by 17 doses of 70 mg/kg every four hours (Prescott 2005). The intravenous dose is 300 mg/kg (21,000 mg in 70 kg individual) divided into three separate IV bag drips over 21hours: a loading dose of 150mg/kgin5%dextroseis given over a 15-minute period, followed by 50 mg/kg in four hours and 100 mg/kg in 16 hours, for a total dose of 300 mg/kg in 20 and one quarter hours (Prescott 2005). The intravenous route is used in Canada, Europe and Australia, whereas the oral route is used in the United States.
Liver damage is prevented most effectively when treatment is administered orally (Smilkstein 1988) or intravenously (Whyte 2007) within eight hours of the acetaminophen overdose. However, treatment should not be denied up to 24 hours after poisoning as there is still life-saving potential (Prescott 2005). Most conditions experimentally treated with NAC have used considerably smaller doses than that used for acetaminophen toxicity. Limited data exists on the efficacy and safety of nebulized NAC.
Pharmacokinetics
When 600mg of NAC was administered orally to healthy human volunteers, 6.4-10% was absorbed into the bloodstream intact (Borgström 1986). In an animal model, it has been found that low oral bio-availability is due, in part, to de-acetylation and conversion to other sulphur-containing compounds within the digestive tract, but that a significant amount of NAC reaches the blood as other-sulphur containing compounds (Cotgreave 1987).
The half-life of NAC in healthy adults has been reported differently by different investigators, including 2.27 hours (Borgström 1986) and 5.7 hours (Prescott 1989) for the intravenous route, and 3.7 hours for the oral route (Nolin 2010). The newborn half-life of NAC has been reported to be between 7.8 and 15.2 hours when administered intravenously, but depends largely on weight and gestational age (Ahola 1999). The half-life of NAC is significantly longer when given orally to patients with end-stage renal disease (Nolin 2010), or chronic liver disease (Jones 1997).
Pregnant women with acetaminophen poisoning should be treated with a standard high-dose oral NAC protocol due to its life-saving potential for the mother and fetus (Riggs 1989). If NAC is given to a pregnant woman in high oral or intravenous doses placental transfer will occur (Horowitz 1997). Minimal data exists on the safety and efficacy of IV NAC in pregnant women for treatment of acetaminophen toxicity.
Mechanism of Action
NAC is believed to act through three major mechanisms: providing glutamate for neurotransmission, providing cysteine for the synthesis of glutathione, and cleaving disulphide bonds present in mucous.
Glutathione, the most ubiquitous endogenous antioxidant is composed of three major amino acids: glutamate, glycine and cysteine. Of its three components, cysteine supply is the rate limiting step in glutathione production (Lu 2012, Radtke 2012). Some of the therapeutic effects of NAC have been attributed to its ability to provide glutathione, including in pulmonary conditions and hepatic injury. NAC does not seem to increase plasma glutathione in healthy human controls but will increase plasma glutathione in humans who have depressed glutathione stores from oral acetaminophen dosing (Burgunder 1989).
The activity of NAC in psychiatric conditions has been postulated to be due to its ability to provide glutamate for neurotransmission and in restoring brain glutathione. Altered glutamate status has been reported to be an important factor in psychiatric conditions with an addictive or compulsive component (Dean 2011). NAC’s structure also includes a free sulphhydryl (-SH) group which is thought to act on the relatively weak disulphide bonds within mucous to break it into smaller, less viscous segments which can be more easily cleared.
Clinical Indications
Acetaminophen Toxicity
NAC has been used for over 30 years as an antidote to acetaminophen toxicity (Scalley 1978). NAC’s remarkable efficacy as an acetaminophen antidote can be seen in observational evidence where a delay of NAC administration of even a few hours can be the difference between full recovery and liver failure (Smilkstein 1988). NAC’s ability to replete glutathione is the mechanism by which it antidotes acetaminophen toxicity.
Non-Acetaminophen-Induced Acute Hepatic Failure NAC has proven to be helpful in increasing survival in hepatitis- and drug-induced liver failure at high oral (Mumtaz 2009, Sotelo 2009) and intravenous (Kortsalioudaki 2008, Lee 2009) doses similar to those used in acetaminophen toxicity. Kortsalioudaki found that intravenous NAC administered to children with non-acetominophen acute liver failure resulted in shorter length of hospital stay, higher incidence ofnativeliverrecoverywithouttransplantation,and better survival after transplantation (2008). Much smalleroraldosesof600mg/dayhavebeenassociated with no change in duration of hospitalization compared to controls (Gunduz 2003).
High-dose NAC is a promising treatment in drug- or hepatitis-induced acute hepatic failure. Although no firm dosing schedule can be identified, an oral or intravenous protocol similar to that used in acetaminophen toxicity should be considered due to the increased survival evidenced in four human trials (Mumtaz 2009, Sotelo 2009, Kortsalioudaki 2008, Gunduz2003).
Chronic Obstructive Pulmonary Disease
Several studies have been performed on the effectiveness of NAC for Chronic Obstructive Pulmonary Disease (COPD) using oral doses of 600- 1200mg/day. Some studies (Hansen 1994, Pela 1999, Stav 2009, Völkl 1992, Zuin 2005) though not all (Black 2004, Decramer 2005, Lukas 2005, Schermer 2009) found that use of NAC in addition to conventional treatments is more effective in the management of COPD related symptoms compared to conventional treatment alone. In addition, several trials report improvements in specific measurements of lung function, including FEV1, inspiratory capacity (IC), and functional residual capacity (FRC) (Decramer 2005, Pela 1999, Stav 2009).
It should be noted that although many of the trials utilize FEV1 as the primary measure of effectiveness, failure to show benefit on this outcome should not be strictly interpreted as a failure of treatment success. Stav et al point out that although FEV1 is used to classify disease severity and is a good predictor of COPD mortality, it is a “poor predictor of clinical symptoms, exercise tolerance, and response to bronchodilators in COPD” (2009). Furthermore, COPD is characterized by “disease changes at the level of small airways, which is not usually expressed by the measurement of FEV1… IC [inspiratory capacity], however, is a lung volume measure that has been found to correlate well with patient dyspnea and exercise tolerance (2009). For instance, reduced IC during exercise correlated well with dynamic hyperinflation (Stav 2009). Some trials have shown small but significant improvements in FEV1 associated with NAC treatment (Pela 1999, Völkl 1992, Zuin 2005), while others have not (Decramer 2005).
The BRONCUS trial was a large (N=523), high quality trial showing no effect of 600mg NAC compared with placebo on the maximal forced expiratory volume in one second (FEV1) and prevention of COPD exacerbations (primary outcomes) when given over a three year period (Decramer 2005). However, a significant reduction in the functional residual capacity (FRC), the volume remaining in the lungs at the end of passive expiration, was seen in the NAC group on secondary analysis: FRC decreased from 4·46L to 4·09L in patients assigned to NAC, p<0.0001 (Decramer 2005). Other trials have also noted improvements in other measures of lung function associated with air trapping, including IC and FVC (Stav 2009). Considering its negligible adverse effects, low cost, and data showing benefit on measures of lung function associated with air trapping, NAC deserves to be considered as an adjunctive treatment option in COPD at oral doses of 600-1200mg/day.
Flu Prevention
One large (N=262), high-quality trial has been performed on the effect of NAC on influenza. Elderly patients were treated prophylactically for six months during flu season with oral NAC at 600mg twice daily or placebo. Although influenza infection rates were not different between treatment and placebo groups, influenza-like episodes, symptom severity and length of time confined to bed in the NAC group were significantly lower. The NAC group was also found to have a significant immune stimulation as compared to baseline and compared to the placebo group, as measured through anergy (De Flora 1997).
Idiopathic Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis (IPF) is a condition of unknown etiology which is characterized by scarring of the lungs and most commonly affects people 50-70 years of age. One randomized, double-blind placebo- controlled trial (N=182) administered NAC orally at 600mg three times daily as an add-on to standard treatment in patients with IPF. The NAC group had significantly slowed deterioration of lung vital capacity (VC) and diffusion capacity compared to the placebo group (Demedts 2005). Conversely, data on nebulized NAC suggests that it does not improve outcomes in IPF (Bando 2010, Tomioka 2005) and may even lead to acute exacerbations (Bando 2010). On considering these trials, oral NAC at 600mg three times daily should be considered as an add-on to standard medical treatment for IPF. (Tramadol)
Renal Protection from X-ray Contrast Media
Contrast media used during radiographic examination can cause nephropathy and acute renal failure. Risk factors for contrast-induced nephropathy include compromised kidney function, diabetes and reduced intravascular volume. Numerous clinical trials have been conducted over the past decade on prevention of acute renal failure with most using oral doses of 600mg NAC twice daily on the day before and the day of contrast media administration. As a whole the results have been mixed with some studies showing benefit from NAC (Briguori 2011, Koc 2012, Sar 2010) and others showing no effect (Anderson 2011, Gurm 2012, Jaffery 2012).
As is the case with COPD, the evidence is equivocal, but the intervention has negligible adverse effects and the cost is low. With this in mind, oral NAC at 600mg twice daily on the day before and the day of contrast media administration should be considered for patients with compromised kidney function as an add-on to standard treatment for prevention of acute kidney failure.
Nitrate-treated Angina
Sulfhydryls seem to be fundamental to nitrate- induced vasodilation (Mehra 1994). Data also suggests that in angina patients receiving nitrates, NAC given orally may lead to a significant decrease in ischemic effects as assessed by ECG (Boesgaard 1991), myocardial infarction rates (Ardissino 1997), angina symptoms and death rates (Ardissino 1997). Oral dosages in this setting have ranged from 1800- 2400 mg per day in divided doses (Ardissino 1997, Boesgaard 1991). NAC given intravenously may lead to a decreased tolerance to nitrates (Boesgaard 1992, Pizzulli 1997) and a decreased rate of myocardial infarction (Horowitz 1988) in nitrate- treated angina patients. However, not all trials have shown that NAC is of benefit, when given orally (Hogan 1990) or intravenously (Parker 1987).
Considerable care must be taken when giving NAC to nitrate-treated patients orally (Ardissino 1997) or intravenously (Horowitz 1988) due to NACs ability to potentiate associated hypotension and headaches. If prescribed, oral NAC should be started at a low dose (600mg three (Ardissino 1997) or four times daily (Boesgaard 1991)) with careful monitoring of blood pressure and headache occurrence. No clear recommendation can be given for intravenous dosing.
Schizophrenia
Three trials have examined NAC in patients with schizophrenia (Berk 2008, Carmeli 2012, Lavoie 2008). One double-blind, placebo-controlled trial (N= 140) using oral NAC at 1,000mg twice daily showed statistically significant improvements in those treated with NAC across several standardized schizophrenia measurement scales, and akathisia (restless leg syndrome) also improved significantly compared to placebo (Berk 2008). The mechanism by which NAC treats schizophrenia is thought to be through brain glutamate/ NMDA receptor modulation and reduction of oxidative stress (Dean 2011).
Lavoie et al conducted a randomized, double- blind, cross-over trial comparing 2g NAC to placebo for a period of 60 days to investigate N-methyl-D-aspartate (NMDA) receptor function, characteristically low in schizophrenia (2008). Mismatch negativity (MMN) is an auditory evoked potential (AEP) component related to NMDA receptor function that is impaired in patients with schizophrenia (Lavoie 2008). In this study, treatment with NAC significantly improved MMN generation compared with placebo (p=0.025), suggesting improved NMDA receptor activity, but the study was not continued for long enough to observe changes in clinical severity as reported by the same group in Berk 2008 (above) (Lavoie 2008).
Lastly, a recent proof-of-concept study found that NAC was able to significantly increase multivariate phase synchronization (MPS) on EEG testing compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions in patients with schizophrenia (Carmeli 2012). Authors suggested that this may be an early marker of clinically important treatment effects.
Bipolar Disorder
Two small double-blind, placebo-controlled trials (N=75, N=17) in patients diagnosed with bipolar disorder showed very encouraging improvement in measures of symptom severity, functioning and quality of life with oral NAC at 1,000mg twice daily as an add-on to conventional therapy (Berk 2008, Magalhães 2011A). Improvements were evident by eight weeks (Beck 2008). In a sub-analysis of the study by Berk 2008, six of seven participants with bipolar II in the NAC group experienced a full remission of depressive and manic symptoms, compared to only two of seven in the placebo group (p=0.031) (Magalhaes 2011B). In an analysis of the effect of adjunctive NAC treatment on depressive symptoms in bipolar patients, Magalhaes et al reported “very large effect sizes in favor of NAC … for depressive symptoms and functional outcomes …. Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo” (2011A). A report of a larger cohort (N=149) from the two-month open label phase following an RCT showed similar results, which were described by the authors as a “robust decrement in depression scores” associated with NAC treatment (Berk 2011). Adverse effects were non-significant in all three trials.
Autism
A small (N=33), 12-week double-blind randomized placebo-controlled trial treated autisticpatients(3.2- 10.7 years of age) with oral NAC in an escalating dose schedule reaching a maximum of 900mg three times daily. Compared with the placebo group, the NAC group had sign if i can’t improvements on the Aberrant Behaviour Checklist irritability subscale. Adverse effects were mild and exclusively gastrointestinal (Hardan 2012).
Grooming Disorders
There are several case reports and small trials of oral NAC in the treatment of addiction, compulsive disorder and excessive grooming disorders. It has been suggested that the mechanism of action may involve changes to glutamate levels in the brain (Dean 2011).
One small (N=50) randomized, double-blind trial compared NAC 1,200mg or 2,400mg per day to placebo in the treatment of trichotillomania (compulsive hair pulling). Significant improvements were noticed after nine weeks of treatment in hair pulling with 56% of participants in a NAC treated group reporting “much or very much improved” whereas 16% in placebo group reported the same level of improvement (Grant 2009). Another two cases of trichotillomania showed encouraging improvement when treated with oral NAC at 1,200 mg/day for three and six months, respectively (Rodrigues-Barata 2012).
In the case of nail biting, three patients showedcomplete abstinence of nail-biting after oral NAC at 1,000mg bid for four to seven months (Berk 2009). Encouraging improvement was also seen in one case of trichotillomania, one case of nail biting with trichotillomania and one case of skin picking when treated with oral NAC at 1,800-2,400mg/day (Odlaug 2007).
Obsessive Compulsive Disorder
A small (N=36) randomized, double-blind trial compared 600-2,400mg/day NAC and placebo orally for 12 weeks in patients with obsessive compulsive disorder who were refractory to SSRI treatment. The patients in the NAC group had a 52.6% rate of “full response”, while the patients taking placebo had a 15% rate of “full response”. Full response was defined as a 35% or greater reduction on the Yale- Brown Obsessive Compulsive Scale. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was also significantly improved in the NAC group as a whole (p<0.001) (Afshar 2012).
Addiction
Two small (N=13) (N=15) placebo-controlled trials (LaRowe 2006, 2007) and one small (N=23) open- label trial (Mardikian 2006) have shown significant reductions in cocaine craving and usage with oral doses of NAC at 1200-3600mg/day.
Another small (N=116), eight-week double- blind randomized placebo-controlled trial targeted promoting cannabis abstinence in adolescents. Participants were given 1200mg NAC twice daily or placebo orally, along with brief weekly counselling sessions and a small cash-based reward system. When adjusted for cannabis use at baseline, the NAC group had significantly higher odds than the placebo group of negative urine cannabinoid tests during treatment, OR 2.4 (95% CI 1.1-5.2) (Gray 2012).
An open-label trial followed by a double blind placebo-controlled trial investigated the effect of oral NAC at 1,800mg/day on pathological gambling. Significant improvements were seen in the Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling in the NAC group compared to the placebo group in both sections of the study (Grant 2007).
Although individually these case studies and clinical trials modestly support NAC use, the totality of evidence supports oral NAC at 1,200-3,600mg/day as a viable treatment option in addiction (specifically cocaine, cannabis and gambling), excessive grooming behaviours (specifically trichotillomania, skin picking and nail biting) and obsessive compulsive disorder.
Adverse Effects and Toxicity
A safety analysis of high-dose NAC examined its effects on 503 patients with acetaminophen toxicity. The oral route caused nausea and vomiting in 23% of patients and anaphylactic reactions in 2%. The IV route caused anaphylactic reactions in 9% of patients and nausea and vomiting in 6% of patients. The anaphylactic reactions were, in decreasing order of occurrence, pruritus, tachycardia, flushing, urticaria, non-urticarial rash, hypotension, bronchospasm and syncope (Bebarta 2010).
One retrospective study of 187 patients with acetaminophen toxicity treated with intravenous NAC found only seven adverse reactions, six being cutaneous and one being life-threatening, but not clearly caused by NAC (Kao 2003). Massive accidental intravenous overdoses have been reported to cause kidney failure (Mullins 2011), severe brain injury (Heard 2011) and death (Bailey 2004, Elms 2011).
Oral and intravenous NAC are considered to be of equal efficacy in treating acetaminophen poisoning (Kanter 2006). The intravenous route is not recommended for patients prone to anaphylaxis or at high risk for bronchospasm, such as asthmatics. The oral route is not recommended for patients with nausea or vomiting severe enough to render oral treatment ineffective(Kanter2006).Oraldosesof600mgtwice dailywereassociatedwithaninsignificantadverseeffect profilecomparedtoplaceboina262persontrial(De Flora 1997).
Conclusion NAC, the standard treatment for acetaminophen toxicity, has several relatively unknown clinical uses, including treatment of acute liver failure, COPD, flu prevention, idiopathic pulmonary fibrosis, acute renal failure due to contrast media, schizophrenia, bipolar disorder, autism, grooming disorders, obsessive compulsive disorder, addiction and angina. Care should be taken to avoid adverse effects associated with nitrate potentiation in angina treatment.
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