N-acetyl cysteine in the treatment of alcohol use disorder in patients with liver disease: Rationale for further research

Abstract

Introduction:

Alcoholic liver disease (ALD) is the leading cause of alcohol-related death and one of the most common forms of liver disease. Abstinence from alcohol is crucial to reducing morbidity and mortality associated with the disease. However, there are few pharmacotherapies for alcohol use disorder suitable for those with significant liver disease.

Areas Covered:

This paper presents a rationale for investigating the use of N-acetyl cysteine (NAC) to promote abstinence or reduce heavy alcohol consumption for patients with an alcohol use disorder, particularly in the presence of liver disease. NAC is an antioxidant with glutamatergic modulating and anti-inflammatory properties. Evidence is emerging that oxidative stress, neuro-inflammation and dysregulation of glutamatergic neurotransmission play a key role in alcohol use disorder. Similarly, oxidative stress is known to contribute to ALD. We outline the studies that have investigated NAC to reduce alcohol consumption including preclinical and clinical studies. We also review the evidence for NAC in other addictions as well as psychiatric and physical comorbidities associated with alcohol use disorders.

Expert Opinion:

NAC is low cost, well-tolerated and could have promise for the treatment of alcohol use disorder in the presence of liver disease. Clinical trials directly examining efficacy in this population are required.

1. Introduction

Alcohol misuse is linked to over 200 physical and mental conditions [1] and is a leading cause of morbidity and mortality worldwide. The liver is commonly affected by regular or heavy alcohol use and patients with alcohol-related liver disease present a particular clinical challenge [2]. In terms of alcohol-attributable deaths, alcoholic liver disease (ALD) stands as the most common cause [3] and abstinence from alcohol is key to reducing this mortality. In this paper, we present a rationale for studies investigating N-acetyl cysteine (NAC) to increase abstinence in alcohol use disorder (AUD) in the presence of ALD.

2. Alcohol use disorder and alcoholic liver disease

AUD, as characterized by the Diagnostic Statistical Manual of Mental Disorders (DSM)-V, is a loss of control over alcohol consumption persisting for at least 12 months and including medical and psychosocial harms from alcohol use. This may or may not include alcohol-dependence criteria from the previous DSM-IV definition characterized by a physiological dependence on alcohol with onset of withdrawal symptoms following abrupt cessation of drinking. The development of AUD typically involves repeated exposure to alcohol, tolerance, symptoms of withdrawal and escalating alcohol consumption.

Alcohol consumption is a major cause of liver disease worldwide and half of all global liver cirrhosis deaths are related to alcohol [1]. Specifically, ALD can be grouped into three diseases that frequently coexist: alcoholic fatty liver or steatosis, alcoholic hepatitis, and alcoholic cirrhosis whereby cirrhosis describes irreversible hepatic fibrosis associated with disruption of hepatic circulation and regeneration [2]. The impact of ALD on hospital admission rates is on the rise in several countries including Australia and United States [4]. However, despite the prominent burden of ALD, very little progress has been made with regards to treatment.

Abstinence from alcohol is a key factor in reducing ALD mortality. Alcohol consumption, even in low doses, after the onset of liver disease, increases the risk of severe consequences [5]. The ideal treatment for AUD in the presence of ALD should therefore aim for abstinence and the prevention of relapse. However, current approaches to the treatment of AUD have limited efficacy and use, and this is particularly the case for those with clinically significant liver damage [6]. Moreover, psychosocial interventions have been observed to have limited success in maintaining abstinence from alcohol in patients with chronic liver disease [7]. Thus, an effective pharmacotherapy aimed at achieving and maintaining abstinence that does not compromise liver function is required for this clinical population.

3. Pharmacotherapy for AUD in the presence of ALD

Pharmacological treatment of AUD is now widely accepted and medications such as acamprosate, oral naltrexone, and disulfiram are approved for treatment of AUD in the United States, Europe, and Australia. Furthermore, extended-release injectable naltrexone is approved in the United States, oral nalmefene is approved in Europe, and other medications (e.g. topiramate, gabapentin, baclofen, and prazosin) are sometime used off-label for AUD, especially in some specific countries. A metaanalysis of 122 randomized controlled trials reported only modest but significant effects for naltrexone and acamprosate to reduce the return to drinking (with moderate support for nalmefene and topiramate) [8]. The number needed to treat (NNT) to prevent return to any drinking for was 12 and 20 for acamprosate and oral naltrexone respectfully. The NNT to prevent return to heavy drinking was 12 for oral naltrexone.

With regards to ALD, disulfiram and oral naltrexone are extensively metabolized by the liver and both are contraindicated in patients with clinically relevant liver diseases [9]. There is some debate in the literature regarding the clinical significance of liver toxicity from naltrexone treatment in ALD [10] particularly in mild cases. However, use is still limited in ALD patients with advanced liver disease and caution is nonetheless still recommended [6]. With regards to acamprosate, although there is no evidence to suggest it is unsafe in the presence of liver disease, the regimen of six tablets per day along with modest efficacy indicates the need for further medication development. While topiramate is a promising agent for reducing heavy drinking days, it may induce hyperammonemia and cause significant changes in hepatic function tests [11]. Moreover, topiramate may be associated with cognitive impairment and mood changes which can confound a diagnosis of hepatic encephalopathy in advanced liver disease [6]. It is thus less ideal for use in ALD patients. Nalmefene could be a potential option for patients with ALD given that it has been reported to have similar efficacy to naltrexone in the treatment of AUD but without documented hepatotoxicity [12]. However, the safety of nalmefene in the case of advanced liver disease is not yet established.

Baclofen has emerged as popular pharmacotherapy and while results are somewhat mixed, a recent metaanalysis has reported some efficacy, particularly in patients with higher levels of alcohol consumption before randomization [13]. There have been only two formal placebo-controlled studies of an alcohol pharmacotherapy in patients specifically diagnosed with ALD and both of these trials demonstrated efficacy of baclofen at low to medium doses 30–75 mg/day [14,15]. Some studies have observed an adverse event profile including fatigue, sleepiness, and sedation in medium to higher doses 75–150 mg/day [14,16]. It is important to note the risk of overdose following deliberate self-poisoning with baclofen [14,17]. This can be a concern in the case of comorbid psychiatric conditions such as bipolar or borderline personality disorder [18,19]. Since the emergence of interest in baclofen there have been increased reports to poison control agencies both in Australia [17] and France [20]. This uncertain harm-benefit balance arguably precludes widespread use of baclofen in the community whereby it is not recommended for patients with mood disorders or risk of deliberate self-poisoning. Accordingly, there are few safe and effective medications aimed at reducing alcohol consumption for ALD patients that can be widely prescribed.

4. N-acetyl cysteine

NAC is a low cost, antioxidant with also antiinflammatory and glutamatergic modulating properties. NAC has an established record of being safe and well tolerated [21]. It is currently used in many countries for the symptomatic treatment of cystic fibrosis, chronic obstructive pulmonary disease [22], and to reverse hepatic oxidative stress following acetaminophen-induced acute liver failure [21]. NAC is a cysteine precursor that activates the cystine-glutamate exchanger (xc⁻) which is an important means for preserving extrasynaptic glutamate concentrations [23,24]. NAC also normalizes expression of the glutamate transporter 1 (GLT-1), a high-affinity astroglial glutamate transporter, which also is a key process to restoring glutamate homeostasis. NAC replenishes the intracellular levels of glutathione (GSH), is a fundamental antioxidant synthesized in cells, and interacts with reactive oxygen species [25]. For these reasons, NAC has emerged as a promising agent in treating disorders associated with glutamatergic dysregulation, oxidative stress, and inflammation including hepatic diseases [26], psychiatric disorders [27] and, more recently, addictive disorders [28] (see below for detail).

5. Neurobiological mediators of AUD

5.1. Glutamatergic signaling

Glutamate is a critical regulator of subcortical plasticity during all phases of alcohol consumption, with dysregulation of cortical glutamatergic neurotransmission observed with heavy drinking [29]. Preclinical studies show that chronic alcohol intake leads to reduced glial GLT-1 protein levels, abnormalities in glutamate receptor signaling (e.g. mGluR2/3) [30], and disruption of glutamatergic input from the prefrontal cortex (PFC) to reward areas [29]. Preclinical studies also show that the glutamatergic system plays a crucial role in alcohol seeking behaviors. For example, cue-induced reinstatement of alcohol-seeking behaviors and alcohol intake in rodents are attenuated by glutamate receptor antagonists [31] and also compounds that modulate GLT-1 [32]. Glutamate transporters remove glutamate from the synaptic cleft and control extracellular glutamate levels that moderate the motivation to seek alcohol [33]. Clinical studies using magnetic resonance spectroscopy (MRS) have found significant alterations in glutamate levels in alcohol-dependent individuals, whereby an increase or decrease depends on the brain region examined and also the duration of abstinence duration prior to scanning [34,35]. Cortical glutamate in alcohol patients has also been demonstrated to be modulated by the presentation of alcohol cues [36] and by the administration of acamprosate [37]. Thus, agents that modulate GLT-1 and restore glutamate homeostasis and the dysregulation of glutamatergic transmission between prefrontal and reward brain regions have become candidates for potential pharmacotherapies in the treatment of AUD [37].

Preclinical studies demonstrate that NAC administration reverses glutamate dysregulation induced by chronic cocaine use, including normalization of the two glial processes critical for maintaining glutamate homeostasis: cystine-glutamate exchange [38] and glutamate transport via the GLT-1 [39]. Clinical studies using MRS have reported that NAC administration reduces dorsal anterior cingulate cortex (dACC) glutamate activity in cocaine users but not healthy controls [40]. This indicates that NAC normalizes cortical glutamate levels in the case of excessive glutamatergic signaling such as observed in patients with substance use disorder. There have been no studies examining NAC on glutamate neurotransmission in alcohol patients.

5.2. Oxidative stress and neuroinflammation

There is also an important link emerging between the neuropsychological changes associated with AUD and modulations in the immune system induced by chronic alcohol use. Alcohol consumption activates the toll-like receptor system leading to a “leaky gut” triggering a leakage of lipopolysaccharides and peptidoglycans from the gut lumen [41]. This also leads to the circulation of microbial products that stimulate immune cells to secrete proinflammatory cytokines in the periphery (notably interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which then prime brain microglia and astrocytes to release central nervous system cytokines) [42]. Preclinical studies demonstrate that this alcohol-induced chronic proinflammatory state leads to oxidative stress with reduced GSH and diminished neural function [43]. Neuroinflammation also modifies several neurotransmitter systems important in addiction including the expression of serotonin transporters, GABA receptors, and also glutamatergic neurotransmission via the kynurenine pathway [44]. Preclinical studies report peripheral immune system changes occurring with chronic alcohol use [45] and already at the hazardous drinking stage [46]. Clinical studies report increased levels of peripheral cytokines in patients with AUD, compared to healthy controls [47]. Recent evidence shows that expression of brain translocator protein, a marker of activated glia, is associated with cognitive impairment [48] and alcohol-dependence severity [49].

Preclinical studies show that NAC prevents neuroinflammation induced by chronic alcohol consumption as measured by a decrease in proinflammatory cytokines and increase in anti-inflammatory cytokines in the brain [50]. NAC has also been found to prevent oxidative stress in animals exposed to ethanol, as measured by the production of reactive oxygen species [51].

6. Biological mediators of ALD

Chronic excessive alcohol consumption leads to hepatocellular injury and liver inflammation via pro- and antiinflammatory cytokine interactions [52], oxidative stress, and impairment of intracellular GSH homeostasis [53]. GSH deficiency is a pathophysiological characteristic of ALD [54] and improving GSH deficiency has been hypothesized as a promising therapeutic strategy to recover from oxidative stress-induced liver damage in patients with ALD [54]. Neuroinflammation is particularly exacerbated in alcoholic patients with liver disease and marked abnormalities such as microglial dystrophy and neuronal loss have been reported [52,53,55].

Preclinical studies have demonstrated NAC to be protective against liver injury [56] and to interact synergistically with abstinence from ethanol to improve serum lipids and hepatic antioxidant defenses [56]. One clinical study reported a trend to improve survival from alcoholic hepatitis following a short NAC regimen (i.v. 5 days; N = 174) plus glucocorticoids versus glucocorticoids only [57]. In addition, one clinical study observed significantly decreased serum alanine aminotransferase (ALAT) with a 12 week NAC regimen (1200 mg/day; N = 30) in patients with nonalcoholic fatty liver disease whereby no side effects were reported [58]. This latter study is important because it demonstrates that NAC is safe, if not beneficial, in the presence of liver injury in the oral regimen used in clinical trials in addiction.

Accordingly, unlike other medications reviewed above which are safe when used for AUD in patients with ALD, NAC has the potential of being an effective medication for both AUD and ALD, therefore making the rationale for testing it in this specific subpopulation particularly compelling and promising.

7. Evidence for NAC in reducing alcohol consumption

Studies examining the efficacy of NAC on reducing alcohol consumption or alcohol seeking behaviors are depicted in Table 1.

Table 1.

Preclinical and clinical studies of N-acetyl cysteine on alcohol consumption and alcohol seeking behaviors.

Reference	Dose and Duration	Subjects	Study Design	Outcome Measures	Results	Comments
Preclinical
Lebourgeois et al. (2017)	25, 50 or 100 mg/kg NAC or Saline (control) 60 minutes before each test	Male Long Evans rats trained to self-administer 20% ethanol in operant cages for several weeks	NAC vs vehicle on acquisition, extinction and reacquisition	Lever presses during: -Self-administration of ethanol -Ethanol-seeking behaviour during extinction -Reacquisition of ethanol self-administration	NAC reduced self-administration of ethanol NAC reduced ethanol seeking (responding during extinction) NAC reduced reacquisition following protracted abstinence	NAC reduces ethanol-seeking behaviors and reacquisition in rats Strongest efficacy in largest dose
Quintanilla et al. (2016)	30 and 60 mg/kg NAC or Saline (control) 14 days	Female Wistar-derived rats selectively bred as alcohol consumers	NAC vs vehicle on acquisition phase and maintenance phrase (chronic intake)	Voluntary ethanol intake during acquisition phase maintenance phrase (chronic) and saccharin intake	No difference in first intake of ethanol (acquisition) NAC markedly inhibited ethanol consumption during chronic intake NAC prevented excessive saccharin intake following chronic alcohol use	Efficacy of NAC in both doses in reducing ethanol consumption Strongest efficacy in largest dose
Schneider et al (2015)	60 and 90 mg/kg NAC or Saline (control) 4 days	Male Wistar rats treated with 2 g/kg ethanol, twice daily, by gavage for 30 days; control animals received an appropriate dose of glucose to balance caloric intake	NAC vs vehicle during withdrawal phase (24 hours following 30 days of ethanol)	Corticosterone and leptin serum levels Behaviours on elevated plus maze (anxiety)	NAC prevented increases in corticosterone and leptin NAC prevented hypoactivity	Both NAC doses prevented corticosterone increases Largest dose prevented increases in leptin
Clinical
Squeglia et al. (2016)	2400 mg/day NAC or placebo 8 weeks	N = 77 Cannabis Dependence DSM-IV-TR 72% Male Alcohol use past 30 days Age: 15–21	NAC vs PL on cannabis cessation Secondary analysis: Alcohol use, compensatory alcohol use with cannabis use	Total standard drinks, drinking days, heavy drinking days (≥4 drinks for women and ≥ 5 drinks for men)	In NAC patients, lower cannabis use associated with lower alcohol use, but not in placebo patients No significant differences in compensatory alcohol use with cannabis reductions	Secondary analysis (not a direct trial) Drinking outcomes not independent of cannabis use No AUD diagnosis
Squeglia et al (2018)	2400 mg/day NAC or placebo 12 weeks	N = 277 Cannabis Dependence DSM-IV-TR 77% Male Alcohol use past 30 days Age: 18–50	DBRCT NAC vs PL Cannabis cessation Secondary analysis: Alcohol use	Total standard drinks Drinking days Heavy drinking days (≥4 drinks for women and ≥ 5 drinks for men)	NAC increased weekly abstinence NAC decreased drinks per week (33% less) NAC decreased drinking days per week (31% less)	Secondary analysis (not a direct trial) but controlled for baseline drinking Drinking outcomes independent of cannabis use No AUD diagnosis
Bernardo et al. (2009)	2000 mg/day NAC or placebo 24 weeks	N = 75 Bipolar 40% Male Age: 18–65 79% any alcohol use	NAC vs PL	Substance Use (CGI-SU) Dichotomised (1–4 = improvement or no change; 5–7 became worse)	No significant differences in substance/alcohol use scores at any week (p's > 0.11)	Secondary analysis (not a direct trial) No comprehensive alcohol use measures No AUD diagnosis Small sample (~18 NAC-treated patients with any use analysed)
Back et al. (2016)	2400 mg/day NAC or placebo 8 weeks	N = 35 DSM-IV Substance Use Disorder and PTSD 100% Male Age: 18–65 82% Alcohol use disorder	NAC vs PL	Substance Use (TLFB), depression (BDI), and PTSD symptoms (CAPS)	No significant differences in substance/alcohol use (p = 0.07) NAC reduced craving NAC reduced depression NAC reduced PTSD symptoms	Baseline levels of use were low Patients were abstinent for > 7 days at the time of study enrolment Small sample (10 NAC-treated patients with AUD) Poly drug use

Notes: Abbreviations: DBRCT = double blind randomised controlled trial, n.s. = not significant, DSM-IV-TR = Diagnostic Statistical Manual of Mental Disorders, AUD = Alcohol Use Disorder, CBT = cognitive behavioural therapy, BDI = Beck Depression Inventory, TLFB = Time Line Follow Back, CGI-SU = Clinical Global Impression-Substance Use, PTSD = Post Traumatic Stress Disorder, CAPS = Clinician Administered PTSD Scale, NAC = N-Acetylcysteine, PL = placebo.

7.1. Preclinical studies

Recent rat studies have robustly shown that NAC reduces ethanol intake and ethanol-seeking behaviors. While not attenuating initial intake of ethanol, different doses of NAC have been demonstrated to markedly inhibit ethanol consumption by up to 70% compared to saline during a chronic intake paradigm [59,60]. These effects were sustained and observed with both low and high doses (30 and 60 mg/kg). Most recently, Lebourgeois and colleagues demonstrated that NAC reduced self-administration of ethanol, ethanol seeking during extinction and also reduced reacquisition following extinction [60]. The strongest efficacy was observed in the highest dose group (100 mg/kg) with an 81% decrease in alcohol consumption in the NAC administered group compared to the saline group. Finally, NAC has also been shown to reduce the neuroendocrine (elevations in corticosterone and leptin) and behavioral symptoms (anxiety-like behaviors) induced following ethanol cessation (withdrawal) [61].

There are several mechanisms by which NAC could improve outcomes for AUD including glutamatergic transmission (GLT-1 or cysteine-glutamate exchange), inflammatory pathways, oxidative stress, and GSH metabolism. In terms of reducing alcohol consumption and relapse, the modulation of GLT-1 and consequent stabilization to a hyperactive glutamate system is likely to be crucial. Finally, preclinical studies have robustly demonstrated that NAC administration reduces cue-induced cocaine reinstatement whereby restoring GLT-1, not cystine-glutamate exchange, is a key mechanism [62]. However, the mechanism of action of NAC remains to be entirely explained.

7.2. Clinical studies

There have been no clinical trials to date directly investigating the potential role of NAC on AUD. There has been one recent secondary analysis of drinking outcomes in a trial of oral NAC (2400 mg/day for 12 weeks; N = 277) to reduce cannabis use in participants with cannabis use disorder [63]. These authors reported a significant increase in abstinence from alcohol, reduced weekly drinking, and fewer drinking days between visits in the NAC-treated participants compared to those treated with placebo [63]. Alcohol outcomes were independent of change in cannabis use and adverse events were infrequent with no differences between NAC and placebo groups. Reductions in drinking were also previously reported in a secondary analysis of a positive trial of NAC (2400 mg/day; N = 116) for cannabis use in adolescents by this same group [64]. These reductions in alcohol consumption were associated with changes in cannabis use.

A pilot trial of NAC in the treatment of comorbid substance use (with 82% AUD) in patients with a posttraumatic stress disorder (PTSD) suggested that NAC (2400 mg/day for 8 weeks; N = 35) might be a promising treatment for AUD given significant reduction in cravings [65]. Significant reductions in alcohol use were not reported although these patients were abstinent for at least 7 days before enrolment and indeed, no changes in substance use in general was observed, most likely due to low baseline levels across the treatment groups. Significant reductions occurred however in PTSD symptoms, craving and depression in NAC-treated patients versus placebo. This was a small trial whereby the sample size for the NAC group reporting AUD was only 10 patients. Nonetheless, the significant reductions in craving and depression are promising. Finally, although one secondary analysis of a trial of NAC for bipolar disorder (2000 mg/day for 24 weeks; N = 75; 79% reported alcohol use of any frequency) observed minimal change in alcohol use, alcohol consumption was not adequately measured whereby no detail regarding frequency, quantity or level of severity was obtained [66]. Clinical trials designed to directly investigate the effect of NAC treatment on heavy alcohol consumption in the AUD population are required.

8. Evidence for NAC in treating other addictions

Clinical studies investigating a role for NAC in the treatment of addiction in general have been well documented [67]. Briefly, beneficial effects of NAC (2400 mg/day for 5 days) on measures of cocaine use have recently been demonstrated in cocaine users including abstinence from cocaine (% positive urine) and reduced dependence severity [68]. A small placebo-controlled study also observed an effect of NAC on cocaine use cessation [69]. Regarding methamphetamine use disorder, Mousavi et al. [70] found NAC (1200 mg/day, 8 weeks) to be safe and to significantly reduce craving for methamphetamine in a crossover trial. There have been two large trials of NAC for the treatment of cannabis cessation. The first trial in adolescents demonstrated strong signals of efficacy in reducing cannabis use [64], but this was not replicated in an adult sample with cannabis use disorder [71]. A promising signal of efficacy of NAC on reducing daily smoking and levels of depression in tobacco use disorder has been demonstrated [72] in addition to a reduction of the rewarding effect of a cigarette following a period of abstinence [73]. This was not replicated more recently by a recent 14-day pilot study in active smokers [74] which may be due to continued smoking throughout the trial and concurrent pharmacotherapy. NAC has also been shown to be effective in disorders associated with impulse control including problem gambling [75] and in patients with skin-picking and hair-pulling [76,77].

9. Evidence for NAC in common comorbidities of AUD and ALD

Recent studies have demonstrated that individuals with AUD display a blunted proinflammatory response to an immune challenge relative to healthy controls [49]. This suggests that heavy alcohol use is associated with a potentially impaired immune functionality and increased vulnerability to comorbid health conditions.

9.1. Psychiatric disorders

There is a high rate of psychiatric comorbidity including depression and suicide risk in people with chronic liver disease [78] and especially in patients with ALD as opposed to patients with non-ALD [79]. Individuals with an AUD and psychiatric comorbidity are significantly more disabled, use considerably more health services than those with an AUD alone. Moreover, in AUD patients with comorbid depression or anxiety treatment drop-out is more frequent, time to relapse shorter, and long-term alcohol consumption higher [80]. Depression is also a predictor of return to drinking following a liver transplant for ALD [81].

Increasing evidence suggests that depression and suicidal behavior is associated with glutamatergic dysregulation, oxidative stress [82], and chronic inflammation [83,84]. These pathways are also thought to be critically involved in the comorbidity between AUD and depression [42,85]. Taken together, it possible that hepatocellular injury, as observed in ALD, then provides further pressure at the neuroimmune interface to sustain this cycle and further entrench these multimorbidities.

There have been several studies investigating oral NAC in the treatment of psychiatric disorders and NAC appears to have a good safety profile in this clinical population with a low frequency of adverse events reported across studies [27]. Signals of efficacy have been reported in patients with more severe major depressive disorder [86], obsessive compulsive disorder [87], and also for reducing depressive symptoms in patients with bipolar disorder [88]. Moreover, NAC treatment has been observed to lead to significant reductions in suicidal ideation in patients with bipolar disorder [89] and reductions in nonsuicidal self-injurious behavior and depression in adolescents and young adults [90]. This suggests that NAC is suitable for patients with AUD and ALD, given it appears safe for patients with suicide risk and potentially beneficial for psychiatric comorbidity.

9.2. Cognitive impairment

Chronic heavy alcohol use is well documented to be associated with cognitive impairment including reduced executive functioning, episodic memory, and visuospatial capacities [91]. Moreover, impaired liver function, resulting from chronic and excessive alcohol use or otherwise, can produce subtle but measurable cognitive deficits [92]. The evidence for NAC in improving cognition across a range of different patient groups is still equivocal given the paucity of the literature, but some positive effects on cognition have been reported [93], including improved measures of processing speed in schizophrenia [94]. There have been several experimental studies demonstrating NAC to be effective in improving cognition in patients with cocaine use disorder including improved inhibition using the stop signal task [68] and attentional bias [95].

9.3. Other common physical comorbidities

Chronic excessive alcohol consumption is associated with alcoholic heart disease and high rates of diabetes and obesity. Administration of NAC in rat models prevents ethanol-induced calorimetric changes and to reduced myocardial oxidative stress [56]. In addition, NAC supplementation in mice has shown to inhibit the increase of fat mass and the development of obesity during a high fat diet and suppressed hepatic lipid accumulation [96]. Chronic excessive alcohol use can also impair multiple critical cellular functions in the lung leading to alcoholic lung disease. Preclinical studies have demonstrated that NAC prevents alcohol-induced lung complications such as alcohol-induced ciliary dysfunction (AICD) [97]. In addition, alcohol consumption has been shown to produce detrimental effects on bone metabolism and alcohol binging alters the quality of fracture healing after a traumatic injury. Concurrent administration of NAC has been demonstrated to reverse these effects [98].

10. Conclusion

In conclusion, NAC has demonstrated some signals of efficacy in a range of conditions aligned with AUD and is safe, and possibly beneficial, for ALD and common psychiatric comorbidities including mood disorders. Clinical studies in specific populations are required in order to avoid overestimating or underestimating the evidence of NAC.

11. Expert opinion

The preclinical literature shows that NAC prevents alcohol seeking behaviors and clinical studies suggest that NAC may reduce alcohol consumption. However, it is relevant to also note that there have been mixed results for the efficacy of NAC in most substance use disorders, which are probably due to inconsistencies in treatment goal, small sample sizes, abstinence at enrolment and concurrent substance use [67]. Most positive signals of efficacy for NAC on substance use from the clinical literature have occurred in the context of promoting continued abstinence, rather than the promotion of initial cessation, and this mirrors the robust findings found in the reinstatement model from the preclinical literature [67]. NAC may be particularly beneficial in the context of managing patients with ALD given that the treatment goal is generally to maintain abstinence and prevent relapse in order to prevent the progression of liver injury rather than reduce consumption. Nonetheless, with regards to the preclinical literature for alcohol consumption, studies have found efficacy for NAC during several phases of alcohol consumption including withdrawal, chronic alcohol intake, and reinstatement following extinction, with less evidence for reducing initial intake (acquisition). Moreover, the secondary analyses of drinking outcomes from a cannabis trial found NAC to significantly reduce both abstinence and heavy drinking days. Thus, at this point the phase of treatment that yields the most effective outcomes for alcohol consumption is unknown. Clinical trials directly examining NAC in treatment seeking alcohol patients will have to further elucidate these factors.

It is important to note that, with regards to the efficacy of NAC in the antioxidant setting, results from the general literature reinforce the concept that NAC should not be considered to be a powerful antioxidant per se, but rather that NAC replenishes GSH in deficient cells and thus it is likely to be ineffective in cells replete in GSH [99]. This hypothesis is supported by a recent study observing that the beneficial response of NAC to reduce positive symptoms in schizophrenia was predicted by baseline blood GSH peroxidase activity [94]. Although it is unknown as to whether the antioxidant properties of NAC are a key mechanism for reducing alcohol consumption and/or symptoms of associated comorbidities, the GSH deficiency observed with hepatic injury and chronic drinking suggests that ALD patients are most likely to receive maximal benefits of NAC treatment.

The converging evidence suggests some therapeutic potential of NAC in the treatment of AUDs. There is a need for well-powered, direct examinations of the efficacy of NAC in treatment seeking AUD patients, particularly in the context of patients with GSH deficiency and those aiming to sustain abstinence such as patients with ALD. NAC is inexpensive and is a currently registered medication in many countries worldwide such that positive results could lead to timely integration into service delivery for a clinical group that currently has very few treatment options.

Article highlights.

• Alcoholic liver disease (ALD) is the leading cause of alcohol-related death and one of the most common forms of liver disease.

• Abstinence from alcohol is crucial to reducing morbidity and mortality associated with the disease yet there are few treatment options for those with significant liver disease.

• N-acetyl cysteine (NAC) is an antioxidant with glutamatergic modulating and anti-inflammatory properties that is low cost and well-tolerated.

• Animal studies demonstrate efficacy of N-acetyl cysteine (NAC) for preventing relapse to alcohol consumption and improving liver function.

• Preliminary evidence in humans is emerging to show significant benefits of NAC to increase abstinence from alcohol.

  Clinical trials directly examining efficacy in this clinical population are required.