Exploring N-Acetylcysteine in Psychiatry

Anna Giménez-Palomo, MD;Seetal M. Dodd, PhD;Olivia M. Dean, PhD;Chiara Bortolasci, MSc, PhD;Michael Berk, MD, PhD;

The goal of this activity is to provide an understanding of N-acetylcysteine, an agent with several mechanisms of action and efficacy in various conditions.

After engaging with the content of this CME activity, you should be better prepared to:

• Discuss how N-acetylcysteine can be effective for unrelated conditions by having several mechanisms of action.

• Understand that N-acetylcysteine may be useful in psychiatry and has been successfully trialed as an adjunctive therapy.

• Feel confident considering using N-acetylcysteine in patients who may benefit from this treatment.

This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

Drs Giménez-Palomo, Dodd, Bortolasci, and Dean have nothing to disclose regarding the topic of this article. Dr Berk notes he has received grant/research support from NHMRC Senior Principal Research Fellowship, has served as a consultant for Janssen Pharmaceuticals, Inc. and the Royal Australian and New Zealand College of Psychiatrists, and is on the Speakers bureau for MedPlan. James Lake, MD, (external reviewer) and the staff members of Physicians’ Education Resource®, LLC and Psychiatric Times have no relevant financial relationships with commercial interests.

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Dr Giménez-Palomo is a Psychiatry Resident, Bipolar and Depressive Disorders Unit, Institute of Neuroscience, University of Barcelona, Spain. Dr Dodd is Clinical Associate Professor; Dr Dean is Associate Professor (Research); Dr Bortolasci is Alfred Deakin Postdoctoral Research Fellow; and Dr Berk is Alfred Deakin Professor, Faculty of Health, School of Medicine, Deakin University, Victoria, Australia.

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

N-Acetylcysteine (NAC) is a synthetic derivate of the endogenous amino acid L-cysteine (Figure 1) and a precursor of glutathione. It is known for its role in modulating oxidative stress and several pathophysiological processes, such as apoptosis, inflammation, mitochondrial dysfunction, and neurotransmission. The clinical benefits of NAC have been widely studied.

NAC is available in oral, inhalation, and intravenous (IV) formulations. When it is orally administered, NAC reaches peak plasma concentrations between 30 minutes and 1 hour. After being absorbed in the small intestine, NAC undergoes first-pass hepatic metabolism to be finally hydrolyzed to cysteine and available to synthesize glutathione, especially in the liver. Its oral bioavailability is poor, and that is the reason why IV formulation is preferred in acute paracetamol (acetaminophen) overdose.¹

The first clinical use of NAC was in the 1960s for cystic fibrosis. In the 1970s, its efficacy for the treatment of paracetamol overdose was discovered. Since then, a great number of applications have been attributed to NAC mainly due to its implication in oxidative stress. Recent studies suggest potential implications of NAC in several psychiatric disorders.

Reactive oxygen species, such as superoxide radical, hydrogen peroxide, and the hydroxyl radical, are products from oxidative phosphorylation of the mitochondria, where water is produced from molecular oxygen and also from peroxisomes, which degrade fatty acids into hydrogen peroxide. These oxidant agents can produce oxidative stress, which occurs when oxidants exceed the antioxidant capacity.

Glutathione exerts a protective effect on cells as an antioxidant defense, since its free sulfhydryl group provides a source to reduce equivalents to scavenge harmful reactive oxygen species. The antioxidant activity of glutathione peroxidase, a defense mechanism against peroxides, is also allowed by the reducing equivalents that glutathione provides.

Regarding NAC, its free sulfhydryl group and its role as a glutathione precursor make it an antioxidant agent. The mechanisms of NAC on its most studied therapeutic effects are well known. Regarding mucolysis, NAC breaks the disulfide bonds of mucus glycoproteins, thereby reducing mucus viscosity. As an antidote to paracetamol poisoning, NAC restores the hepatic glutathione pool depleted in the drug detoxification process. Current evidence shows that NAC can potentially improve the course of many other illnesses related to oxidative stress.¹

Apart from its efficacy as a mucolytic agent for the treatment of respiratory diseases, NAC has been found to increase alveolar surfactant, to have antioxidant, antimicrobial, and anti-inflammatory properties.^2-4 This may explain why several clinical trials have assessed NAC for the treatment of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

In clinical practice, NAC is commonly used as an antidote to paracetamol poisoning. Paracetamol is over 90% metabolized through phase II conjugation reactions, and a small part by cytochrome P450 2E1 to produce the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). After that, NAPQI is conjugated and detoxified with cellular glutathione, and a minimum quantity binds to proteins. When the amount of NAPQI is greater, protein adduct formation increases, including mitochondrial production, which promotes oxidative stress. Reactive species are responsible for acute liver injury induced by paracetamol overdose. Oxidative stress also activates a mitogen-activated protein (MAP) kinase pathway, which amplifies mitochondrial oxidative stress, leading to cell necrosis.

Considering that paracetamol hepatotoxicity is based on glutathione depletion, NAC can be considered a good antidote for paracetamol overdose, which is the treatment of choice according to the established nomogram for paracetamol toxicity.⁵ It acts as a protector agent by scavenging NAPQI and by preventing protein adduct formation. Excess NAC not being used for glutathione synthesis is converted to Krebs cycle intermediates and supports mitochondria in order to produce higher ATP levels in hepatocytes and to avoid mitochondrial dysfunction, which is crucial in paracetamol-induced liver injury.

NAC has also been suggested to act as an antidote to other drugs, such as paraquat, mushroom toxins, essential oils, chloroform, carbon tetrachloride and heavy metals, but evidence is still limited.

The use of NAC has also been studied in cardiovascular diseases and in the prevention of contrast-induced nephropathy, but researches have yielded controverted results. NAC has shown favorable results in small clinical trials in ophthalmology. Regarding retinitis pigmentosa, cone photoreceptors death occurs due to the accumulation of oxygen in the retina as a product of rod cells death. Animal studies assessing NAC effects showed that it promoted cone cell function and survival in mice with retinitis pigmentosa.^6,7

Findings from animal models suggest that NAC has the potential for the treatment of chronic neuropathic pain.^8-11 However, few human clinical trials have been conducted so far.

Other animal studies have also shown a beneficial action of NAC on cognition in cases of mitochondrial dysfunction, inherited metabolic disorders, heavy metal neurotoxicity, and Alzheimer disease, which is produced at least in part by increasing neuronal glutathione levels and by the maintenance of glutamate homeostasis.²

The role of NAC in a great number of psychiatric disorders has been extensively studied.^2,12-14 Many of these have a strong relationship with cognitive dysfunction, which is enhanced by oxidative stress. Some studies have shown that NAC significantly improves cognitive function in patients with neurological or psychiatric diseases, but the clinical relevance of the effects is still unclear. A great part of preclinical evidence has reported that NAC may be involved in glutamate homeostasis modulation.

Glutamate is the most abundant excitatory neurotransmitter in the CNS and participates in learning and memory processes. Its action enhances the influx of extracellular Ca2+, which is mediated by neuronal and glial membrane transporters in order to maintain the homeostasis of extracellular glutamate. NAC has demonstrated to activate presynaptic system Xc– (Sxc-) receptors, which mediate the exchange of extracellular cysteine and intracellular glutamate. When these presynaptic receptors are activated, glutamate release from excitatory nerve endings is inhibited. NAC also induces the expression of glutamate transporter-1 (GLT1) in astrocytes, which clears synaptic and extra-synaptic glutamate and enhances the maintenance of glutamate homeostasis.

Psychiatric and neurodegenerative disorders are known to be associated with excessive release of glutamate and impaired glutamate homeostasis. Current evidence suggests that NAC may be effective in treating various psychiatric conditions.

The hypothesized mechanism of action of NAC in substance use relies on the glutamate homeostasis hypothesis of addiction, where glutamate signaling in the nucleus accumbens has been disrupted. In drug-naive states, glutamate binds to postsynaptic receptors and glia clears excess of glutamate through the transporter GLT-1. The glia receptor Sxc- also enhances glutamate release by its exchange with cystine, thereby glutamate binds to presynaptic metabotropic receptors (mGluRs), which provides inhibitory feedback for further release (Figure 2).

Clinical data have supported the underlying hypothesis of imbalances in glutamate homeostasis in addictive brains by showing reductions in GLT-1 levels and of the catalytic union of Sxc-.² This leads to an increase of extrasynaptic glutamate and thus the activation of postsynaptic N-methyl-d-aspartate (NMDA) receptors, which increases the risk of relapse. Another consequence is the reduction of presynaptic inhibition through mGluR2/3 receptors. When NAC is converted to cysteine, it is exchanged into the glia for glutamate, which provides inhibitory feedback on presynaptic receptors, thereby limiting the release of glutamate. NAC has also been shown to increase the expression of GLT-1 and Sxc- transporters.² Given that NAC has been shown to help to reach the glutamatergic homeostasis, most investigations of NAC in psychiatry focus on the treatment of addictions.

The therapeutic activity of NAC relies on several mechanisms of action, such as the reduction of oxidative stress, modulation of mitochondrial dysfunction, apoptosis, inflammatory processes, and modulation of glutamate homeostasis.

A few double-blind, placebo-controlled trials have reported a decrease in cocaine-related withdrawal symptoms, less craving and less cocaine use with NAC. An open-label trial of NAC among cocaine users showed a reduction in biochemically confirmed cocaine use.¹⁵ Moreover, NAC improved retention rates and, after a 4-week period, most subjects either discontinued the use of cocaine or significantly reduced the use of cocaine during treatment. On the other hand, a large randomized trial did not show a reduction in active cocaine use, although NAC seemed to increase the time to relapse and reduced craving.¹⁶ In an open-label, randomized, cross-over study, cocaine-dependent patients showed higher glutamate levels in the dorsal anterior cingulate cortex compared with healthy controls.^17,18 In a recent randomized, placebo-controlled trial, a 25-day treatment with NAC was associated with less cocaine consumption, but did not show beneficial effects on cocaine craving.

A randomized clinical trial showed that NAC reduced cannabis use in adolescents, but this was not evidenced in adults.¹⁹ This improvement did not seem to be related with craving changes.

Regarding smoking cessation, an open label-study assessing the combination of NAC and varenicline showed a reduction of cigarettes consumption as well as a reduction in craving and smoking reward.²⁰ A few clinical trials showed a significant reduction in cigarette consumption after 12 weeks as well as increased rates of abstinence and reduced craving with NAC.²¹ However, other studies did not show a significant decrease in tobacco use. In a double-blind, placebo-controlled, 4-day study of 23 young adults NAC produced no difference in nicotine craving but reduced withdrawal scores and measures of the rewarding properties of the first cigarette posttreatment.¹⁷

A clinical trial showed contrary results regarding the reduction of metamphetamine craving with NAC.²² Another trial found benefits of NAC in gambling disorder.²³

A systematic review of 9 studies confirmed the potential of NAC for the treatment of addiction, especially to cocaine and cannabis.²⁴ And, a recent meta-analysis showed that NAC is superior to placebo in reducing drug craving.²⁵ Nevertheless, the evidence is limited.

Despite controversy in current clinical evidence, most of the studies showed a potential therapeutic effect of NAC in addiction disorders.

Anxiety involves disruptions in the hypothalamic-pituitary-adrenal (HPA) axis signaling pathways and affects the stress response, which may be associated with oxidative stress. So far, only a case study using NAC in anxiety has been reported.²

ADHD is a neurodevelopmental disorder where a disruption of brain dopamine, norepinephrine and glutamate systems, as well as oxidative stress and mitochondrial dysfunction may be involved. However, clinical trials assessing NAC treatment are still lacking.²

Regarding the pathophysiology of autism spectrum disorders, evidence suggests mitochondrial dysfunction, oxidative stress and abnormalities in redox regulation, immune dysfunction and inflammation, environmental toxicants and disruption in other metabolic processes, including folate and cobalamin.² Although some controlled trials failed to show improvements on clinical outcomes in autism, one of them showed improvement in oxidative stress, and others to have benefits in irritability, social abilities, and aggression.^26-30 Larger clinical trials are needed to assess the response of core autism symptoms to NAC.

Bipolar disorder has been related to oxidative stress, mitochondrial dysfunction, and immune dysregulation. High-quality studies have demonstrated that NAC can improve depressive symptoms during maintenance phase treatment, the scores in MADRS and Bipolar Depression Rating Scale (BDRS), response rate, symptom remission, quality of life, and functioning.³¹ Time to a new mood episode has not shown significant differences with the use of NAC versus placebo.

Animal studies have shown reductions in hippocampal mGlu2 receptors in mice that were not resilient to stress and higher susceptibility to stress in mice lacking mGlu2 receptor.³² A decrease in mGlu2 receptors and in the catalytic subunit of Sxc- in chronic stress was also reported.³³ As mentioned, NAC enhances the activation of Sxc-, which has been linked to resilience to stress in animal studies. Antidepressant effects of NAC were blocked by antagonists of the inotropic glutamate receptor AMPA in mice studies, which suggests the involvement of AMPA receptors in the antidepressant-like effects of NAC.³⁴ Use in depression is also supported by the presence of oxidative stress in depression.

Clinical trials are overall in the same line, suggesting a potential of NAC as adjunctive treatment in depression. Although no differences in depressive symptoms assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) were found in a clinical trial comparing NAC with placebo, differences were significant and in favor of NAC at the 16-week post discontinuation endpoint, which was also seen in other clinical outcomes.³⁵ Reduction in depressive symptoms and benefits in quality of life were also found in secondary analysis of other studies. A recent meta-analysis including 5 studies assessing depressive symptoms with a follow-up of 12 to 24 weeks revealed significantly greater improvements in MADRS and functionality with NAC compared with placebo.³⁶

A large quantity of trials has assessed NAC in impulse-control disorders. A small placebo-controlled clinical trial and one case series suggest the potential efficacy of NAC in nail biting.^37,38 Greater evidence has shown the benefit of NAC in excoriation and in trichotillomania.^39,40 The use of NAC is recommended in these cases. Larger controlled trials should be conducted to confirm the advantages of NAC in impulse-control disorders.

OCD’s pathophysiology relies on excessive glutamatergic activity and altered dopamine reward system signaling, which worsens oxidative stress. The ability of NAC to modulate glutamate and dopamine neurotransmission and its antioxidant properties have led to the study of NAC as an adjunctive therapy in OCD. One clinical trial found improvements in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Clinical Global Impression (CGI) Severity Scale after 12 weeks, compared with placebo, although not on the CGI Improvement Scale.⁴¹ However, evidence regarding the treatment effects of NAC in OCD is still limited, and further research is needed.

Along with genetic predisposition and environmental factors, oxidative stress, mitochondrial dysfunction and immune abnormalities seem to be implicated in the etiopathology of schizophrenia. Some clinical trials have reported positive results with NAC, especially for negative symptoms, assessed with PANSS and the CGI, but not for positive symptoms.^14,42The benefits of NAC could be based on the regulation of glutamate homeostasis with NAC. Further clinical trials are needed to confirm these findings.

Clinical studies and use in clinical practice have shown that treatment with oral NAC is well tolerated and safe, even at high doses. The most common adverse effect of NAC is gastrointestinal discomfort (eg, emesis, diarrhea). Severe skin reactions have been seen in very rare cases, and a reduction in platelet aggregation has been also observed. Antitussive medicines should not be administered concomitantly with NAC due to the decrease in the cough reflex, which could enhance the accumulation of bronchial secretions. The administration of oral antibiotics and NAC should be spaced by at least 2 hours, because the coadministration may be associated with decreased antibiotic activity. The concomitant administration of NAC and nitroglycerin should be avoided or at least monitored, because it induces hypotension.

Regarding patients with bronchial asthma, NAC should be discontinued in case of bronchospasm. NAC is contraindicated in children aged younger than 2 years because mucolytics can cause bronchial obstruction. Caution is advised for patients with a history of peptic ulcer. NAC is contraindicated in patients with hypersensitivity to the active substance or any of the excipients, during pregnancy and breastfeeding.

Clinical research and clinical practice have shown that NAC is effective, safe, and mostly well tolerated. The therapeutic activity of NAC relies on several mechanisms of action, such as the reduction of oxidative stress, modulation of mitochondrial dysfunction, apoptosis, inflammatory processes, and modulation of glutamate homeostasis. This has led researchers to assess its potential use in several fields, including many different psychiatric disorders, as an adjunctive therapy.

Preclinical studies with NAC are promising, but clinical evidence is lacking in some areas. Clinical studies assessing NAC in depression suggest the efficacy of NAC in symptom improvement as an adjunctive therapy. The role of NAC in addictions is the most studied, particularly in cannabis or cocaine users, with mixed results in terms of relapse prevention, but suggesting that NAC might be more effective at preventing psychostimulant relapse than promoting initial cessation.

Although further larger studies are needed to increase the accuracy of current recommendations, NAC has shown to be a potential adjunctive treatment for many different disorders.

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