N-Acetylcysteine (NAC) is the N-acetyl derivative of cysteine, and is less reactive, less toxic, and less susceptible to oxidation than cysteine, as well as being more soluble in water. For these reasons it is a better source of cysteine than the parenteral administration of cysteine itself [1]. NAC is rapidly absorbed, with time to peak plasma levels (tmax) being 1.4 ± 0.7 h following oral administration. The average elimination half-life (t1/2) has been reported to be 2.5 ± 0.6 h [2]. The bioavailability of NAC increases according to the dose, with the peak serum level being on average 16 µmol/L after 600 mg and 35 µmol/L after 1200 mg [3]. When taken orally NAC is readily taken up in the stomach and gut and sent to the liver where it is converted almost entirely to cysteine and used for glutathione (GSH) synthesis [4]. Cysteine that is not converted to GSH is capable of crossing the blood–brain barrier by means of sodium-dependent transport systems [5].
The endogenous tripeptide GSH is the most abundant low-molecular-weight thiol in human cells and plays a central role in antioxidant defense from ROS [6] as well as protection against toxic compounds [7]. GSH is synthesized in tissue from the amino acids L-cysteine, L-glutamic acid, and glycine, where the availability of cysteine is generally the rate-limiting factor in its production [8]. Across a number of studies, supplementation using NAC has been found to be an effective way of increasing intracellular GSH levels, in clinical cases of deficiency [9–11] as well as amongst healthy volunteers [12]. Due to its effectiveness in raising GSH levels and protecting the human body from oxidative stress and toxins, NAC supplementa-tion has been investigated as a treatment for a wide number of conditions including paracetamol intoxication, HIV, cancer, radiocontrast-induced nephropathy, and chronic obstructive pulmonary disease [6]. There is evidence to suggest that in Alzheimer’s disease (AD), GSH levels are decreased in both cortical areas and the hippocampus [13]. For this reason NAC may play a neuroprotective role by restoring GSH levels to a normal state.
In vitro research by Chen and colleagues [14] revealed that pretreatment of cortical neurons with NAC protected mitochondrial function and membrane integrity under conditions of oxidative stress. Similarly, Olivieri and colleagues [15] found a neuroprotective effect for NAC in neuroblastoma cells exposed to oxidative stress. Pretreatment with NAC resulted in a reduction in oxidative stress resulting from exposure to amyloid-O proteins, as well as a reduction in phosphotau levels. Research by Martinez and colleagues [16] revealed that aged mice fed NAC for 23 weeks performed better on a passive avoidance memory test than age-matched controls. Furthermore, lipid peroxide and protein carbonyl contents of the synaptic mitochondria were found to be significantly decreased in the NAC-supplemented animals compared to the controls.
Mice deficient in apolipoprotein E undergo increased oxidative damage to brain tissue and cognitive decline when maintained on a folate-free diet. Tchantchou et al. [17] found that dietary supplementation with NAC (1 g/kg diet) alleviated oxidative damage and cognitive decline, and restored GSH synthase and GSH levels to those of normal mice. There is also evidence to suggest that NAC supplementation may
bring about a reduction in amyloid-O formation. In an animal model of AD using 12-months-old SAMP8 mice with an overexpression of the amyloid precursor pro-tein, Farr et al. [18] found chronic administration of NAC to bring about significantly improved memory performance on the T-maze avoidance paradigm and lever press appetitive task. In an animal model of AD using TgCRND8 mice, Tucker et al. [19] found chronic treatment of NAC for 3 months to result in a significant reduction of amyloid-O in cortex. Similarly, research by Fu et al. [20] revealed that mice with amyloid-O peptide intracerebroventricularly injected performed significantly better in behavioral tests of memory and learning when pretreated with NAC in compari-son to those without pretreatment. NAC pretreatment was also found to significantly reverse reductions in GSH and ACh.
While considerable experimental evidence exists for the neuroprotective role of NAC, there is currently a scarcity of clinical studies examining its efficacy in the treatment and prevention of dementia. One such study, a double-blind clinical trial of NAC in patients with probable AD was conducted by Adair and colleagues [21]. Forty-three patients were randomized to either placebo or 50 mg/kg/day NAC for 6 months and tested at baseline as well as at 3 and 6 months on MMSE as well as a cognitive battery. NAC supplementation was not found to be associated with significant differences in MMSE scores compared to placebo at either 3 or 6 months; however, patients receiving NAC showed significantly better performance on the letter fluency task compared to placebo, as well as a trend toward improvement in performance on the Wechsler memory scale immediate figure recall test. Further, ANOVA using a composite measure of cognitive tests favored NAC treatment at both 3 and 6 months.
In a 12 month open-label study of the efficacy of a nutraceutical and vitamin formulation in the treatment of early-stage AD, Chan et al. [22] administered 600 mg of NAC daily as part of a larger formulation of substances including ALCAR, alpha-tocopherol, B6, folate, and S-adenosyl methionine to 14 community-dwelling individuals. Participants were found to be significantly improved on the dementia rating scale (DRS) at both 6 and 12 months, with an overall improvement of 31%. However, a limitation of this study was that no placebo group was used for comparison, although the authors claim that the efficacy of their nutraceutical formulation exceeded that of historical placebos in previous studies of mild-to-moderate AD. In a follow-up study by the same group [23], the efficacy of the same nutraceutical formulation containing NAC was tested in a group of 12 nursing home residents with moderate to late-stage AD over a 9 month period. This time participants were randomized to either treatment or placebo. The nutraceutical formulation was found to delay cognitive decline as measured by the DRS for approximately 6 months, whereas in the placebo group a similar rate of decline was observed at only 3 months. While it is difficult to differentiate the efficacy of NAC from the other substances included in the formulation, these studies provide preliminary evidence for the efficacy of NAC in improving symptom severity in early-stage AD, and delaying the onset of decline in moderate to late-stage AD.
Group II metabotropic glutamate receptors (mGluR2/3) are located presynaptically on neurons in a large number of brain regions including the cortex, amygdala, hippocampus, and striatum [24], and play an important role in the regulation of the synaptic release of glutamate [25]. Stimulation of mGluR2/3 receptors by extracellular glutamate has an inhibitory effect on the synaptic release of glutamate [26]. Extracellular levels of glutamate are maintained primarily by means of the cystine–glutamate antiporter [27]. This Na+-independent antiporter is bound to plasma membranes and is found ubiquitously throughout the body, while being located predominantly on glial cells in the human brain [28]. Cystine is the disulfide derivative of cysteine, consisting of two oxidized cysteine residues. When extracellular levels of cystine are increased in the brain, the antiporters on glial cells exchange extracellular cystine for intracellular glutamate. This leads to the stimulation of mGluR2/3 receptors and inhibition of synaptic glutamate release. For this reason, cysteine prodrugs have the ability to reduce the synaptic release of glutamate, with important implications for the treatment of psychiatric disorders.
INHIBITION OF GLUTAMATE RELEASE IN OBSESSIVE COMPULSIVE DISORDER
A number of magnetic resonance spectroscopy (MRS) studies of obsessive compulsive disorder (OCD) have revealed abnormal glutamate transmission in brain regions associated with cortico-striatal-thalamo-cortical (CSTC) neurocircuitry. Glx, a composite measure of glutamate, glutamine, homocarnosine, and GABA, has been found to be elevated in the caudate in OCD patients and to normalize again following SSRI treatment [29–33]. This finding is consistent with the metabolic hyperactivity in CSTC circuits, which is a known hallmark of OCD [34]. In contrast, Glx levels have been found to be decreased in the anterior cingulate [35], a finding that parallels the inverse relationship between anterior cingulate and basal ganglia volume in OCD patients [36]. Further evidence of elevated glutamate levels associated with OCD comes from a study by Chakrabarty et al. [37], who reported increased levels of glutamate in the CSF of drug-naive OCD patients.
A number of studies have investigated the effects of glutamate-modulating drugs in the treatment of OCD spectrum disorders. In an open-label study using Riluzole, a pharmacological agent which reduces synaptic glutamate release, Pittenger et al. [38–39] reported a significant decrease in symptoms in 13 treatment-resistant OCD patients over a 12 week period. However, it has been found that not all anti-glutamatergic agents have been found to be effective, with topiramate (Topamax) being found to exacerbate OCD symptoms and Lamotrigine found to be ineffective [36]. There have also been mixed results found to date for the efficacy of memantine in the treatment of OCD [40]. This is most likely due to differences in the mechanism of action associated with each of these varied compounds.
Due to the effects of inhibiting synaptic glutamate release through glial cystine– glutamate exchange, NAC also been investigated as a possible treatment for OCD. In a case study of a 58 year-old woman with SRI-refractory OCD, Lafleur et al. [41] reported that NAC augmentation of fluvoxamine resulted in a marked reduction in OCD symptoms (Y-BOCS), and a clinically significant improvement in OCD symptoms. The NAC dose used in this study was titrated up from 1200 mg PO daily to 3000 mg daily over a 6 week period, and then maintained at this dosage level for a further 7 weeks. It is interesting to note that a reduction of 8 points on the Y-BOCS scale was noticed after only 1 week of treatment, which is indicative of rapid onset of treat-ment effects in comparison to conventional SSRI treatments for OCD, which may take several weeks for effects to become noticeable [42]. The possibility is also raised that there are acute effects associated with NAC use, whereby a patient with OCD may be able to use NAC on as-needed basis as an augmentation strategy for days when their symptoms are worse than usual. Two clinical trials are currently underway to test the efficacy of NAC in the treatment of OCD. Costa and colleagues from the University of Sao Paulo are conducting a 16-week intervention study using 3000mg/day NAC as an adjunctive treatment in OCD (NCT01555970) while Pittenger and colleagues from Yale University are conducting a 12-week study using 2400mg/day NAC for children aged 8–17 years (NCT01172275). It is hoped that these studies will provide important data as to the efficacy of NAC as treatment strategy for OCD.
A disorder related to OCD, which is classified as part of the OCD spectrum dis-orders is trichotillomania, characterized by repetitive hair pulling. Grant et al. [43] conducted a double-blind trial to assess the efficacy of NAC (1200–2400 mg/day) in 50 participants with trichotillomania over a 12 week period. Patients in the NAC treat-ment group were found to have significantly greater reductions in hair-pulling symptoms in comparison to placebo. Significant improvements were observed from 9 weeks of treatment onwards. Fifty-six percent of patients were found to be “much or very much improved” from the NAC treatment group in comparison to only 16% assigned to the placebo group. Another OCD spectrum disorder that NAC use has been investigated as a potential treatment strategy is compulsive nail-biting. Berk et al. [44] present three case studies where patients with a life-long history of compulsive nail-biting were found to benefit from NAC treatment. In the first case study, a 46 years old woman is reported to stop nail-biting altogether over a 7 months period using a dosage of 1000 mg NAC BID. In the second case study, a 44 years old woman is reported to stop nail biting after 4 months of treatment with NAC 1000 mg BID, and to have not recommenced on a 2 month follow-up. In the third case study, a 46 years-old patient was not reported to stop nail-biting all together, but noticed a reduction in this behavior after 28 weeks after starting NAC treatment. In addition to trichotillomania and nail-biting, NAC has also been reported to be effective in the reduction of skin-picking behavior [45].
A number of concerns will need to be addressed in assessing the suitability of NAC as a viable treatment option for OCD and related disorders, beyond a demonstration of efficacy. Considering the high degree of comorbidity of depression with OCD [46], it is necessary in further research to investigate the effects of NAC on mood. Although preclinical evidence to date is promising, it suggests that agonist acting on the mGluR2/3 receptors may dampen responses to stress and have a potential antidepressant effect [47–48], and the case study by Lafleur et al. [41] also reported a decrease in depression in their patient as measured by the HAM-D over the course of the trial. It may be important to monitor possible acute side effects of cognitive slowing that may result from over-regulation of glutamatergic tone with high-dose NAC use, as has been occasionally reported in relation to Riluzole [49].
Increased glutamate transmission in the nucleus accumbens has been found to be a mediator of drug-seeking behavior, while in the case of repeated use of drugs of abuse such as cocaine, a reduction in basal levels of extracellular glutamate in the nucleus accumbens are also observed [50,51]. Alterations in cystine–glutamate exchange and metabotropic glutamate receptor activity has also been found to regulate vesicular release of dopamine, another central neurotransmitter in reward-related behavior [26,52]. Due to its effects in inhibiting the synaptic release of glutamate in the CNS, NAC has been investigated for use in the treatment of substance abuse. Preclinical research by Baker et al. [52] revealed that systemic administration of NAC to cocaine-treated rats restored extracellular glutamate levels in the nucleus accumbens in vivo. Further, due to its effects on stimulating cystine–glutamate exchange, NAC was found to block cocaine-primed reinstatement of drug-taking behavior. In rats withdrawn from cocaine use, there is a change in the ability to create synaptic plasticity, which is related to alterations in prefrontal glutamatergic innervation of the nucleus accumbens core. Moussawi et al. [53] reported that the administration of NAC to cocaine-treated rats reversed the deficit in synaptic plasticity by indirect stimulation of mGlu2/3 and mGlu5 receptors, responsible for long-term potentiation and long-term depression, respectively.
In a pilot study investigating the effects of NAC on craving in 15 cocaine-dependent humans, LaRowe et al. [54] reported that 600 mg NAC administered at 12 h intervals over a 3 day period resulted in a significant reduction in the desire to use cocaine, interest in cocaine and cue viewing time, in the presence of cocaine-related cues. An open-label dose-ranging study of NAC in the treatment of cocaine dependence in humans was conducted by Mardikian et al. [55]. Twenty-three treat-ment-seeking cocaine-dependent patients were assigned to either NAC 1200, 2400, or 3600 mg/day over a 4 week trial. Sixteen of the patients completed the trial, and the majority of these either stopped using cocaine or significantly reduced their intake by the end of the trial. The higher doses of 2400 and 3600 mg/day were found to be more effective in treating cocaine-dependence, with higher retention rates in comparison to the lower dose of 1200 mg/day.
In human research using other drugs of abuse, similar results have been reported. In an open-label study investigating the use of NAC in cannabis addiction, Gray et al. [56] reported that 1200 mg NAC twice daily resulted in significant reductions in marijuana craving amongst 24 cannabis-dependent participants, as well as a trend-level reduction in marijuana usage, over a 4 week period. Knackstedt et al. [57] conducted a study to investigate the effect of nicotine on cystine–glutamate exchange in the nucleus accumbens and the efficacy of NAC in the treatment of nicotine addiction, using both animal and human data. Over a 21 day period, rats self-administered nicotine intravenously and 12 h following the last nicotine dose the brains were removed and immunoblotting was conducted in order to investigate changes in the catalytic subunit of the cystine–glutamate exchanger (xCT) or the glial glutamate transporter (GLT-1) in the nucleus accumbens, the ventral tegmental area (VTA), the amygdala, and the PFC. Decreased expression of the xCT was observed in the nucleus accumbens and the VTA, and decreased GLT-1 expression was observed in the nucleus accumbens. In the second part of the study, 29 nicotine-dependent human subjects were administered 2400 mg NAC/daily versus placebo for 4 weeks in a double-blind design. Smokers treated with NAC were found to report a greater reduction in the number of cigarettes smoked over the 4 week period in comparison to placebo, with a significant time × treatment group interaction when controlling for alcohol consumption.
Preclinical studies have demonstrated that levels of glutamate in the nucleus accumbens mediate reward-seeking behaviors in general [58], not only addictive behaviors related to pharmacological agents. A pilot study by Grant et al. [59] investigated the efficacy of NAC in the treatment of pathological gambling. Twenty-seven pathological gamblers were administered NAC over an 8 week period in an open-label design, start-ing with an initial dose of 600 mg/day that was titrated up over the first 4 weeks until a noticeable clinical improvement was seen, with a maximum possible dose being 1800 mg/day. The Yale-Brown obsessive compulsive scale modified for pathological gambling (PG-YBOCS) was used as the primary endpoint. PG-YBOCS scores were found to be significantly decreased by the end of the 8 weeks, with a mean effective NAC dose of 1476.9 ± 311.13 mg/day. Sixteen participants were classified as responders, defined by a 30% or greater reduction in PG-YBOCS score. Of these, 13 participants entered a double-blind follow-up phase, where they were randomized to either continue receiving their maximum dose from the open-label phase versus placebo over a 6 week period. At the end of the double-blind phase, 83.3% of the NAC group still met responder criteria in comparison to only 28.6% of those assigned to placebo. Although the first of its kind, this well-designed pilot study provides preliminary data in support of the efficacy of NAC in the treatment of pathological gambling.
A longer-term study by Bernardo et al. [60] investigating the effect of 2 g/day NAC on the use of alcohol, tobacco, and caffeine use in patients with bipolar disorder failed to find efficacy for NAC. Seventy-five participants were randomized to NAC or placebo over a 6 month period, with no significant changes in substance use observed over the length of the trial, with the exception of reduced caffeine intake in the NAC group at week 2. However, it is important to note that patients were selected for the study on the basis of clinical criteria for bipolar disorder, rather than a primary substance abuse disorder. For this reason, there were low rates of substance use in the cohort, which detracted from the statistical power necessary to determine a treatment effect.
CSF levels of GSH have been found to be decreased by 27% in drug-naive schizophrenia patients, while MRS has revealed that levels in the medial PFC are reduced by as much as 52% [61]. Decreased levels of GSH have also been reported in the caudate region in schizophrenia patients, as revealed by post-mortem assay [62]. There is evidence to suggest that decreased levels of GSH in schizophrenia are due to genetic polymorphisms in the genes responsible for GSH synthesis [63,64]. Due to the efficacy of NAC in boosting GSH levels in the CNS, it has been investigated for possible clinical benefits in the treatment of schizophrenia. Berk et al. [65] administered NAC 2000 mg/day versus placebo over a 6 month period to 140 patients with chronic schizophrenia, as augmentation to their regular antipsychotic medication. Patients receiving NAC were found to have a significant reduction in negative symptoms of schizophrenia as measured by the positive and negative symptoms scale (PNSS) as well as a reduction in clinical global impression of symptom severity (CGI-S) and CGI-improvement. These findings are corroborated by the research of Lavoie et al. [66], which has demonstrated that chronic NAC use at 2000 mg/day over 60 days improves mismatch negativity, a measure of NMDA receptor function, in schizophrenia patients. While the reason why restoring GSH levels and reducing oxidative stress in the brain brings about a clinical improvement in the negative symptoms of schizophrenia remains to be elucidated, these findings provide encouraging preliminary evidence for the efficacy of NAC as an augmentation strategy in treating this disorder.
Alterations in GSH metabolism have also been described as a feature of bipolar disorder as well as schizophrenia [67–69]. By applying the same rationale to bipolar disorder, Berk et al. [70] investigated whether boosting GSH levels through NAC supplementation would improve depressive symptoms in this disorder. Using a randomized controlled study design 75 individuals with bipolar disorder were administered NAC 2000 mg/day versus placebo over a 6 month period. NAC treatment was found to be associated with a significant improvement on the Montgomery Asberg depression rating scale (MASRS) after 20 weeks. The authors hypothesized that the clinical improvement could be attributed to the restoration of oxidative imbalances that are perturbed in bipolar disorder.
Oral doses of NAC up to 8000 mg/day have not been known to cause clinically significant adverse reactions [10], and in a review of over 46 placebo-controlled tri-als, with NAC administered orally to a total of 4000 people, no significant adverse effects from NAC treatment were observed [4]. In relation to high oral doses of NAC (around 10,000 mg) typically used in cases of acetaminophen overdose, a review by Miller and Rumack [71] reported that mild symptoms such as headache, lethargy, fever, or skin rash occur in around 1%–5% of patients, while more moderate symptoms such as increased blood pressure, chest pain, hypertension, rectal bleeding, and respiratory distress occur in less than 1% of patients. One potential cause for concern over NAC supplementation was raised in a study by Palmer et al. [72] where rats receiving high-dose NAC in vivo for 3 weeks developed pulmonary arte-rial hypertension (PAH). The authors linked the finding of PAH to the conversion of NAC to S-nitroso-N-acetylcysteine (SNOAC) and a resultant hypoxia-mimetic effect. However, it is important to note that the rats were continuously exposed to a dose per weight roughly 40 times higher than the dose typically used in human studies. Good manufacturing practice (GMP) is important for NAC to ensure minimal oxidization to its dimeric form (di-NAC). Di-NAC is pharmacologically active at very low concentrations, and has immunological effects opposite to that of NAC [73]. For this rea-son it is important that any NAC obtained for chronic usage is from a trusted source.
NAC is a substance with the potential to treat a diverse range of neuropathologies (see Table below for a summary of clinical research). In whole NAC is well tolerated, with a low incidence of adverse events in the dose ranges typically required for clinical effects. As a highly effective cysteine prodrug, NAC can both significantly boost endogenous GSH production and influence the synaptic release of glutamate due to its effects on cystine–glutamate exchange. For these reasons, NAC can be used as a means of ameliorating symptoms in wide range of disorders of the CNS including neurodegenerative disorders as well as obsessive-compulsive spectrum disorders, substance abuse disorders, behavioral addictions, schizophrenia, and bipolar disorder. Further large-scale trials of NAC are warranted in order to better establish clinically effective dosage ranges and treatment schedules for these varied neurodegenerative and neuropsychiatric conditions.
AD, Alzheimer’s disease; CGI, clinical global impression; DRS, dementia rating scale; MADRS, Montgomery Asberg depression rating scale; OCD, obsessive compulsive disorder; PANSS, positive and negative symptoms scale; PG-YBOCS, Yale-Brown obsessive compulsive scale modified for pathological gambling; RCT, double-blind randomized placebo-controlled trial; Y-BOCS, Yale-Brown obsessive compulsive scale.
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