title: Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial Glutathione Precursor N-Acetyl-Cysteine Modulates EEG Synchronization in Schizophrenia Patients: A Double-Blind, Randomized, Placebo-Controlled Trial N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson's Disease: Preliminary Clinical and Cell Line Data Randomized, Double-Blind, Placebo-Controlled Trial of N-Acetylcysteine Augmentation for Treatment-Resistant Obsessive-Compulsive Disorder. A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms N-Acetylcysteine Normalizes Glutamate Levels in Cocaine-Dependent Patients: A Randomized Crossover Magnetic Resonance Spectroscopy Study N-Acetyl Cysteine in the Treatment of Obsessive Compulsive and Related Disorders: A Systematic Review [N-acetyl-L-cysteine reduces the ozone-induced lung inflammation response in mice]. Complementary and alternative medicine use in Australia: a national population-based survey. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence.
abstract: Background N-acetyl cysteine ( NAC ) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial . The current study aim ed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder . Method The efficacy of a double blind r and omized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined . Participants ( n = 149 ) had a Montgomery Asberg Depression Rating Score of ≥12 at trial entry and , after eight weeks of open-label NAC treatment , were r and omized  to adjunctive NAC or placebo , in addition to treatment as usual . Participants ( primarily out patients ) were recruited through public and private services and through newspaper advertisements .  Time to intervention for a mood episode was the primary endpoint of the study , and changes in mood symptoms , functionality and quality of life measures were secondary outcomes . Results There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase . During the subsequent double-blind phase , there was minimal further change in outcome measures with scores remaining low . Consequently , from this low plateau , between-group differences did not emerge on recurrence , clinical functioning or quality of life measures . Conclusions There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial ; however , these findings may be confounded by limitations .Trial Registration The trial was registered with the Australian New Zeal and Clinical Trials Registry ( ACTRN12607000074493 ) Glutathione ( GSH ) dysregulation at the gene , protein , and functional levels has been observed in schizophrenia patients . Together with disease-like anomalies in GSH deficit experimental models , it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization , and thus possibly causing schizophrenia symptoms . To determine whether increased GSH levels would modulate EEG synchronization , N-acetyl-cysteine ( NAC ) , a glutathione precursor , was administered to patients in a r and omized , double-blind , crossover protocol for 60 days , followed by placebo for another 60 days ( or vice versa ) . We analyzed whole-head topography of the multivariate phase synchronization ( MPS ) for 128-channel resting-state EEGs that were recorded at the onset , at the point of crossover , and at the end of the protocol . In this proof of concept study , the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal , the right temporal , and the bilateral prefrontal regions . These changes were robust both at the group and at the individual level . Although MPS increase was observed in the absence of clinical improvement at a group level , it correlated with individual change estimated by Liddle 's disorganization scale . Therefore , significant changes in EEG synchronization induced by NAC administration may precede clinical ly detectable improvement , highlighting its possible utility as a biomarker of treatment efficacy . Trial Registration Clinical Trials.gov Backgound The purpose of this study was to assess the biological and clinical effects of n-acetyl-cysteine ( NAC ) in Parkinson ’s disease ( PD ) . Methods The overarching goal of this pilot study was to generate additional data about potentially protective properties of NAC in PD , using an in vitro and in vivo approach . In preparation for the clinical study we performed a cell tissue culture study with human embryonic stem cell (hESC)-derived midbrain dopamine ( mDA ) neurons that were treated with rotenone as a model for PD . The primary outcome in the cell tissue cultures was the number of cells that survived the insult with the neurotoxin rotenone . In the clinical study , patients continued their st and ard of care and were r and omized to receive either daily NAC or were a waitlist control . Patients were evaluated before and after 3 months of receiving the NAC with DaTscan to measure dopamine transporter ( DAT ) binding and the Unified Parkinson ’s Disease Rating Scale ( UPDRS ) to measure clinical symptoms . Results The cell line study showed that NAC exposure result ed in significantly more mDA neurons surviving after exposure to rotenone compared to no NAC , consistent with the protective effects of NAC previously observed . The clinical study showed significantly increased DAT binding in the cau date and putamen ( mean increase ranging from 4.4 % to 7.8 % ; p<0.05 for all values ) in the PD group treated with NAC , and no measurable changes in the control group . UPDRS scores were also significantly improved in the NAC group ( mean improvement of 12.9 % , p = 0.01 ) . Conclusions The results of this preliminary study demonstrate for the first time a potential direct effect of NAC on the dopamine system in PD patients , and this observation may be associated with positive clinical effects . A large-scale clinical trial to test the therapeutic efficacy of NAC in this population and to better eluci date the mechanism of action is warranted . Trial Registration Clinical Trials.gov OBJECTIVE To evaluate the efficacy of serotonin reuptake inhibitor ( SRI ) augmentation with N-acetylcysteine ( NAC ) , a glutamate modulator and antioxidant medication , for treatment-resistant obsessive-compulsive disorder ( OCD ) . METHODS We conducted a r and omized , double-blind , placebo-controlled , 16-week trial of NAC ( 3,000 mg daily ) in adults ( aged 18 - 65 years ) with treatment-resistant OCD , established according to DSM-IV criteria . Forty subjects were recruited at an OCD-specialized outpatient clinic at a tertiary hospital ( May 2012-October 2014 ) . The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale ( Y-BOCS ) scores . To evaluate the variables group , time , and interaction effects for Y-BOCS scores at all time points , we used nonparametric analysis of variance with repeated measures . Secondary outcomes were the severity scores for anxiety , depression , specific OCD symptom dimensions , and insight . RESULTS Both groups showed a significant reduction of baseline Y-BOCS scores at week 16 : the NAC group had a reduction of 4.3 points ( 25.6 to 21.3 ) , compared with 3.0 points ( 24.8 to 21.8 ) for the placebo group . However , there were no significant differences between groups ( P = .92 ) . Adding NAC was superior to placebo in reducing anxiety symptoms ( P = .02 ) , but not depression severity or specific OCD symptom dimensions . In general , NAC was well tolerated , despite abdominal pain being more frequently reported in the NAC group ( n [ % ] : NAC = 9 [ 60.0 ] , placebo = 2 [ 13.3 ] ; P < .01 ) . CONCLUSIONS Our trial did not demonstrate a significant benefit of NAC in reducing OCD severity in treatment-resistant OCD adults . Secondary analysis suggested that NAC might have some benefit in reducing anxiety symptoms in treatment-resistant OCD patients . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01555970 BACKGROUND Cannabis use disorder ( CUD ) is a prevalent and impairing condition , and established psychosocial treatments convey limited efficacy . In light of recent findings supporting the efficacy of N-acetylcysteine ( NAC ) for CUD in adolescents , the objective of this trial was to evaluate its efficacy in adults . METHODS In a 12-week double-blind r and omized placebo-controlled trial , treatment-seeking adults ages 18 - 50 with CUD ( N=302 ) , enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites , were r and omized in a 1:1 ratio to a 12-week course of NAC 1200 mg ( n=153 ) or placebo ( n=149 ) twice daily . All participants received contingency management ( CM ) and medical management . The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment , compared between NAC and placebo participants . RESULTS There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence ( odds ratio=1.00 , 95 % confidence interval 0.63 - 1.59 , p=0.984 ) . Overall , 22.3 % of urine cannabinoid tests in the NAC group were negative , compared with 22.4 % in the placebo group . Many participants were medication non-adherent ; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group . CONCLUSIONS In contrast with prior findings in adolescents , there is no evidence that NAC 1200 mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM . This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development , cannabis use profiles , responses to embedded behavioral treatment , medication adherence , and other factors BACKGROUND Brain glutathione levels are decreased in schizophrenia , a disorder that often is chronic and refractory to treatment . N-acetyl cysteine ( NAC ) increases brain glutathione in rodents . This study was conducted to evaluate the safety and effectiveness of oral NAC ( 1 g orally twice daily [ b.i.d . ] ) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period . METHODS A r and omized , multicenter , double-blind , placebo-controlled study . The primary readout was change from baseline on the Positive and Negative Symptoms Scale ( PANSS ) and its components . Secondary readouts included the Clinical Global Impression ( CGI ) Severity and Improvement scales , as well as general functioning and extrapyramidal rating scales . Changes following a 4-week treatment discontinuation were evaluated . One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were r and omized ; 84 completed treatment . RESULTS Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [ -5.97 ( -10.44 , -1.51 ) , p = .009 ] , PANSS negative [ mean difference -1.83 ( 95 % confidence interval : -3.33 , -.32 ) , p = .018 ] , and PANSS general [ -2.79 ( -5.38 , -.20 ) , p = .035 ] , CGI-Severity ( CGI-S ) [ -.26 ( -.44 , -.08 ) , p = .004 ] , and CGI-Improvement ( CGI-I ) [ -.22 ( -.41 , -.03 ) , p = .025 ] scores . No significant change on the PANSS positive subscale was seen . N-acetyl cysteine treatment also was associated with an improvement in akathisia ( p = .022 ) . Effect sizes at end point were consistent with moderate benefits . CONCLUSIONS These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia Background Clozapine is an effective treatment for a proportion of people with schizophrenia ( SZ ) who are resistant to the beneficial effects of other antipsychotic drugs . However , anything from 40–60 % of people on clozapine experience residual symptoms even on adequate doses of the medication , and thus could be considered ‘ clozapine resistant ’ . Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ .  N-Acetylcysteine ( NAC ) is one such possible agent . Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population . The aim of the study reported here is to exp and this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ . Methods This study is an investigator initiated , multi-site , r and omised , placebo-controlled trial . It aims to include 168 patients with clozapine-resistant SZ , divided into an intervention group ( NAC ) and a control group ( placebo )  . Participants in the intervention group will receive 2 g daily of NAC . The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale ( PANSS ) . Secondary outcome measures will include : changes in quality of life ( QoL ) as measured by the Lancashire Quality of Life Profile ( LQoLP ) and cognitive functioning as measured by the total score on the MATRICS . Additionally we will examine peripheral and cortical glutathione ( GSH ) concentrations as process outcomes . Discussion This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine . This trial , if successful , will establish a cheap , safe and easy-to-use agent ( NAC ) as a ‘ go to ’ adjunct in patients that are only partly responsive to clozapine . Trial registration Australian and New Zeal and Clinical Trials Registration Number : Current R and omised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015 Treatment with N-acetylcysteine ( NAC ) normalizes glutamate ( Glu ) homeostasis and prevents relapse in drug-dependent animals . However , the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated . Proton magnetic resonance spectroscopy ( 1H MRS ) was used to investigate Glu changes in the dorsal anterior cingulate cortex ( dACC ) after a single dose of NAC in cocaine-dependent patients and normal controls . In an open-label , r and omized , crossover study , 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions : one group receiving no compound and the other following a single administration of 2400 mg NAC . The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity . In the medication-free condition , Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls . After administration of NAC , Glu levels were reduced in the cocaine-dependent group , whereas NAC had no effect in healthy controls . Higher baseline Glu levels were associated with higher impulsivity , and both were predictive of greater NAC-induced Glu reduction . The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients . These findings may have important implication s for treatment , because abnormal Glu levels are related to relapse , and treatment with NAC prevented relapse in animal studies . Furthermore , clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients , and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities Objective Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established . N-acetyl cysteine ( NAC ) is a glutamate modulator with promising therapeutic effect . This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders . A further objective was to detail the methodology of current clinical trials being conducted in the area . Methods PubMed , Web of Science and Cochrane Library Data base were search ed for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder ( OCD ) or obsessive compulsive related disorders . Research ers with known involvement in NAC studies were contacted for any unpublished data . Results Four clinical trials and five case reports/series were identified . Study duration s were commonly 12-weeks , using 2,400–3,000 mg/day of NAC . Overall , NAC demonstrates activity in reducing the severity of symptoms , with a good tolerability profile and minimal adverse effects . Currently there are three ongoing r and omized controlled trials using NAC for OCD ( two adults and one pediatric ) , and one for excoriation . Conclusion Encouraging results have been demonstrated from the few pilot studies that have been conducted . These results are detailed , in addition to a discussion of future potential research In this study , we investigated the protective effect of the antioxidant N-acetyl-L-cysteine ( NAC ) on the lung inflammation caused by ozone ( O3 ) exposure in mice . Thirty-two C57BL/6 mice were r and omly divided into control group , O3 group , O3+NAC group and NAC group . Mice were exposed to O3 ( 1.0 ppm ) or fresh air for 3 h on the day 1 , day 3 and day 5 , respectively . NAC ( 100 mg/kg ) was intraperitoneally applied to the mice 1 h before each exposure . At 24 h after the 3-time exposure , the alveolar wall structure was severely damaged and the infiltrated inflammatory cells were apparent perivascularly and peribronchiolarly . Significant increases in the total white blood cell count , macrophage , lymphocyte and neutrophil counts , as well as total protein concentration were observed in the bronchoalveolar lavage fluid ( BALF ) ( P < 0.05 ) . The IL-6 , IL-8 ( P < 0.01 ) and MDA levels ( P < 0.05 ) in the lung homogenates were elevated coherently . Administration of NAC could attenuate the alveolar wall structure damage induced by O3 exposure and reduce the amount of infiltrated inflammatory cells , total and differential leukocyte counts ( P < 0.05 ) , as well as the IL-6 , IL-8 ( P < 0.01 ) and MDA release ( P < 0.05 ) . Western blotting results showed that the O3 exposure up-regulated the p38 MAPK and NF-κB p65 protein expression in the lung tissue of mice ( P < 0.05 ) , which could be alleviated by NAC ( P < 0.05 ) . These results indicated that NAC could protect against O3-induced pulmonary inflammation in mice . The beneficial effect of NAC might be related with the p38 MAPK and NF-κB p65 signal pathway OBJECTIVE To investigate the use of and expenditure on 17 of the most popular forms of complementary and alternative medicine ( CAM ) by adult Australians , sociodemographic characteristics of CAM users , and communication between  CAM users and their doctors . METHODS In May-June 2005 , a sample of 1067 adults , 18 years and older , from all Australian states and territories , was recruited by r and om-digit telephone dialing and interviewed about their CAM use in the previous 12 months . RESULTS In the 12-month period , 68.9 % ( 95 % CI : 66.1%-71.7 % ) of those interviewed used at least one of the 17 forms of CAM  and 44.1 % ( 95 % confidence interval : 41.1%-47.1 % ) visited a CAM practitioner . The estimated number of visits to CAM practitioners by adult Australians in the 12-month period ( 69.2 million ) was almost identical to the estimated number of visits to medical practitioners ( 69.3 million ) . The annual " out of pocket " expenditure on CAM  , nationally , was estimated as 4.13 billion Australian dollars ( US $ 3.12 billion ) . Less than half of the users always informed their medical practitioners about their use of CAM . The most common characteristics of  CAM users were : age , 18 - 34 ; female ; employed ; well-educated ; private health insurance coverage ; and higher-than-average incomes . CONCLUSIONS CAM use nationally in Australia appears to be considerably higher than estimated from previous Australian studies . This may reflect an increasing popularity of CAM ; however , regional variations in CAM use and the broader range of CAM included in the current study may contribute to the difference . Most frequently , doctors would not appear to be aware of their patient use of CAM BACKGROUND There remains no FDA approved medication for the treatment of cocaine dependence . Pre clinical studies and early pilot clinical investigations have suggested that N-acetylcysteine ( NAC ) may be useful in the treatment of the disorder . OBJECTIVE The present report assessed the efficacy of NAC in the treatment of cocaine dependence . METHODS Cocaine-dependent volunteers ( n = 111 ) were r and omized to receive daily doses of 1,200 mg of NAC , 2,400 mg of NAC , or placebo . Participants were followed for 8 weeks ( up to three visits weekly ) . At each of these visits , urine sample s were collected , along with self-reports of cocaine use . Urine sample s were assessed for quantitative levels of benzoylecognine ( ie , cocaine metabolite ) . RESULTS Overall , the primary results for the clinical trial were negative . However , when considering only subjects who entered the trial having already achieved abstinence , results favored the 2,400 mg NAC group relative to placebo , with the 2,400 mg group having longer times to relapse and lower craving ratings . CONCLUSION While the present trial failed to demonstrate that NAC reduces cocaine use in cocaine-dependent individuals actively using , there was some evidence it prevented return to cocaine use in individuals who had already achieved abstinence from cocaine . SCIENTIFIC SIGNIFICANCE N-acetylcysteine may be useful as a relapse prevention agent in abstinent cocaine-dependent individuals
target: Good evidence exists to support the use of N-acetylcysteine as an adjunct treatment to reduce the total and negative symptoms of schizophrenia .
  N-acetylcysteine also appears to be effective in reducing craving in substance use disorders , especially for the treatment of cocaine and cannabis use among young people , in addition to preventing relapse in already abstinent individuals .
  Oral N-acetylcysteine is safe and well tolerated without any considerable adverse effects .
background: N-acetylcysteine , a sulphur-containing amino acid for the treatment of paracetamol overdose and chronic obstructive pulmonary disease , is a widely available off-the-shelf oral antioxidant supplement in many countries .
  With the potential to modulate several neurological pathways , including glutamate dysregulation , oxidative stress , and inflammation that can be beneficial to the brain functions , N-acetylcysteine is being explored as an adjunctive therapy for many psychiatric conditions .
  This narrative review synthesis es and presents the current evidence from systematic review s , meta-analyses , and latest clinical trials on N-acetylcysteine for addiction and substance abuse , schizophrenia , obsessive-compulsive and related disorders , and mood disorders .