CoChat
Sign Up
Cited by 69Smoking Behavior and CessationSubstance Abuse Treatment and OutcomesNicotinic Acetylcholine Receptors Study

N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study

Open access
Prado, Eduardo, Maes, Michael, Piccoli, Luiz Gustavo, Baracat, Marcela, Barbosa, Décio Sabattini, Franco, Olavo, Dodd, Seetal, Berk, Michael +1 more·2015·Redox Report
DOI 10.1179/1351000215y.0000000004PMC PMC6837411
Open this paper in CoChat — free accountOpen PDF

Abstract

INTRODUCTION: N-Acetylcysteine (NAC) may have efficacy in treating tobacco use disorder (TUD) by reducing craving and smoking reward. This study examines whether treatment with NAC may have a clinical efficacy in the treatment of TUD. METHODS: A 12-week double blind randomized controlled trial was conducted to compare the clinical efficacy of NAC 3 g/day versus placebo. We recruited 34 outpatients with therapy resistant TUD concurrently treated with smoking-focused group behavioral therapy. Participants had assessments of daily cigarette use (primary outcome), exhaled carbon monoxide (CO(EXH)) (secondary outcome), and quit rates as defined by CO(EXH) < 6 ppm. Depression was measured with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using conventional and modified intention-to-treat endpoint analyses. RESULTS: NAC treatment significantly reduced the daily number of cigarettes used (Δ mean ± SD = -10.9 ± 7.9 in the NAC-treated versus -3.2 ± 6.1 in the placebo group) and CO(EXH) (Δ mean ± SD = -10.4 ± 8.6 ppm in the NAC-treated versus -1.5 ± 4.5 ppm in the placebo group); 47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking as defined by CO(EXH) < 6 ppm. NAC treatment significantly reduced the HDRS score in patients with tobacco use disorder. CONCLUSIONS: These data show that treatment with NAC may have a clinical efficacy in TUD. NAC combined with appropriate psychotherapy appears to be an efficient treatment option for TUD.

Integrity signals

Registry

Crossref · 10.1179/1351000215y.0000000004

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    NAC treatment significantly reduced Hamilton Depression Rating Scale scores from baseline to endpoint compared with placebo in patients with tobacco use disorder.

    “NAC treatment significantly reduced the HDRS score in patients with tobacco use disorder.”
    • Also stated in: § Effects of treatment on other outcome measurements and side effects · plain
      “We found a significant effect of NAC reducing the HDRS score as compared with placebo.”
    • Also stated in: § Discussion · plain
      “Another important finding is that treatment with NAC significantly reduced the HDRS score from baseline to 3 months later.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Missing outcome data were missing at random, so the last observation carried forward method yields valid estimates.
    • Rests on an assumption: The NAC and placebo groups received comparable amounts of behavioral therapy and other concurrent care.
  • Findingown data

    In patients with therapy-resistant tobacco use disorder, 12 weeks of NAC 3 g/day significantly reduced the daily number of cigarettes from baseline to endpoint compared with placebo in the intention-to-treat analysis (mean change -10.9 ± 7.9 vs -3.2 ± 6.1; F = 8.77, df = 1/29, P = 0.006).

    “NAC treatment significantly reduced the daily number of cigarettes used (Δ mean±SD = -10.9± 7.9 in the NAC-treated versus -3.2 ± 6.1 in the placebo group)”
    • Also stated in: § Effects of treatment on the primary outcome · plain
      “The Δ (mean± SD) daily number of cigarettes from baseline to three months later was -10.9 ± 7.9 in NAC-treated versus -3.2 ± 6.1 in placebo-treated patients (F = 8.77, df = 1/29, P = 0.006).”
    • Also stated in: § Discussion · plain
      “reducing the daily number of cigarettes used (Δ mean ± SD = -10.9± 7.9 in the NAC versus -3.2 ± 6.1 in the placebo group)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Missing outcome data were missing at random, so the last observation carried forward method yields valid estimates.
    • Rests on an assumption: The NAC and placebo groups received comparable amounts of behavioral therapy and other concurrent care.
    • Rests on an assumption: Self-reported daily cigarette use is a valid measure of actual smoking behavior.
  • Findingown data

    There was a significant correlation between the change in exhaled carbon monoxide and the change in daily cigarette use (r = 0.705, P < 0.001, n = 31).

    “There was a significant correlation between the Δ CO EXH and Δ daily cigarette usage (r = 0.705, P < 0.001, n = 31).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Self-reported daily cigarette use is a valid measure of actual smoking behavior.
  • Interpretationown data

    NAC treatment may have an advantage because it does not induce weight gain.

    “Our findings thus suggest that treatment with NAC may have another advantage since it does not induce weight gain.”
    Quote in the paperSubstantial claim
  • Interpretationown data

    NAC may have clinical efficacy in treating tobacco use disorder.

    “These data show that treatment with NAC may have a clinical efficacy in TUD.”
    • Also stated in: § Discussion · hedged
      “All in all, our findings provide some evidence that treatment with NAC 3 g/day may significantly augment the efficacy of behavioral therapy in the treatment of tobacco use disorder.”
    Quote in the paperSubstantial claim
  • May combine two claims. 13
  • The quote only partly states this claim. 3
  • Classified as probably not a substantial claim. 13

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    In NAC-treated patients, the quit rate defined by exhaled carbon monoxide below 6 ppm was 8/17 (47.1%), a significant increase from baseline (McNemar P = 0.008), whereas placebo-treated patients had 3/14 (21.4%) with no significant change (P = 0.250).

    “47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking as defined by CO EXH <6 ppm.”
    • Also stated in: § Discussion · plain
      “47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking (as defined by COEXH <6 ppm).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Missing outcome data were missing at random, so the last observation carried forward method yields valid estimates.
    • Rests on an assumption: The NAC and placebo groups received comparable amounts of behavioral therapy and other concurrent care.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There was a marginally significant effect of NAC reducing body mass index compared with placebo.

    “There was also a marginally significant effect of NAC reducing the BMI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There were no significant correlations between change in Hamilton Depression Rating Scale score and change in daily cigarette use (r = 0.316, P = 0.201, n = 18) or change in exhaled carbon monoxide (r = 0.14, P = 0.577, n = 18).

    “There were no significant correlations between the Δ HDRS (from baseline to endpoint) and Δ number of daily cigarettes (r = 0.316, P = 0.201, n = 18) or Δ CO EXH (r = 0.14, P = 0.577 n = 18).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    There were no significant effects of NAC versus placebo on the other outcome measurements, including Sheehan Disability Scale and blood pressure, in the per-protocol analyses.

    “There were no significant effects of NAC versus placebo treatment on the other measurements (see Table 2).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In patients with therapy-resistant tobacco use disorder, 12 weeks of NAC 3 g/day significantly reduced exhaled carbon monoxide from baseline to endpoint compared with placebo in the intention-to-treat analysis (mean change -10.4 ± 8.6 ppm vs -1.5 ± 4.5 ppm; F = 12.20, df = 1/29, P = 0.002).

    “CO EXH (Δ mean± SD = -10.4± 8.6 ppm in the NAC-treated versus -1.5 ± 4.5 ppm in the placebo group)”
    • Also stated in: § Effects of treatment on secondary outcomes · plain
      “The Δ (mean ± SD) CO EXH from baseline to 3 months later was -10.4 ± 8.6 in NAC-treated patients versus -1.5 ± 4.5 in placebo-treated patients (F = 12.20, df = 1/29, P = 0.002).”
    • Also stated in: § Discussion · plain
      “CO EXH levels (Δ mean ± SD = -10.4± 8.6 ppm versus -1.5 ± 4.5 ppm in the placebo group)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Missing outcome data were missing at random, so the last observation carried forward method yields valid estimates.
    • Rests on an assumption: The NAC and placebo groups received comparable amounts of behavioral therapy and other concurrent care.

  • May combine two claims.

    Findingown data

    No serious treatment-emergent adverse events were reported, and there were no significant differences in adverse events such as nausea, diarrhea, skin allergy, or respiratory allergy between NAC and placebo groups.

    “No serious treatment emerging adverse events were reported during the course of the study.”
    • Also stated in: § Effects of treatment on other outcome measurements and side effects · plain
      “There were no significant differences in any of these adverse events between patients treated with NAC or placebo.”
    • Also stated in: § Discussion · boosted
      “Overall, NAC treatment (3 g/day) was well tolerated and only few participants reported adverse effects, nausea being the most frequent, not exceeding that of placebo.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study was registered on clinicaltrials.gov under number NCT02124525.

    “The study was registered on clinicaltrials.govnumber NCT02124525.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study was approved by the Ethics Research Committee of UEL, and all individuals gave written informed consent.

    “The study was evaluated and approved by the Ethics Research Committee of UEL.All individuals gave written informed consent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    NAC treatment may attenuate immune-inflammatory and oxidative/nitrosative pathways that drive serotonin depletion, thereby reducing nicotine use and improving tobacco use disorder.

    “NAC treatment by attenuating IO&NS pathways 1 may therefore dampen the IO&NS forces that drive serotonin depletion.Such an effect would attenuate the use of nicotine and thus lead to an improvement in tobacco use disorder.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Morris G, Mol Neurobiol.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The raters of the primary and secondary outcome measures were blind to treatment assignment.

    “The raters of the primary and secondary outcome measures were blind to treatment assignment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The study was a 12-week randomized, double-blind, placebo-controlled trial in which patients were allocated to NAC or indistinguishable placebo.

    “This randomized clinical trial was designed to examine the clinical efficacy of NAC for tobacco use disorder.We randomized the patients (n = 34) into two groups (17 patients in each group) in a double-blind manner to receive NAC or indistinguishable placebo.”
    • Also stated in: § Abstract · plain
      “A 12-week double blind randomized controlled trial was conducted to compare the clinical efficacy of NAC 3 g/day versus placebo.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The data were analyzed using conventional intention-to-treat, modified intention-to-treat, and per-protocol approaches.

    “We performed a conventional intention-to-treat (ITT) analysis on the basis of an as-randomized approach with inclusion of all patients treated or not; and a modified ITT (mITT) with an as-treated (AT) protocol design, i.e. patients who started treatment and who had at least one rating 1 month after starting the treatment.”
    • Also stated in: § Statistical analyses · plain
      “We also performed a per protocol (PP) approach whereby only patients who completed all measurements were included (treatment received).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The diagnosis of tobacco use disorder was made by a research psychiatrist using a Portuguese translation of the semi-structured DSM-IV interview (SCID).

    “The diagnosis of tobacco use disorder was made by a research psychiatrist using a Portuguese translation of the semi-structured DSM-IV interview (SCID).21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    A cut-off point of exhaled carbon monoxide ≤6 ppm was used as the criterion for smoking cessation.

    “A cut-off point for CO EXH levels ≤6 ppm was used as a criterion for smoking cessation.27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The Fagerstrom Test for Nicotine Dependence was used to assess severity of tobacco dependence, with a cut-off point of >5 for nicotine dependence.

    “We also scored the Fagerstrom Test for Nicotine Dependence (FTND) and used this scale to assess the severity of tobacco by dependence.23”
    • Also stated in: § Measurements · plain
      “We used a cut-off point for FTND nicotine dependence >5.25,26”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] source

      Not checked in the free run.

    • cites [25] source

      Not checked in the free run.

    • cites [26] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NAC is well tolerated, with a side-effect profile not significantly different from placebo when administered orally at doses up to 3 g/day.

    “NAC is well tolerated, with a side-effect profile that does not differ significantly from placebo when administered orally at doses up to 3 g/day.3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In major depressive disorder, the prevalence of tobacco use disorder is as high as 40-60%.

    “In major depressive disorder, the prevalence of tobacco use disorder is as high as 40-60%.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A first small placebo-controlled study with 29 nicotine-dependent patients using 2.4 g/day NAC found no significant differences in exhaled carbon monoxide or daily cigarette use between NAC and placebo.

    “A first small placebo-controlled study with 29 nicotine-dependent patients used 2.4 g/day of NAC as a treatment for tobacco cessation.There were no significant differences in exhaled carbon monoxide (CO EXH ) levels between patients treated with NAC and placebo, and no significant difference between NAC and placebo treatment in the daily use of cigarettes.14”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Tobacco use disorder is two to four times more likely to be diagnosed in subjects with psychiatric disorders.

    “Tobacco use disorder is two to four times more likely to be diagnosed in subjects with psychiatric disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NAC increases intracellular glutathione and modulates oxidative, immune-inflammatory, glutamatergic, and neurotrophic pathways.

    “N-Acetylcysteine (NAC) is a widely available, tolerable, and affordable nutraceutical supplement that increases the intracellular levels of glutathione, a major antioxidant, and modulates oxidative, immune-inflammatory, glutamatergic, and neurotrophic pathways.1,2”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Morris G, Mol Neurobiol.

      Not checked in the free run.

    • cites [2] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A second pilot double-blind study found that smokers treated with NAC 3.6 g/day reported the first cigarette after 3.5 days of abstinence was significantly less rewarding than placebo, and reported a non-significant trend toward fewer withdrawal symptoms.

    “These authors found that smokers treated with NAC reported that the first cigarette after an abstinence period of 3.5 days was significantly less rewarding than reported by subjects who were treated with placebo.The authors also reported a non-significant trend toward fewer withdrawal symptoms in the patients treated with NAC. 8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Hamilton Depression Rating Scale was translated and adapted for the Brazilian population.

    “The HDRS was translated and adapted for the Brazilian population.28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Moreno RA, 1998, Rev Psychiatr Clin

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NAC may reduce craving and reward behaviors in nicotine dependence, which are both modulated by glutamate.

    “NAC may reduce craving and reward behaviors in nicotine dependence, which are both modulated by glutamate.9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NAC has clinical efficacy in unipolar depression and bipolar disorder.

    “There is some evidence that NAC has clinical efficacy in unipolar depression and bipolar disorder.18,19”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] source

      Not checked in the free run.

    • cites [19] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NAC can improve some of the damage caused by tobacco smoke exposure, such as oxidative damage to the lung and other tissues.

    “Moreover, NAC can improve some of the damage caused by tobacco smoke exposure, such as oxidative damage to the lung and other tissues.12”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Current smoker status was diagnosed according to US Centers for Disease Control and Prevention criteria.

    “We diagnosed 'current smokers' according to the US Centers for Disease Control and Prevention (CDC) criteria, i.e. individuals who and at the time of interview reported smoking every day or some days and had during their lifetime smoked at least 100 cigarettes.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Centers for Disease Control and Prevention (CDC), 2011, MMWR Morb Mortal Weekly Rep

      Not checked in the free run.

26 of 26

  • The paper relies on this without support.

    The group behavioral therapy provided to participants was appropriate and effective psychotherapy.

    “They received monthly group behavioral therapy treatments before and during the course of the study.”
    “NAC combined with appropriate psychotherapy appears to be an efficient treatment option for TUD.”

  • The paper relies on this without support.

    Missing outcome data were missing at random, so the last observation carried forward method yields valid estimates.

    “These analyses were performed using the last observation carried forward method.”

  • The paper relies on this without support.

    The NAC and placebo groups received comparable amounts of behavioral therapy and other concurrent care.

    “They received monthly group behavioral therapy treatments before and during the course of the study.”

  • The paper relies on this without support.

    Self-reported daily cigarette use is a valid measure of actual smoking behavior.

    “The primary outcome measurement (number of cigarettes per day) was collected by face-to-face interviews by a trained, senior psychiatrist (blinded to treatment conditions) using a semi-structured interview at baseline and 4, 8, and 12 weeks later.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Nausea was more frequent with NAC, not placebo

    Minor

    The discussion says nausea with NAC did not exceed that with placebo. Table 3 reports more nausea cases in the NAC group at every listed time point: 6 versus 0, 4 versus 1, and 6 versus 0.

  • Smoking-cessation cutoff differs across sections

    Minor

    The measurements section counts a CO reading of exactly 6 ppm as smoking cessation, while the results define cessation using a threshold below 6 ppm. A participant with a reading of 6 ppm would be classified differently under the two definitions.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 10

  1. Morris G, Mol Neurobiol.
  2. Azevedo E, Rev Bras Psiquiatr
  3. Centers for Disease Control and Prevention (CDC), 2011, MMWR Morb Mortal Weekly Rep, 60, 1513
  4. Carmo JT, 2002, Rev Bras Med, 59, 73
  5. Moreno RA, 1998, Rev Psychiatr Clin, 25, 262
  6. Taylor G, 2014, BMJ, 13, 348
  7. American Psychiatric Association, American Psychiatric Association, Diagnostic and statistical manual of mental disorders, 571
  8. Hernandez-Lopes S, 2013, Rev Neurosci, 24, 455
  9. Khadrawy YA, 2011, Eur Rev Med Pharmacol Sci, 15, 863
  10. Chitty KM, J Psychiatr Res

Cited by

Sorted by citations

Related

Authors
Prado, E., Maes, M., Piccoli, L. G., Baracat, M., Barbosa, D. S., Franco, O., Dodd, S., Berk, M., & Vargas Nunes, S. O.
Affiliations
  • Universidade Estadual de Londrina (BR)
  • Deakin University (AU)
  • Barwon Health (AU)
Corresponding author
Maes, Michael
ORCID
Venue
Redox Report
Publisher
Informa UK Limited
Published
2015-03-02
Volume
20
Issue
5
Pages
215-222
ISSN
  • 1351-0002 (ISSN-L)
  • 1743-2928
DOI
10.1179/1351000215y.0000000004
PMC
PMC6837411
OpenAlex
W2079345780
Cited by
69
References
43
Citations by year
2025: 5 · 2024: 7 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 8 · 2018: 13 · 2017: 3 · 2016: 5 · 2015: 2
FWCI
5.64
Type
journal article
Language
en
Open access
Locations
  • Redox Report (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion)
Funders
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Universidade Estadual de Londrina
  • National Health and Medical Research Council (1059660)
Topics
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
N-acetylcysteine, tobacco use disorder, smoking cessation, exhaled carbon monoxide, depression, cigarette craving, pharmacotherapy
MeSH terms
Acetylcysteine, Adolescent, Adult, Aged, Double-Blind Method, Female, Glutathione, Humans, Male, Middle Aged, Pilot Projects, Tobacco Use Disorder, Treatment Outcome, Oxidative Stress, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review