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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Drug Alcohol Depend. 2021 Jun 18;225:108815. doi: 10.1016/j.drugalcdep.2021.108815

Evaluating N-acetylcysteine for early and end-of-treatment abstinence in adult cigarette smokers

Erin A McClure 1,2,*, Amy E Wahlquist 3, Rachel L Tomko 1, Nathaniel L Baker 4, Matthew J Carpenter 1,2, Elizabeth D Bradley 1, Patrick A Cato 1, Cassandra D Gipson 5, Kevin M Gray 1
PMCID: PMC8282766  NIHMSID: NIHMS1717954  PMID: 34171822

Abstract

Background.

There is robust preclinical literature and preliminary clinical findings supporting the use of N-Acetylcysteine (NAC) to treat substance use disorders, including tobacco use disorder (TUD). However, randomized controlled trials have yielded mixed results and NAC’s efficacy for TUD has not been established. The goals of this study were to assess the efficacy of NAC in promoting early and end-of-treatment abstinence and preventing relapse among adult smokers.

Methods.

This randomized, double-blinded clinical trial enrolled adult, daily smokers (N=114; ages 23–64; 51% female; 65% White; 29% Black/African American; 7% Hispanic/Latinx), who were randomized 1:1 to receive NAC (n=59) or placebo (n=55) (1200 mg b.i.d.) for eight weeks. Participants received brief cessation counseling and incentives for abstinence during the first three days of the quit attempt. Primary outcomes: (i) carbon monoxide (CO)-confirmed abstinence during the first three days of the quit attempt. Secondary outcomes: (ii) time to relapse; (iii) biologically confirmed abstinence at Week 8.

Results.

No differences were found between NAC and placebo groups on measures of early abstinence (3-day quit attempt; 11% for NAC vs. 15% for placebo; all p>0.11), time to relapse (p=0.19), and end-of-treatment abstinence (7% for NAC vs. 11% for placebo; all p>0.40].

Conclusions.

Results indicate that NAC is a well-tolerated pharmacotherapy but is unlikely to be efficacious as a monotherapy for TUD in adults. Considered in the collective context of other research, NAC may potentially be more useful in a younger population, as a combination pharmacotherapy, or in the presence of more intensive psychosocial treatment.

Keywords: N-acetylcysteine, tobacco, smoking cessation, pharmacotherapy, relapse, glutamate, abstinence

1.0. Introduction

Tobacco use, mostly through combustible cigarette smoking, continues to exert an enormous impact on health globally (World Health Organization, 2012; Yoon et al., 2014), with an estimated 1.3 billion tobacco smokers worldwide (World Health Organization, 2020). While the prevalence of cigarette smoking continues to decline globally (Global Burden of Disease 2015 Tobacco Collaborators, 2017; Wang et al., 2018), initiating and maintaining abstinence remains a hurdle for those with tobacco use disorder (TUD) (U.S. Department of Health and Human Services, 2020). Though the majority of smokers are interested in quitting (Babb et al., 2017), fewer than one in ten smokers making an unassisted quit attempt are likely to succeed and maintain continued multi-year abstinence (Centers for Disease Control and Prevention, 2011; Cohen et al., 1989; Creamer et al., 2019; Hughes, 2003; Hughes et al., 2004), making relapse the most likely outcome of any given quit attempt (Piasecki, 2006). Approved pharmacotherapies for TUD increase the odds of quitting smoking two to threefold compared to placebo (Cahill et al., 2013; Hartmann-Boyce et al., 2014), though abstinence rates are still approximately 40–50% up to 6–12 months (Gonzales et al., 2006; Jorenby et al., 2006; Oncken et al., 2006; Piper et al., 2009), and only one in three smokers uses approved pharmacotherapies or counseling to quit (U.S. Department of Health and Human Services, 2020). This high rate of treatment failure justifies the need to expand cessation pharmacotherapy options to focus not only on promoting initial cessation, but also on preventing relapse to smoking.

Preclinical literature has shown that glutamate plays an important role in the maintenance of substance use disorders (SUDs), and glutamatergic compounds could be potentially beneficial in treating SUDs (Cano-Cebrián et al., 2021; Gipson et al., 2013; Kalivas et al., 2009; Kalivas and Volkow, 2011; Roberts-Wolfe and Kalivas, 2015; Sondheimer and Knackstedt, 2011; Spencer and Kalivas, 2017). Specific attention has been given to N-Acetylcysteine (NAC) due to its amelioration of glutamatergic dysregulation (Duailibi et al., 2017;McClure et al., 2014; Tomko et al., 2018) and as a treatment for psychiatric disorders more broadly (Berk et al., 2013; Ooi et al., 2018; Zheng et al., 2018). Preclinically, NAC appears to restore normal glutamate signaling and robustly decreases heroin, cocaine, and nicotine reinstatement (Garcia-Keller et al., 2019; Knackstedt et al., 2009; LaLumiere and Kalivas, 2008; Moussawi et al., 2009; Moussawi et al., 2011; Murray et al., 2012; Powell et al., 2019; Ramirez-Nino et al., 2013; Reichel et al., 2011; Zhou and Kalivas, 2008). Clinical NAC research focused on SUDs has demonstrated evidence of reduced drug use and/or reduced craving and withdrawal scores during NAC administration among those with cocaine and cannabis use disorders (Amen et al., 2011; Gray et al., 2010; LaRowe et al., 2006; LaRowe et al., 2007; Mardikian et al., 2007), and improvement in psychiatric symptomology among those with co-occurring disorders (Back et al., 2016). These studies also demonstrated tolerability and safety of oral NAC dosing.

There is a small but suggestive evidence base supporting the evaluation of NAC for TUD (Gómez-Coronado et al., 2018). Pilot studies to date have shown: 1) reduced subjective reward of the first cigarette smoked after three days of abstinence during NAC administration (N=22; Schmaal et al., 2011); 2) reduced nicotine dependence scores after six weeks of NAC treatment (N=28; Grant et al., 2014); and 3) increased abstinence during a three day period and lower self-reported cigarette craving (N=16; Froeliger et al., 2015). Additionally, two pilot clinical trials assessed smoking abstinence during NAC or placebo administration. One found a trend-level reduction in cigarettes per day for the NAC group during a 4-week trial, but no benefit on biochemical measures of smoking, craving or withdrawal ratings (N=33; Knackstedt et al., 2009). The other pilot study demonstrated impressive abstinence rates favoring NAC compared to placebo at the end of 12 weeks of treatment (47% in the NAC group versus 21% in the placebo group) (N=34; Prado et al., 2015).

Despite promising preclinical and preliminary clinical findings, randomized controlled trials (RCTs) evaluating NAC’s efficacy for SUDs have been mixed (Back et al., 2016; Grant et al., 2010; Gray et al., 2012; Gray et al., 2017; LaRowe et al., 2013) and not easily explainable. Some evidence suggests that NAC’s efficacy may rely on administration under a period of abstinence (LaRowe et al., 2013), rather than during periods of use, which may explain mixed results from clinical trials. Given these gaps in the literature and a small evidence base focused on NAC for TUD, the aims of the current study were to compare NAC and placebo groups on the following outcomes: 1) efficacy in promoting early abstinence during a quit attempt; 2) time to relapse (among those who achieve early abstinence); and 3) 7-day point prevalence abstinence at the end-of-treatment (Week 8).

2.0. Methods

2.1. Participants

Treatment-seeking adult smokers recruited from the community in Charleston, South Carolina (USA) were enrolled and randomized to receive either double-blinded NAC or placebo (1200 mg b.i.d.) for eight weeks. Study enrollment took place from August 2016 through August 2019. Eligibility criteria required that participants: 1) were 18–65 years old; 2) smoked an average of 5 cigarettes per day (CPD) for at least 6 months; 3) have some interest in quitting smoking (2+ on a 10-point scale); 4) be willing to engage in a 3-day quit attempt; 5) be willing to abstain or limit use of other tobacco/nicotine products and/or cannabis during the study; and 6) using birth control during study (if female of child-bearing potential). Participants were excluded if they were/had: 1) serious/unstable medical/psychiatric disorder (including severe SUDs) that may have interfered with participation or safety; 2) currently pregnant or breastfeeding; 3) currently using cessation medications; 4) known hypersensitivity to NAC, or 5) use of carbamazepine, nitroglycerin, or any other medication deemed hazardous if taken with NAC within 14 days of study participation.

A total of 176 participants provided informed consent (Figure 1), of which 62 were excluded from the study prior to randomization (40 were ineligible, 22 were eligible, but withdrew consent or were lost to follow-up prior to randomization; specific reasons listed in Figure 1). A total of 114 participants (51% female) were randomized to either NAC (n=59) or placebo (n=55), from which 24 later withdrew (n=19; 17%) or were lost to follow-up (n=5; 4%).

Figure 1.

Figure 1.

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CONSORT diagram.

2.2. Procedures

Procedures were approved by the Institutional Review Board at the Medical University of South Carolina, and the study was registered on clinicaltrials.gov (Clinicaltrials.gov ID: NCT02737358). Screening procedures included informed consent, health history, physical and psychiatric evaluation, and urine collection to determine drug use, pregnancy, and cotinine (metabolite of nicotine). Smoking/tobacco history and current use was assessed, and past 30-day cigarette and other substance use was collected via Timeline Follow-Back procedures (Robinson et al., 2014; Sobell et al., 1988). All screening procedures were conducted in-person.

Eligible participants completed a training visit (prior to randomization), in which they uploaded practice CO and medication videos (see below) in preparation of the quit attempt (videos uploaded remotely). Participants were randomized at Day 0 and received a 2-week supply of blinded medication (NAC or matched placebo) and were instructed that their 3-day smoking quit attempt would begin at midnight. Participants were provided with brief cessation counseling to prepare for their quit attempt, based on the National Cancer Institute’s Clearing the Air brochure. Emphasis was placed on an initial 3-day abstinence period, though participants were encouraged to quit for longer. If participants failed to quit or relapsed during the trial, they were encouraged to set another quit date and continue to try to abstain from smoking. To further increase initial abstinence rates (i.e., to assess the impact of NAC on relapse; Aim 2), all participants received financial incentives contingent upon video confirmation of abstinence via expired-air breath carbon monoxide (CO). During the first week of the study, videos were submitted remotely twice per day (morning and evening; 8+ hours apart) to verify both breath CO and medication ingestion. Breath CO has a short half-life (Benowitz et al., 2020), and as such, twice per day breath CO samples are recommended to confirm abstinence (Sigmon et al., 2008) and have been used previously for longer periods of time (Dallery et al., 2017).

Breath CO monitors were loaned to participants at training or Day 0, and videos were submitted via REDCap (Harris et al., 2009). These procedures have been described elsewhere (Tomko et al., 2019). During the 3-day quit attempt (Days 1–3), participants in both treatment groups received $20 for each abstinent CO sample that was submitted ($120 possible). Abstinence from smoking was defined as breath CO measures of ≤ 6 parts per million (ppm) (Benowitz et al., 2020) or a 75% reduction from the participant’s averaged ad-libitum CO values at baseline (included up to 14 once per day remote ad-lib CO values collected until Day 0 and in-person study visit CO values up until Day 0 [Screening, Training, and Day 0/Randomization visits]).

Participants returned to the clinic weekly during the 8-week treatment period and for a Week 12 follow-up visit. Breath CO and qualitative urinary cotinine tests were completed, along with self-report assessments. Adverse events (AEs) were assessed at study visits and documented/followed throughout the study.

2.3. Treatment Intervention and Randomization

Participants were randomized in a 1:1 ratio using a stratified random block design to receive either orally administered NAC (2400 mg per day; 1200 mg b.i.d. as two 600 mg capsules) or matched placebo (no titration required). Dosing of 2400 mg was based on past studies in adults (LaRowe et al., 2013; LaRowe et al., 2006). NAC was prepared and blinded by a compounding pharmacy and drug was United States Pharmacopeia (USP) grade. Randomization was stratified based on baseline CPD (≥14 CPD or <14 CPD; which we have found to be the median CPD in past adult tobacco cessation studies conducted within our group). At each visit, participants were dispensed a medication bottle for the upcoming week and a rescue bottle in the case of a missed or late visit (2-week supply). Participants took their first dose of medication on the morning of Day 1.

2.4. Measures

2.4.1. Screening/Baseline Assessments:

Demographics, smoking history, and past 30-day cigarette and other substance use via Timeline Follow-Back procedures (Robinson et al., 2014; Sobell et al., 1988) were collected. Nicotine dependence was evaluated via the Fagerström Test for Nicotine Dependence (Heatherton et al., 1991). Readiness and confidence to quit smoking (also administered at randomization) was assessed through a 10-point scale (not ready/confident=1 to extremely ready/confident=10).

2.4.2. Biological Verification of Smoking:

Breath CO was captured at all in-person study visits, once daily during training (prior to randomization), and twice daily during the first week of treatment (Days 1–6) using Bedfont® Scientific Ltd. CO monitors (piCO™ Smokerlyzer® and the Micro+™ basic monitors). Urine samples were collected and tested for qualitative cotinine (200 ng/ml cut-off) at all study visits, and quantitative cotinine (< 80 ng/ml cut-off for abstinence) was collected at key time points (Screening, Randomization, Weeks 4, 8, and 12).

2.4.3. Mobile Daily Diaries:

Participants completed daily diaries on their mobile phone (Screening through Week 8) in which they reported the number of cigarettes smoked, use of other nicotine/tobacco products, alcohol use, and drug use for the previous calendar day. During treatment, participants also reported their medication dosing times (or missed doses) in the past day. Survey links were delivered via text message and email, and surveys were completed through REDCap (Harris et al., 2009; Tomko et al., 2019). Completion of diaries was reviewed at weekly visits, and missing data were collected using TLFB methods.

2.4.4. Mobile CO and Medication Videos.

Survey links to upload videos remotely to REDCap were sent via text message twice per day on Days 1–6. All videos were reviewed by research staff. Videos were considered compliant if participant identity could be confirmed, the CO value was visible, and exhalation was sufficient (~10–20 seconds). Due to non-compliant CO videos early in the study, practice videos were implemented prior to randomization (75% of participants completed training videos). Medication videos during Days 1–6 were added later in the trial to confirm adherence during the quit attempt (87% completed medication videos; n=99). Participants were compensated for video submissions ($5 per set of videos [$2.50 for each CO video and $2.50 for each med video] twice per day for six days; $60 possible) and abstinence ($120 possible) at their Week 1 visit. Video capture terminated after Day 6, at which point, abstinence was self-reported and confirmed through weekly, in-person breath CO and cotinine. Medication adherence was confirmed by self-report for the remainder of the trial.

2.5. Outcomes and Abstinence Determination

Outcomes included: (i) CO-confirmed abstinence during the first three days of the quit attempt; (ii) among those who achieved initial abstinence, time to relapse starting on Day 4, and (iii) among the entire sample, biologically confirmed abstinence (cotinine and breath CO) at the Week 8 EOT visit. Abstinence from smoking during the first three days of the quit attempt was defined as twice per day breath CO measures of ≤ 6 ppm or a 75% reduction from the participant’s averaged ad-libitum smoking CO samples. The 75% reduction was implemented for those participants with high ad-libitum CO values. For all participants, the 75% reduction cut-off was used to determine abstinence for a total of 19 samples (out of 684 possible) and was largely among those with ad-lib CO averages of 40 ppm or higher. The pre-registered primary outcome (NCT02737358) was CO-confirmed abstinence on all six samples during the first three days of the quit attempt (defined as Level 1 abstinence). However, participants noted increases in smoking just before midnight prior to the quit attempt, making the abstinence criteria for the first sample on Day 1 overly stringent for particularly heavy smokers. Therefore, we additionally defined abstinence as CO-confirmed abstinence (≤ 6 ppm or a 75% reduction) on 5 out of 6 samples, but only by excluding the first sample (morning) of Day 1 (Level 2). Among those who achieved early abstinence (Level 2), relapse to smoking following the quit attempt (secondary outcome) was defined as seven consecutive days of smoking following a period of abstinence (Ossip-Klein et al., 1986; Shiffman et al., 2006). Week 8 EOT abstinence (secondary outcome) was defined as 7-day point prevalence (PPA) abstinence confirmed by CO or quantitative cotinine (<80 ng/ml) among all participants (missing CO samples were considered not abstinent).

2.6. Statistical Analyses

Baseline demographics were compared between NAC and placebo groups via Chi-squared tests, Fisher’s Exact tests, two-sample t-tests, and Wilcoxon Ranked Sum tests, as appropriate. For Aims 1 and 3 (early and EOT abstinence), binary outcomes (CO-confirmed abstinence for both Levels 1 and 2 during the 3-day quit attempt and EOT 7-day PPA for both CO and quantitative cotinine) were compared between groups initially via Fisher’s Exact tests. Sex was examined as a potential effect modifier by including it as a main effect along with an interaction term (between treatment group and sex) in the models. Logistic regression models were used to examine the effect of treatment group (NAC vs. placebo), sex, and the interaction between treatment and sex. When the interaction was not significant (p>0.05), sex was removed from the model in order to examine the main effect of sex on the outcome of interest. For Aim 2 (time to relapse), survival analyses including Kaplan-Meier curves and log-rank tests were used to examine differences in treatment effects. Only those participants who were abstinent during the 3-day quit attempt (Level 2) were included in this analysis. Significance was determined at the alpha=0.05 level for all analyses.

2.6.1. Sample Size Calculation.

A priori power calculations determined that a sample size of N=110 would provide adequate power (80%) with a type 1 error rate of 5% to detect abstinence rate differences (at end of the 3-day quit attempt) of as low as 20% between NAC and placebo groups based on preliminary data (Froeliger et al., 2015).

2.6.2. Data Availability.

Of 114 randomized participants (i.e., all participants who were dispensed study medication and set a quit date), 107 (94%) provided primary outcome data during the quit attempt (at least one compliant CO sample submitted; Figure 1), and 79% (90/114) completed the Week 8 (EOT) visit. Attrition in the study was similar across treatment groups at Week 8 (22% in the NAC group vs. 20% in the placebo group; p=0.8) and Week 12 (25% attrition in NAC vs. 16% in placebo; p=0.3). For the primary outcome analysis (based on first three days of CO sample submissions), 22% of CO videos were either missing (15%; 103/684) or non-compliant (7%; 45/684), and CO levels therefore could not be verified. These samples were treated as not abstinent. Rates of missing or non-compliant videos did not differ between treatment groups (22% [78/354] in the NAC group vs. 21% [70/330] in the placebo group.

3.0. Results

Study participants (N=114) averaged (standard deviation [SD] 42 (11.9) years of age (Range: 23–64), 51% of the sample were female, 65% were White, 29% were African American/Black, and 7% were Hispanic/Latinx. Participants smoked an average of 16 (8.3) cigarettes per day and had been smoking at their current rate for around four years (median=48 months). There were few differences in demographics or clinical characteristics at screening (Table 1). Participants randomized to placebo reported higher income compared to NAC participants (p=0.04) and higher baseline breath CO values (p=0.02).

Table 1.

Demographics and clinical characteristics of the enrolled sample (N=114) separated by NAC (n=59) and placebo (n=55) treatment groups.

Demographics Overall
(N=114)		 Placebo
(n=55)		 NAC
(n=59)		 p-value
Age (years) – Mean (SD) 42.0 (11.9) 43.9 (11.4) 40.2 (12.2) 0.10
Male – n (%) 56 (49.1) 27 (49.1) 29 (49.2) 0.99
Race – n (%) 0.29
 White 74 (65.0) 38 (69.1) 36 (61.0)
 African American/Black 33 (29.0) 12 (21.8) 21 (35.6)
Hispanic – n (%) 8 (7.0) 6 (10.9) 2 (3.4) 0.15
Education – n (%) 0.23
 < HS 8 (7.0) 5 (9.1) 3 (5.1)
 HS or equivalent 28 (24.6) 10 (18.2) 18 (30.5)
 > HS 78 (68.4) 40 (72.7) 38 (64.4)
Income – n (%) 0.035
 ≤ $20k 28 (24.6) 11 (20.0) 17 (28.8)
 >$20k – ≤ $40k 37 (32.5) 15 (27.3) 22 (37.3)
 > $40k 41 (36.0) 27 (49.1) 14 (23.7)
Smoking Characteristics
Age started smoking (regularly) – Mean (SD) 19.2 (6.0) 19.3 (6.3) 19.0 (5.7) 0.80
Current rate of smoking (months) – Median [Q1–Q3] 48.0 [18.0 – 141.0] 30.0 [12.0 – 120.0] 48.0 [18.0 – 180.0] 0.29
Number past quit attempts (24+ hours) – Median [Q1–Q3] 4.0 [2.0 – 8.0] 4.0 [2.0 – 10.0] 3.0 [2.0 – 6.0] 0.28
Cigs per day (past 30 days) – Mean (SD) 16.2 (8.3) 16.5 (8.3) 15.9 (8.3) 0.69
FTND Total Score – Mean (SD) 4.6 (2.2) 4.6 (2.3) 4.6 (2.1) 0.98
CO Level (ppm) – Mean (SD) 24.5 (14.2) 27.6 (16.2) 21.6 (11.5) 0.023
Urinary COT (ng/ml) – Median [Q1–Q3 1474.5 [823.0 – 1987.0] 1509.0 [751.0 – 3028.0] 1441.0 [915.0 – 1970.0] 0.52
Readiness to quit (10-point scale)‡ – Median [Q1–Q3 9.0 [8.0 – 10.0] 9.0 [8.0 – 10.0] 9.0 [8.0 – 10.0] 0.71
Confidence to quit (10-point scale)‡ – Median [Q1–Q3 8.0 [7.0 – 10.0] 8.0 [7.0 – 10.0] 8.0 [7.0 – 9.0] 0.70
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HS=High school; CPD=Cigarettes per day; FTND=Fagerström Test for Nicotine Dependence. CO=carbon monoxide. COT=cotinine.

‡

=Readiness and confidence to quit measures are reported for Day 0/Randomization given use of these values in predictive models.

3.1. Early Abstinence

Abstinence during the initial 3-day quit attempt (pre-registered primary outcome [Level 1] and Level 2 abstinence) is shown in Table 2. Overall, 3-day Level 1 abstinence was 11%, while Level 2 abstinence was 32%. No differences were demonstrated between NAC and placebo groups at either level of abstinence during the 3-day quit attempt (Level 1: p=0.38; Level 2: p=0.11).

Table 2.

Smoking abstinence outcomes across NAC and placebo treatment groups for Levels 1 and 2 early abstinence and biologically confirmed EOT (Week 8) abstinence for all randomized participants (N=114) and completers (N=90).

Smoking Abstinence Outcomes Overall
(N=114)		 Placebo
(n=55)		 NAC
(n=59)		 p-value
Early Abstinence n (%) n (%) n (%)
Level 1 (3-day continuous abstinence) 13 (11.4) 8 (14.6) 5 (8.5) 0.38
Level 2 (5/6 abstinent samples) 37 (32.5) 22 (40.0) 15 (25.4) 0.11
End-of-treatment Abstinence (Week 8) – ITT Overall
(N=114)		 Placebo
(n=55)		 NAC
(n=59)
Cotinine-confirmed 7-day PPA 10 (8.8) 6 (10.9) 4 (6.8) 0.52
CO-confirmed abstinence 15 (13.2) 9 (16.4) 6 (10.2) 0.41
End-of-treatment Abstinence (Week 8) – Completers Overall
(N=90)		 Placebo
(n=44)		 NAC
(n=46)
Cotinine-confirmed 7-day PPA 10 (11.1) 6 (13.6) 4 (8.7) 0.52
CO-confirmed abstinence 15 (16.7) 9 (20.5) 6 (13.0) 0.40
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Level 1 abstinence indicates 6 out of 6 negative CO samples submitted during the 3-day quit attempt. Level 2 abstinence indicates 5 out of 6 negative CO samples submitted (excluding only samples on the morning of Day 1; quit attempt began at midnight). ITT=intent to treat. PPA=point prevalence abstinence.

3.2. Relapse

Kaplan-Meier survival curves displaying time to relapse (secondary outcome) for NAC and placebo groups are shown in Figure 2, for those participants achieving Level 2 abstinence during the 3-day quit attempt. No significant difference in time to relapse was found between NAC and placebo groups, among those who achieved early abstinence (p=0.19).

Figure 2.

Figure 2.

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Relapse survival probabilities separated by NAC (solid line; light gray shading) and placebo (dashed line; dark gray shading) groups beginning on Day 4 of the quit attempt among those who abstained (Level 2; 5 out of 6 abstinent samples) during the 3-day quit attempt.

3.3. End-of-Treatment Abstinence

Abstinence rates at the Week 8 EOT visit (secondary outcome) are shown in Table 2 for cotinine-confirmed 7-day PPA and CO-confirmed abstinence for all randomized participants (N=114) and completers of the Week 8 visit (N=90). Overall abstinence at the end of the 8-week treatment phase was 9% (cotinine-confirmed), while CO-confirmed abstinence was slightly higher (13%). No differences were demonstrated between NAC and placebo groups on EOT abstinence outcomes (cotinine: p=0.52, CO: p=0.40, p=0.41).

3.4. Medication Adherence and Safety

Among participants who completed medication adherence videos during the first week (n=99), 49% were adherent for all six doses during the 3-day quit attempt (2 per day), and 70% were adherent on at least five of the six doses (>80%). Following the 3-day quit attempt (Days 4–6), 48% were adherent for all six doses, with 68% having >80% adherence. For the remainder of the study, self-reported average medication adherence was 72% (SD=32%). Among participants who were adherent to medication dosing (>80% doses taken) during the 3-day quit attempt, there were no NAC-related differences in CO-confirmed abstinence (Level 1: p=0.84, Level 2: p=0.14). Abstinence did not differ among adherent participants (>80% doses taken) at EOT either (cotinine p=0.37; CO p=0.25).

Among randomized participants, 57% (n=65) reported at least one AE during the trial (126 total events reported). AEs across all participants considered to be possibly related to study treatment (n=24; 19% of all events reported) did not differ between NAC (n=13) and placebo groups (n=11). The most common related AEs included gastrointestinal events (diarrhea, n=4; dyspepsia, n=4) and renal/urinary events (chromaturia, n=3). Participants who withdrew from study procedures (n=19; 17%) did not endorse AEs or health concerns related to the study medication as a reason for withdrawal.

4.0. Discussion

This double-blinded RCT enrolled adult daily cigarette smokers and evaluated NAC, compared to placebo, in promoting early abstinence during a quit attempt (first 3 days), time to relapse, and abstinence following eight weeks of treatment. We found no differences between NAC and placebo on any pre-registered or post-hoc primary or secondary outcomes, indicating that NAC is unlikely to promote abstinence from smoking or preventing relapse in adult daily smokers. To our knowledge, this is the first and only randomized study that was designed specifically to examine both the ability to achieve initial and end-of-treatment abstinence, and among those who did achieve early abstinence, time to relapse. This is also the largest study to date assessing NAC for TUD treatment and was powered to detect treatment differences on abstinence outcomes.

These results are inconsistent with past studies demonstrating a positive impact of NAC with smokers. Prior studies have found that NAC: 1) increased initial abstinence during a three day period (Froeliger et al., 2015); 2) reduced subjective reward of the first cigarette smoked after a period of brief abstinence (Schmaal et al., 2011); and 3) increased abstinence compared to placebo at the end of 12 weeks of treatment (NAC: 47% vs. placebo: 21%) (Prado et al., 2015). The current results fail to replicate findings indicating that NAC may be an efficacious pharmacotherapy for TUD. Notably, Prado et al. (2015) is the most similar study to the current design, but treatment consisted of 3000 mg dosing for 12 weeks. Therefore, it is possible that our trial did not dose sufficiently or for long enough to see a medication effect. However, our findings are consistent with fully-powered RCTs that have examined NAC in the treatment of other SUDs (cannabis and cocaine) (Gray et al., 2017; LaRowe et al., 2013) that also resulted in null effects.

The preclinical and early clinical findings supporting the use of NAC in RCTs across substances have been robust, and the failure to show treatment effects in fully powered, adult RCTs remains unexplained. There may be several reasons why NAC has not translated to improved treatment outcomes in larger adult trials. One possibility is the age of participants and developmental specificity of NAC treatment (Gray et al., 2017). Among cannabis users, NAC was shown to be effective in promoting abstinence in youth (Gray et al., 2012), but this result was not replicated in adults (Gray et al., 2017). Further, NAC did not impact alcohol self-administration or subjective effects in a human laboratory study with adults (Stoops et al., 2020), but a secondary analysis found a positive impact of NAC on alcohol use among youth (Squeglia et al., 2018). The mechanism by which NAC may be efficacious for youth substance use remains unknown and unexplored. If NAC efficacy is age-dependent, it may be explained by a shorter history of substance use, lower rates of use or dependence levels, or stage of neurodevelopment and greater plasticity of the glutamatergic system. The current study had three participants under the age of 25 and only 21% of the sample was under the age of 30, which precluded exploratory subgroup analyses to examine age-related treatment differences, though this will be an important area to explore further. Other individual characteristics, including sex, which has been explored in preclinical NAC studies, may also merit consideration (Goenaga et al., 2020).

Several promising compounds currently being explored for TUD may result in higher cessation rates, though work with new compounds is still preliminary (Gendy et al., 2019; Gómez-Coronado et al., 2018). Novel compounds, as well as those already established for smoking cessation, could be combined with NAC, which may be preferable compared to NAC alone (McClure et al., 2015). NAC maintains a favorable safety profile, allowing for combination pharmacotherapy evaluation. Additionally, NAC may have benefits beyond promoting smoking abstinence. For example, a recent study found that when NAC was added to first-line pharmacotherapies (bupropion and nicotine replacement therapy), and adjunctive cognitive therapy, the NAC group (vs. placebo + first-line treatment and therapy) showed improvements on measures of inflammation and metabolism (Machado et al., 2020), but no added benefit on smoking rates or withdrawal. While NAC may not serve as an efficacious monotherapy for adult TUD, it may have potential as an adjunctive treatment for smokers to improve other health outcomes.

The current study has several limitations that should be noted. This study was designed to evaluate NAC’s effects on both initial and end-of-treatment abstinence, as well as relapse prevention. The initial 3-day period of abstinence-contingent reinforcement was designed to increase power to assess relapse (Aim 2). Yet even with incentives, we found relatively low rates of abstinence. Thus, the power to detect NAC’s effects on relapse prevention may have been diminished. There was also a moderate rate of missing or non-compliant CO sample videos (22%) during the 3-day quit attempt, though this rate did not differ between treatment groups. We used stringent criteria to determine a useable CO sample, which contributed to 7% of submitted samples being deemed unusable. Additionally, the counseling provided as part of this trial was minimal and may not have been intensive enough to promote abstinence and augment any NAC effects. Finally, NAC has poor bioavailability when administered orally (Borgström et al., 1986) and our dosing may have been too low to exert an effect.

Our results indicate that while NAC is safe and well-tolerated in adult smokers, it is unlikely to have utility and efficacy as a monotherapy to treat TUD. Considered in the collective context of other NAC-focused research, NAC may potentially be more useful in a younger population, as a combination pharmacotherapy, or in the presence of intensive psychosocial treatment. NAC may also be beneficial in reducing inflammation in smokers, when used in combination with other cessation strategies, thus improving health outcomes among this population. Forthcoming results from ongoing NAC trials (NCT03707951 and R01 DA038700; Arancini et al., 2019) will bolster understanding of NAC’s translational potential and its potential role in treating SUDs.

Highlights.

  • NAC was evaluated for early and sustained abstinence and relapse prevention.

  • NAC was safe and well-tolerated in adult daily smokers.

  • NAC did not promote greater abstinence or delayed time to relapse.

  • NAC is unlikely to be successful as a monotherapy for adult smokers.

Acknowledgments:

The authors would like to thank the research and medical staff of the Addiction Sciences Division of the Medical University of South Carolina for the successful execution of this study protocol. Specifically, we would like to thank current and past members of the Project Quit team at MUSC; Lori Ann Ueberroth, Kathryn Mase, Danielle Schwartz, Jaclyn Condo, Kathryn Meltzer, Kayla McAvoy, and Breanna Tuck. We would like to thank Robert Malcolm for assistance with the study design and NAC expertise. Finally, we would like to thank the participants for their involvement in this study.

Role of Funding Source:

The funding sources had no role in the development of this manuscript. This study was supported by a grant from the National Institute on Drug Abuse (NIDA R34 DA042228, PI McClure), in part by pilot research funding from the Hollings Cancer Center’s Cancer Center Support Grant P30 CA138313 at the Medical University of South Carolina (MUSC), and pilot funding from the MUSC Department of Psychiatry and Behavioral Sciences at Chair’s Development Research Fund. Additional funding and support came from the National Center for Advancing Translational Sciences (NCATS UL1TR001450, PI Brady) and NIDA grant K01 DA036739 (McClure).

Footnotes

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Conflicts of Interest: Drs. Gray and Carpenter have provided consultation to Pfizer, Inc. Dr. Tomko has provided consultation to the American Society of Addiction Medicine. No other authors have conflicts of interest to declare.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Of 114 randomized participants (i.e., all participants who were dispensed study medication and set a quit date), 107 (94%) provided primary outcome data during the quit attempt (at least one compliant CO sample submitted; Figure 1), and 79% (90/114) completed the Week 8 (EOT) visit. Attrition in the study was similar across treatment groups at Week 8 (22% in the NAC group vs. 20% in the placebo group; p=0.8) and Week 12 (25% attrition in NAC vs. 16% in placebo; p=0.3). For the primary outcome analysis (based on first three days of CO sample submissions), 22% of CO videos were either missing (15%; 103/684) or non-compliant (7%; 45/684), and CO levels therefore could not be verified. These samples were treated as not abstinent. Rates of missing or non-compliant videos did not differ between treatment groups (22% [78/354] in the NAC group vs. 21% [70/330] in the placebo group.

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