N-acetylcysteine as Adjunctive Therapy for Therapy-resistant Tobacco Use Disorder
By Carrie Decker, ND
Founder and Medical Director, Blessed Thistle, Madison, WI
Dr. Decker reports no financial relationships relevant to this field of study.
SYNOPSIS: Tobacco cessation programs have variable success rates and often employ use of multiple strategies, including behavioral counseling and pharmaceutical treatments. This study investigates the use of N-acetylcysteine in combination with group behavioral therapy as a treatment for tobacco use disorder resistant to first-line smoking cessation treatments.
SOURCE: Prado E, et al. N-acetylcysteine for therapy-resistant tobacco use disorder: A pilot study. Redox Rep 2015 Mar 2 [Epub ahead of print].
- Current smokers diagnosed with tobacco use disorder resistant to first-line therapies were randomized to supplementation with 1500 mg of N-acetylcysteine (NAC) twice daily or a placebo in conjunction with smoking-focused group behavioral therapy.
- The use of NAC in conjunction with behavioral therapy was found to reduce daily cigarette consumption by an average of 10.9 cigarettes a day compared to a reduction of 3.2 cigarettes a day in the placebo group.
- Supplementation with NAC was also observed to reduce levels of exhaled carbon monoxide and improve depression scores measured by the Hamilton Depression Rating Scale.
N-acetylcysteine (NAC), an antioxidant that is a precursor to glutathione (GSH), has been studied for use in a wide range of conditions. Some common therapeutic uses of NAC include intravenous therapy for acetaminophen overdose and as a mucolytic agent for conditions such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), and upper respiratory infections.1 More recently it has become the topic of research for use in a variety of psychiatric conditions including addiction, obsessive-compulsive disorder, depression, bipolar disorder, and schizophrenia with the potential mechanism of action in these realms being via modulating glutamatergic, neurotropic, and inflammatory pathways.2,3 The use of NAC has been investigated for use in treatment of nicotine, cannabis, methamphetamine, and cocaine addictions, with the hypothesized mechanism of action being function as a glutamatergic agent.4,5
In this double-blind, controlled trial, 34 current smokers with tobacco use disorder as diagnosed by the DSM-IV criteria were randomized to treatment with a placebo or 1500 mg of NAC twice daily (3000 mg total) for a period of 12 weeks. Study participants were refractory to first-line smoking cessation treatments of nicotine replacement therapy, bupropion, or varenicline, and were involved in a smoking-focused group behavioral therapy before and during the study. The mean pack-years (cigarettes per day times number of years smoking) of the placebo and intervention group were 31.43 ± 18.369 and 32.64 ± 18.519, respectively. Participants ranged in age from 18 to 65 years, and were excluded from the study if they had unstable systemic disease, active gastrointestinal ulcers, were pregnant or breast feeding, or had a history of a reaction to NAC. Individuals were not excluded if they had mood disorders.
The primary outcome of this study was the number of cigarettes per day, evaluated at baseline, 4, 8, and 12 weeks. The secondary outcome measure of smoking reduction was the level of exhaled carbon monoxide (COEX), also evaluated at baseline, 4, 8, and 12 weeks. Breath carbon monoxide levels have been observed in other studies to be related to smoking or non-smoking status, with mean levels in smokers being 17.4 ± 11.6 ppm vs 1.8 ± 1.3 ppm in non-smokers (P < 0.001).6 Additional parameters evaluated were the severity of depression via the Hamilton Depression Rating Scale (HDRS) and body mass index (BMI). Evaluation of outcomes was performed with both a conventional intention-to-treat (ITT) generalized linear model (GLM) analysis with inclusion of all patients who enrolled in the study, and a modified ITT GLM analysis including patients who had at least one rating 1 month after starting treatment.
Evaluation of the primary outcome of cigarette use per day with the ITT GLM analysis found that the number of cigarettes smoked at the endpoint was significantly lower in the NAC group compared with placebo, with a change in daily cigarettes at the 3-month endpoint of -10.9 ± 7.9 in the NAC-treated group and -3.2 ± 6.1 in the placebo group (P = 0.006). The modified ITT GLM analysis also showed that endpoint daily cigarette use was significantly lower with NAC treatment than in placebo group (Wald = 7.38, P = 0.007). Both the modified ITT and ITT analysis found a significant effect of the baseline number of cigarettes per day.
The secondary outcome of COEX also was significantly lower in the NAC treatment group after 3 months of treatment. With the ITT GLM analysis a decrease in COEX of -10.4 ± 8.6 ppm in the NAC-treated group vs only -1.5 ± 4.5 ppm in the placebo group (P = 0.002) was observed. The modified ITT GLM analysis also found that endpoint daily COEX was significantly lower with NAC treatment than in the placebo group (Wald = 5.60, P = 0.018). Both the ITT and modified ITT analysis showed a significant effect of baseline COEX.
Treatment with NAC also was found to have a significant effect of reducing HDRS score compared to placebo (values not reported in terms of effect). However, there was no significant correlation between the change in HDRS score and the change in number of daily cigarettes smoked or COEX. NAC treatment was observed to have a marginally significant effect of reducing BMI.
Of the 34 individuals who began the study, 10 individuals from the placebo group and six from the treatment group did not complete the study. The reasons for discontinuing included family and social matters (8), referral for other clinical problems (5), and refusal to take medication (3). Two individuals allocated to the NAC group reported an adverse effect of nausea as a reason for discontinuation, while up to six individuals reported symptoms of nausea at the evaluation time points yet did not withdraw from the study. Additional adverse events reported during the study included diarrhea, skin allergy, and respiratory allergy, with the majority occurring in the NAC treatment group, but these events were not significant enough for participants to be withdrawn from the study. No serious treatment-related adverse events were reported.
Clinical benefits have been seen with NAC as a hepatoprotective agent in settings of acetaminophen overdose and other drug toxicity,7,8 as an agent that may improve fertility in women with polycystic ovarian syndrome,9 and as a supportive agent for a variety of mental health conditions.2 NAC has been shown to be an antioxidant that supports levels of GSH, but also may reduce endothelial dysfunction, inflammation, and fibrosis.10 Studies investigating the use of NAC in areas of addiction and mental health have hypothesized that the potential benefits seen with NAC are associated with its ability to act as a glutamate modulator.2
The use of NAC is the topic of multiple ongoing trials for the treatment of obsessive compulsive disorder, and promising results have been seen in pilot studies.11 Dosages in those studies are comparable to the current study, ranging from 2400-3000 mg daily for a period of 12 weeks. In other small studies pertaining to nicotine use, NAC was shown to not have an effect on cravings, but decreased the reward associated with cigarette smoking after a period of abstinence.12 Another small study reported a reduction in cigarettes smoked, and no effect of NAC on CO levels, craving, or withdrawal.13 In other small addiction studies, the use of NAC was found to decrease the desire to use cocaine14 and normalize elevated glutamate levels in the dorsal anterior cingulate cortex in cocaine-dependent patients.15 This is of interest as higher baseline glutamate levels are associated with higher impulsivity and relapse.16
In addition to the impact that NAC may have on addictive patterns, GSH is an antioxidant of importance in settings with cigarette smoke exposure. GSH has been shown to be highly concentrated in lung epithelial lining fluid, and levels of GSH in plasma, the liver, and lung epithelial lining fluid have been shown in animal studies to decrease by as much as 50% during an extended period of cigarette smoke exposure.17 With the potential benefit that NAC has on glutathione levels, endothelial dysfunction, inflammation, and fibrosis, there are many potential mechanisms by which it may have positive impacts on the health of former and current cigarette smokers. As an antioxidant at the level of the lungs and liver, systemically it may help to negate some of the damage done by carcinogens associated with cigarette smoke. It also has been shown to be beneficial as a mucolytic agent improving small airway function and decreasing exacerbation frequency in patients with stable COPD.18
There were several limitations of this study. As a small pilot study it does not have a large enough population to appropriately assess safety, efficacy, and effectiveness of NAC as an intervention in this population. There was not a control group without any intervention, as all participants were involved with a smoking-focused behavioral therapy group prior to and during the intervention. Although there was a marginally significant effect of reduction of BMI in the NAC group, this may be attributable to nausea, which was reported as a side effect in up to six participants at the different evaluation points of the study.
Additionally, there was a high dropout rate with 10/17 participants from the placebo group and 6/17 participants from the treatment group not completing the study. Although adverse events of nausea, diarrhea, and respiratory or skin allergy were reported by some individuals in this study, other studies using comparable dosages did not have side effects or effects were mild and transient.11 Many individuals dropped out for family and social reasons, which may have been due in part to the level of obligation necessary for group behavioral therapy for a 12-week period of time. Generally speaking, the success of smoking cessation intervention therapies has been shown to be greater with more intervention sessions and modalities, and some amount of behavioral motivation or counseling in combination with pharmacotherapy has been shown to be most effective.19,20 A larger controlled study using NAC without group behavioral therapy or with brief individual motivational counseling during the study would better demonstrate compliance and effectiveness of this as a monotherapy.
This study, similar to other addiction-related studies involving NAC, demonstrates feasibility using NAC in the treatment of addictions. Although adverse effects of nausea were reported in this study, with other studies this was not a significant problem. Gradually increasing the dosage or introducing a small amount of food with a medication are common strategies to reduce nausea, which may be effective with NAC supplementation as well. Because of the beneficial effects of NAC as an antioxidant and for mental well being, it may be something to recommend for individuals interested in smoking cessation. The positive results of this pilot study provides further support for larger population studies with NAC as a supportive agent for nicotine cessation.
- Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014;141:150-159.
- Dean O, et al. N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011;36:78-86.
- Berk M, et al. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: A double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 2014;75:628-636.
- Asevedo E, et al. Systematic review of N-acetylcysteine in the treatment of addictions. Rev Bras Psiquiatr 2014;36:168-175.
- McClure EA, et al. Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs 2014;28:95-106.
- Middleton ET, Morice AH. Breath carbon monoxide as an indication of smoking habit. Chest 2000;117:758-763.
- Abdoli N, et al. Protective effects of N-acetylcysteine against the statins cytotoxicity in freshly isolated rat hepatocytes. Adv Pharm Bull 2014;4:249-254.
- Maheswari E, et al. Hepatoprotective and antioxidant activity of N-acetyl cysteine in carbamazepine-administered rats. Indian J Pharmacol 2014;46:211-215.
- Thakker D, et al. N-acetylcysteine for polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled clinical trials. Obstet Gynecol Int 2015;2015:817849.
- Zafarullah M, et al. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 2003;60:6-20.
- Oliver G, et al. N-acetyl cysteine in the treatment of obsessive compulsive and related disorders: A systematic review. Clin Psychopharmacol Neurosci 2015;13:12-24.
- Schmaal L, et al. Efficacy of N-acetylcysteine in the treatment of nicotine dependence: A double-blind placebo-controlled pilot study. Eur Addict Res 2011;17:211-216.
- Knackstedt LA, et al. The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry 2009;65:841-845.
- LaRowe SD, et al. Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 2007;164:1115-1117.
- Schmaal L, et al. N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: A randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology 2012;37:2143-2152.
- Uys JD, LaLumiere RT. Glutamate: The new frontier in pharmacotherapy for cocaine addiction. CNS Neurol Disord Drug Targets 2008;7:482-491.
- Gould NS, et al. Lung glutathione adaptive responses to cigarette smoke exposure. Respir Res 2011;12:133.
- Tse HN, et al. High-dose N-acetylcysteine in stable COPD: The 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest 2013;144:106-118.
- Kottke TE, et al. Attributes of successful smoking cessation interventions in medical practice. A meta-analysis of 39 controlled trials. JAMA 1988;259:2883-2889.
- Stead LF, Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking cessation. Cochrane Database Syst Rev 2012;10:CD008286.
Tobacco cessation programs have variable success rates and often employ the use of multiple strategies, including behavioral counseling and pharmaceutical treatments. This study investigates the use of N-acetylcysteine in combination with group behavioral therapy as a treatment for tobacco use disorder resistant to first-line smoking cessation treatments.
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