An Open-label Pilot Trial of N-acetylcysteine and Varenicline in Adult Cigarette Smokers

Overview

Journal Am J Drug Alcohol Abuse

Publisher Informa Healthcare

Specialty Psychiatry

Date 2014 Jul 26

PMID 25062287

Citations 22

Authors

Erin A McClure

Nathaniel L Baker

Cassandra D Gipson

Matthew J Carpenter

Amanda P Roper

Brett E Froeliger

Peter W Kalivas

Kevin M Gray

Affiliations

Soon will be listed here.

Abstract

Background: Varenicline (VAR) has demonstrated superior efficacy over other smoking cessation pharmacotherapies, though 50-60% of those treated do maintain abstinence. Some preclinical findings suggest that new nicotine dependence pharmacotherapies should target the glutamatergic system, given its demonstrated role in addiction. Attention has been given to N-acetylcysteine (NAC), which appears to restore normal glutamate signaling in animal models. It is possible that NAC and VAR may work in concert to promote abstinence at higher rates than with either medication alone.

Objective: To demonstrate the feasibility and safety of co-administering NAC and VAR in nicotine-dependent participants.

Methods: Participants (n = 19) were daily cigarette smokers, and did not need to be seeking treatment. They received 4 weeks of open-label treatment with NAC (1200 mg twice daily) and VAR (1 mg twice daily, following titration) and were assessed weekly for adverse events (AEs), smoking, craving and withdrawal.

Results: Sixteen participants reported a total of 40 AEs, and most were mild (88%). The most commonly reported AE was nausea (15%). Medication adherence, assessed via self-reports and pill counts, was excellent (98%). Exploratory analyses showed reductions in cigarettes per day, though point prevalence abstinence at the end of the study was low.

Conclusions: These preliminary data provide the first demonstration of safety and feasibility of the co-administration of NAC and VAR in cigarette smokers. AEs were consistent with those typically reported for VAR and NAC. These data support future efficacy research on NAC and VAR for smoking cessation.

Citing Articles

The Role of Twice-Daily N-acetylcysteine (NAC) 2400 mg in Smoking Cessation: A Randomized, Placebo-Controlled Trial in Indonesia.

Harlivasari A, Susanto A, Taufik F, Ginting T Cureus. 2024; 16(2):e54322.

PMID: 38500894 PMC: 10944675. DOI: 10.7759/cureus.54322.

The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders.

Bradlow R, Berk M, Kalivas P, Back S, Kanaan R CNS Drugs. 2022; 36(5):451-482.

PMID: 35316513 PMC: 9095537. DOI: 10.1007/s40263-022-00907-3.

Assessing combined effects of varenicline and N-acetylcysteine on reducing nicotine seeking in rats.

Nall R, Beloate L, Meyerink M, Penaloza T, Doolittle J, Froeliger B Addict Biol. 2022; 27(2):e13151.

PMID: 35229943 PMC: 10777539. DOI: 10.1111/adb.13151.

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

McClure E, Wahlquist A, Tomko R, Baker N, Carpenter M, Bradley E Drug Alcohol Depend. 2021; 225:108815.

PMID: 34171822 PMC: 8282766. DOI: 10.1016/j.drugalcdep.2021.108815.

N-acetylcysteine in substance use disorder: a lesson from preclinical and clinical research.

Smaga I, Frankowska M, Filip M Pharmacol Rep. 2021; 73(5):1205-1219.

PMID: 34091880 PMC: 8460563. DOI: 10.1007/s43440-021-00283-7.

References

Hughes J, Hatsukami D . Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry. 1986; 43(3):289-94. DOI: 10.1001/archpsyc.1986.01800030107013. View

Knackstedt L, LaRowe S, Mardikian P, Malcolm R, Upadhyaya H, Hedden S . The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry. 2008; 65(10):841-5. PMC: 2756612. DOI: 10.1016/j.biopsych.2008.10.040. View

Sobell L, Sobell M, Leo G, Cancilla A . Reliability of a timeline method: assessing normal drinkers' reports of recent drinking and a comparative evaluation across several populations. Br J Addict. 1988; 83(4):393-402. DOI: 10.1111/j.1360-0443.1988.tb00485.x. View

McClure E, Vandrey R, Johnson M, Stitzer M . Effects of varenicline on abstinence and smoking reward following a programmed lapse. Nicotine Tob Res. 2012; 15(1):139-48. PMC: 3524062. DOI: 10.1093/ntr/nts101. View

Moussawi K, Zhou W, Shen H, Reichel C, See R, Carr D . Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse. Proc Natl Acad Sci U S A. 2010; 108(1):385-90. PMC: 3017187. DOI: 10.1073/pnas.1011265108. View

Gray K, Carpenter M, Baker N, DeSantis S, Kryway E, Hartwell K . A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 2012; 169(8):805-12. PMC: 3410961. DOI: 10.1176/appi.ajp.2012.12010055. View

. Biochemical verification of tobacco use and cessation. Nicotine Tob Res. 2002; 4(2):149-59. DOI: 10.1080/14622200210123581. View

Patterson F, Jepson C, Strasser A, Loughead J, Perkins K, Gur R . Varenicline improves mood and cognition during smoking abstinence. Biol Psychiatry. 2008; 65(2):144-9. PMC: 2615779. DOI: 10.1016/j.biopsych.2008.08.028. View

Reichel C, Moussawi K, Do P, Kalivas P, See R . Chronic N-acetylcysteine during abstinence or extinction after cocaine self-administration produces enduring reductions in drug seeking. J Pharmacol Exp Ther. 2011; 337(2):487-93. PMC: 3083102. DOI: 10.1124/jpet.111.179317. View

10.

Zhou W, Kalivas P . N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking. Biol Psychiatry. 2007; 63(3):338-40. PMC: 2709691. DOI: 10.1016/j.biopsych.2007.06.008. View

11.

Cahill K, Stead L, Lancaster T . A preliminary benefit-risk assessment of varenicline in smoking cessation. Drug Saf. 2009; 32(2):119-35. DOI: 10.2165/00002018-200932020-00005. View

12.

LaRowe S, Mardikian P, Malcolm R, Myrick H, Kalivas P, McFarland K . Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict. 2006; 15(1):105-10. PMC: 1513138. DOI: 10.1080/10550490500419169. View

13.

Cox L, Tiffany S, Christen A . Evaluation of the brief questionnaire of smoking urges (QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001; 3(1):7-16. DOI: 10.1080/14622200020032051. View

14.

Harris P, Taylor R, Thielke R, Payne J, Gonzalez N, Conde J . Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2008; 42(2):377-81. PMC: 2700030. DOI: 10.1016/j.jbi.2008.08.010. View

15.

Berk M, Malhi G, Gray L, Dean O . The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013; 34(3):167-77. DOI: 10.1016/j.tips.2013.01.001. View

16.

Kalivas P, Volkow N . New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry. 2011; 16(10):974-86. PMC: 3192324. DOI: 10.1038/mp.2011.46. View

17.

West R, Baker C, Cappelleri J, Bushmakin A . Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology (Berl). 2007; 197(3):371-7. DOI: 10.1007/s00213-007-1041-3. View

18.

. Quitting smoking among adults--United States, 2001-2010. MMWR Morb Mortal Wkly Rep. 2011; 60(44):1513-9. View

19.

Ramirez-Nino A, DSouza M, Markou A . N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking. Psychopharmacology (Berl). 2012; 225(2):473-82. PMC: 3697766. DOI: 10.1007/s00213-012-2837-3. View

20.

Rollema H, Coe J, Chambers L, Hurst R, Stahl S, Williams K . Rationale, pharmacology and clinical efficacy of partial agonists of alpha4beta2 nACh receptors for smoking cessation. Trends Pharmacol Sci. 2007; 28(7):316-25. DOI: 10.1016/j.tips.2007.05.003. View