, Volume 59, Issue 1, pp 17–31

Advances in Non-Nicotine Pharmacotherapy for Smoking Cessation

  • Lirio S. Covey
  • Maria A. Sullivan
  • J. Andrew Johnston
  • Alexander H. Glassman
  • Mark D. Robinson
  • David P. Adams
Review Article


Progress in understanding the pharmacological nature of tobacco addiction, along with the modest success rates achieved by the nicotine replacement therapies, has provided the major impetus for the development of non-nicotine drugs as smoking cessation aids. This article reviews evidence from controlled trials of several non-nicotine medications for the treatment of nicotine dependence.

Clonidine was the first non-nicotine medication to show efficacy for smoking cessation in multiple studies, but its effect was found to be limited at best. Positive results across several trials have been consistently demonstrated for amfebutamone (bupropion). Encouraging results have also been observed for nortriptyline and moclobemide. Studies of combined treatments using non-nicotine medications (amfebutamone, mecamylamine, oral dextrose) with nicotine replacement therapy suggest increased efficacy relative to treatments using one or the other treatment strategy alone.

Thus, available evidence indicates that non-nicotine drug treatments offer a promising panoply of therapeutic strategies for the addicted smoker.


  1. 1.
    US Department of Health Education and Welfare. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. 1964. Public Health Service Publication No. 1103Google Scholar
  2. 2.
    Schwartz JL. A critical review and evaluation of smoking control methods. Public Health Rep 1969; 84: 483–506PubMedCrossRefGoogle Scholar
  3. 3.
    Dorsey JL. Control of the tobacco habit. Ann Intern Med 1936; 10: 628–31Google Scholar
  4. 4.
    Davison GC, Rosen RC. Lobeline and reduction of cigarette smoking. Psychol Rep 1972; 31: 443–56PubMedCrossRefGoogle Scholar
  5. 5.
    US Department of Health and Human Services. The Health Consequences of Smoking. Nicotine addiction: a report of the Surgeon General. 1988. DHHS Publication No. (CDC) 88-8406Google Scholar
  6. 6.
    Henningfield J. Nicotine medications for smoking cessation. N Engl J Med 1995; 333: 1196–203PubMedCrossRefGoogle Scholar
  7. 7.
    Hughes JR, Goldstein MG, Hurt RD, et al. Recent advances in the pharmacotherapy of smoking. JAMA 1999; 281: 72–6PubMedCrossRefGoogle Scholar
  8. 8.
    Fiore MC, Smith SS, Jorenby DE, et al. The effectiveness of nicotine patch for smoking cessation: a meta-analysis. JAMA 1994; 263: 2760–5CrossRefGoogle Scholar
  9. 9.
    Cinciripini PM, McClure JB. Smoking cessation treatment: recent developments in behavioral and pharmacological interventions. Oncology; 1998; 12: 1–9Google Scholar
  10. 10.
    Henningfield J, Fant RV, Gopalan L. Non-nicotine medications for smoking cessation. J Respir Dis 1998; 19 Suppl.: S33–42Google Scholar
  11. 11.
    Hughes JR, Stead LF, Lancaster TR. Anxiolytics and antide-pressants in smoking cessation: an update. In: Lancaster T, Silagy C, Fullterton D, editors. Tobacco addiction module of the Cochrane Database of Systematic Reviews. Vol. 4. Oxford: The Cochrane Collaboration, 1999Google Scholar
  12. 12.
    Glassman AH, Jackson WK, Walsh BT, et al. Cigarette craving, smoking withdrawal, and clonidine. Science 1984; 226: 864–6PubMedCrossRefGoogle Scholar
  13. 13.
    Glassman AH, Stetner F, Walsh BT, et al. Heavy smokers, smoking cessation, and clonidine: results of a double-blind, randomized trial. JAMA 1988; 259: 2863–6PubMedCrossRefGoogle Scholar
  14. 14.
    Covey LS, Glassman AH, Stetner F. Depression and depressive symptoms in smoking cessation. Compr Psychiatry 1990; 31: 350–4PubMedCrossRefGoogle Scholar
  15. 15.
    Gourlay SG, Benowitz NL. Is clonidine an effective smoking cessation therapy? Drugs 1995; 50: 197–207PubMedCrossRefGoogle Scholar
  16. 16.
    Hurt RD, Sachs DL, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997; 337: 1195–202PubMedCrossRefGoogle Scholar
  17. 17.
    Berlin I, Said S, Spreux-Varoquaux O, et al. A reversible mono-amine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. Clin Trial Ther 1995; 58: 444–52Google Scholar
  18. 18.
    Hall SM, Reus VI, Munoz F, et al. Nortriptyline and cognitive-behavioral therapy for the treatment of cigarette smoking. Arch Gen Psychiatry 1998; 55: 683–90PubMedCrossRefGoogle Scholar
  19. 19.
    Prochazka AV, Weaver MJ, Keller RT, et al. A randomized trial of nortriptyline for smoking cessation. Arch Intern Med 1998; 158: 2035–9PubMedCrossRefGoogle Scholar
  20. 20.
    Cinciripini PM, Laptizky L, Seay S, et al. A placebo-controlled evaluation of the effects of buspirone on smoking cessation: differences between high- and low-anxiety smokers. J Clin Psychopharmacol 1995; 15: 182–91PubMedCrossRefGoogle Scholar
  21. 21.
    Rose JE, Behm FM, Westman EC, et al. Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone. Clin Trials Ther 1994; 56: 86–9Google Scholar
  22. 22.
    West R, Willis N. Double-blind placebo controlled trial of dextrose tablets and nicotine patch in smoking cessation. Psycho-pharmacology (Berl) 1998; 136: 201–4CrossRefGoogle Scholar
  23. 23.
    Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, nicotine patch, or both for smoking cessation. N Engl J Med 1999; 340(9): 685–91PubMedCrossRefGoogle Scholar
  24. 24.
    Covey LS, Glassman AH, A meta-analysis of double-blind placebo-controlled trials of clonidine for smoking cessation. Br J Addict 1991; 86: 991–8PubMedCrossRefGoogle Scholar
  25. 25.
    Hilleman DE, Mohiuddin SM, Malesker MA, et al. Double-blind, placebo-controlled evaluation of transdermal clonidine in smoking cessation [abstract]. Chest 1989; 96 Suppl.: 208SGoogle Scholar
  26. 26.
    Villagra VG, Rosenberger JL, Girolami S. Transdermal clonidine or smoking cessation: a randomized, double-blind, placebo-controlled trial [abstract]. Circulation 1989; 80 Suppl. II: 58Google Scholar
  27. 27.
    Glassman AH, Covey LS, Dalack GW, et al. Smoking cessation, clonidine, and the vulnerability to nicotine among dependent smokers. Clin Pharmacol Ther 1993; 54: 670–9PubMedCrossRefGoogle Scholar
  28. 28.
    Baldesarrini RJ. Risk rates for depression. 1984 Arch Gen Psychiatry; 41: 103CrossRefGoogle Scholar
  29. 29.
    Hall SM, Munoz RF, Reus VI. Depression and smoking treatment: a clinical trial of an affect regulation treatment. NIDA Res Monogr 1992; 119: 326Google Scholar
  30. 30.
    Glassman AH, Heizer JE, Covey LS, et al. Smoking, smoking cessation, and major depression. JAMA 1990; 264: 1546–9PubMedCrossRefGoogle Scholar
  31. 31.
    Sellers EM, Naranjo CA, Kadlec K. Do serotonin uptake inhibitors decrease smoking? Observations in a group of heavy drinkers. J Clin Psychopharmacol 1986; 7: 417–20Google Scholar
  32. 32.
    Damaj MI, Slemmer, JE, Carroll FI, et al. Pharmacological characterization of nicotine’s interaction with cocaine and cocaine analogs. J Pharmacol Exper Therapeut 1999; 289(3): 1229–36Google Scholar
  33. 33.
    Fryer JD, Lukas RJ. Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther 1999; 288(1): 88–92PubMedGoogle Scholar
  34. 34.
    Ferry LH, Robbins AS, Scariati PD, et al. Enhancement of smoking cessation using the antidepressant, bupropion hydrochloride [abstract]. Circulation 1992; 86: 1–671CrossRefGoogle Scholar
  35. 35.
    Ferry LH, Burchette RJ. Efficacy of bupropion for smoking cessation in non-depressed smokers [abstract]. J Addict Dis 1994; 13: 249Google Scholar
  36. 36.
    Johnston JA, Ascher JA. Bupropion SR for smoking cessation. Presented at the FDA Drug Abuse Advisory Committee Meeting; 1996 Dec 12; Washington, DCGoogle Scholar
  37. 37.
    Berry MD, Juorio AV, Paterson IA. The functional role of monoamine oxidases A and B in the mammalian central nervous system. Prog Neurobiol 1994; 42: 375–91PubMedCrossRefGoogle Scholar
  38. 38.
    Fowler JS, Volkow ND, Wang GJ, et al. Inhibition of monoamine oxidase B in the brains of smokers. Nature 1996; 379: 733–6PubMedCrossRefGoogle Scholar
  39. 39.
    Berlin I, Spreux-Varoquaux O, Said S, et al. Effects of past history of major depression on smoking characteristics, monoamine oxidase-A and -B activities and withdrawal symptoms in dependent smokers. Drug Alcohol Depend 1997; 45: 31–7PubMedCrossRefGoogle Scholar
  40. 40.
    Oreland L, Fowler CJ, Schalling D. Low platelet monoamine oxidase activity in cigarette smokers. Life Sci 1981; 29: 2511–8PubMedCrossRefGoogle Scholar
  41. 41.
    Edwards NB, Murphy JK, Downs AD, et al. Doxepin as an adjunct to smoking cessation: a double-blind pilot study. Am J Psychiatry 1989; 146: 373–6PubMedGoogle Scholar
  42. 42.
    Mizes JS, Sloan DM, Segraves K, et al. Fluoxetine and weight gain in smoking cessation: Examination of actual weight gain and fear of weight gain [poster]. Presented at the New Clinical Drug Evaluation Unit Program, 36th Annual Meeting: 1996 May 28–31; Boca Raton (FL)Google Scholar
  43. 43.
    Niaura R, Goldstein MG, Depue J, et al. Fluoxetine, symptoms of depression, and smoking cessation [abstract]: Proceedings of the 16th Annual Scientific Sessions, Society of Behavioral Medicine. Annals Behav Medicine 1995; 17: 61Google Scholar
  44. 44.
    Hao H, Young D. Effect of clonidine on cigarette cessation and in the alleviation of withdrawal symptoms. Br J Addict 1988; 83: 1221–6PubMedCrossRefGoogle Scholar
  45. 45.
    Lucki I. Serotonin receptor specificity in anxiety disorders. J Clin Psychiatry 1996; 57: Suppl. 6: 5–10PubMedGoogle Scholar
  46. 46.
    Rijnders HJ, Slangen JL. The discriminative stimulus properties of buspirone involve dopamine-2 receptor antagonist activity. Psychopharmacology 1993; 111: 55–61PubMedCrossRefGoogle Scholar
  47. 47.
    Lader M. Can buspirone induce rebound, dependence or abuse? Br J Psychiatry 1991; Suppl. 12: 45–51Google Scholar
  48. 48.
    Cada DJ. Buspirone HCL. In: Cada DJ, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons, 1996: 1453–6Google Scholar
  49. 49.
    Gawin F, Compton M, Byck R. Buspirone reduces smoking. Arch Gen Psychiatry 1989; 46: 288–9PubMedCrossRefGoogle Scholar
  50. 50.
    Robinson MD, Pettice YL, Smith WA, et al. Buspirone effect on tobacco withdrawal symptoms: a randomized placebo-controlled trial. J Am Board Fam Pract 1992; 5: 1–9PubMedGoogle Scholar
  51. 51.
    West R, Hajek P, McNeill A. Effect of buspirone on cigarette withdrawal symptoms and short-term abstinence rates in a smokers clinic. Psychopharmacology (Berl) 1991; 104: 91–6CrossRefGoogle Scholar
  52. 52.
    Schneider NG, Olmstead RE, Steinberg C, et al. Efficacy of buspirone in smoking cessation: a placebo-controlled trial. Clin Pharmcol Ther 1996; 60: 568–75CrossRefGoogle Scholar
  53. 53.
    Hilleman DE, Mohiuddin SM, Del Core MG, et al. Effect of buspirone on withdrawal symptoms associated with smoking cessation. Arch Intern Med 1992; 152: 350–2PubMedCrossRefGoogle Scholar
  54. 54.
    O’Malley SS, Jaffe AJ, Chang G, et al. Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry 1992; 49: 881–7PubMedCrossRefGoogle Scholar
  55. 55.
    Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 1992; 49: 876–80PubMedCrossRefGoogle Scholar
  56. 56.
    Gorelick D, Rose J, Jarvik ME. Effect of naltrexone on cigarette smoking. J Substance Abuse 1989; 1: 143–59Google Scholar
  57. 57.
    Karras A, Kane J. Naloxone reduces cigarette smoking. Life Sci 1980; 27: 1541–5PubMedCrossRefGoogle Scholar
  58. 58.
    Nemeth-Coslett R, Griffiths RR. Naltrexone does not affect cigarette smoking. Psychopharmacology 1986; 89: 261–4PubMedCrossRefGoogle Scholar
  59. 59.
    Sutherland G, Stapleton JA, Russell MH, et al. Naltrexone, smoking behavior, and cigarette withdrawal. Psychopharmacology 1995; 120: 418–25PubMedCrossRefGoogle Scholar
  60. 60.
    Houtsmuller EJ, Clemmey PA, Sigler LA, et al. Effects of naltrexone on smoking and abstinence: problems of drug dependence 1996 [abstract]. Problems of drugs dependence: Proceedings of the 58th Annual Scientific Meeting of the College on Problems of Drug Dependence Inc. NIDA Res Monogr 1997; 174: 68Google Scholar
  61. 61.
    Covey LS, Glassman AH, Sterner F. Naltrexone’s effects on short-term and long-term smoking cessation. Addictive Dis 1999; 18: 31–40CrossRefGoogle Scholar
  62. 62.
    Wong GT, Wolter TD, Croghan GA, et al. A randomized trial of naltrexone for smoking cessation. Addiction 1999; 94: 1227–37PubMedCrossRefGoogle Scholar
  63. 63.
    Stolerman IP, Goldfarb T, Fink R, et al. Influencing cigarette smoking with nicotine antagonists. Psychopharmacologia 1973; 28: 247–59PubMedCrossRefGoogle Scholar
  64. 64.
    Rose JE, Sampson A, Levin ED, et al. Mecamylamine increases nicotine preference and attenuates nicotine discrimination. Pharmacol Biochem Behavior 1989; 32: 933–8CrossRefGoogle Scholar
  65. 65.
    Hughes JR. Non-nicotine pharmacotherapies for smoking cessation. J Drug Develop 1994; 6: 197–203Google Scholar
  66. 66.
    Tennant FS, Tarver AL, Rawson RA. Clinical evaluation of mecamylamine for withdrawal from nicotine dependence. NIDA Res Monogr 1983; 49: 239–246Google Scholar
  67. 67.
    Tennant Jr FS, Tarver AL. Withdrawal from nicotine dependence using mecamylamine: comparison of three-week and six-week dosage schedules. NIDA Research Monogr 1985; 55: 291–7Google Scholar
  68. 68.
    Krantz DS, Grunberg NE, Baum A. Health psychology. Annu Rev Psychol 1985; 36: 349–83PubMedCrossRefGoogle Scholar
  69. 69.
    West R, Hajek P, Burrows S. Effect of glucose tablets on craving for cigarettes. Psychopharmacology 1990; 101: 555–9PubMedCrossRefGoogle Scholar
  70. 70.
    Clarke PB. Nicotine dependence: mechanisms and therapeutic strategies. Biochem Soc Symp 1993; 59: 83–95PubMedGoogle Scholar
  71. 71.
    Balfour DJ, Benwell ME, Birrell CE, et al. Sensitization of the mesoaccumbens dopamine response to nicotine. Pharmacol Biochem Behav 1998; 59: 1021–30PubMedCrossRefGoogle Scholar
  72. 72.
    Kendler KS, Neale MC, Sullivan P, et al. A population-based twin study in women of smoking initiation and nicotine dependence. Psychol Med 1999; 29: 299–308PubMedCrossRefGoogle Scholar
  73. 73.
    Rose JE, Levin ED. Inter-relationships between conditioned and primary reinforcement in the maintenance of cigarette smoking. Br J Addict 1991; 86: 605–9PubMedCrossRefGoogle Scholar
  74. 74.
    Rose JE, Behm FM, Levin ED. Role of nicotine dose and sensory cues in the regulation of smoke intake. Pharmacol Biochem Behav 1993; 44: 891–900PubMedCrossRefGoogle Scholar
  75. 75.
    Westman EC, Behm FM, Rose JE. Airway sensory replacement combined with nicotine replacement for smoking cessation: a randomized, placebo-controlled trial using a citric acid inhaler. Chest 1995; 107: 1358–64PubMedCrossRefGoogle Scholar
  76. 76.
    Lichtenstein E, Hollis JF, Severson HH, et al. Tobacco cessation interventions in health care settings: rationale, model, and outcomes. Addict Behav 1996; 21: 709–20PubMedCrossRefGoogle Scholar
  77. 77.
    Schwartz JL. Methods of smoking cessation. Med Clin North Am 1992; 76: 451–76PubMedGoogle Scholar
  78. 78.
    Schachter S. Pharmacological and psychological determinants of smoking. Annals Inter Med 1978; 88: 104–14Google Scholar
  79. 79.
    Carroll KM, Rounsaville BJ, Keller DS. Relapse prevention strategies for the treatment of cocaine abuse. Am J Drug Alcohol Abuse 1991; 17: 249–65PubMedCrossRefGoogle Scholar
  80. 80.
    Carroll KM, Rounsaville BJ, Nich C, One-year follow-up on psychotherapy and psychopharmacology for cocaine dependence: delayed emergence of psychotherapy effects. Arch Gen Psychiatry 1994; 51: 989–97PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Lirio S. Covey
    • 1
    • 2
  • Maria A. Sullivan
    • 1
    • 2
  • J. Andrew Johnston
    • 3
  • Alexander H. Glassman
    • 1
    • 2
  • Mark D. Robinson
    • 4
  • David P. Adams
    • 5
  1. 1.New York State Psychiatric InstituteNew YorkUSA
  2. 2.Department of Psychiatry, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  3. 3.Glaxo-Wellcome Inc.Research Triangle ParkUSA
  4. 4.Cabarrus Family Medicine Residency ProgramConcordUSA
  5. 5.Department of Family Medicine and Public Health, James Quillen School of MedicineEast Tennessee State UniversityJohnson CityUSA

Personalised recommendations