, Volume 189, Issue 1, pp 125–133 | Cite as

Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial

  • F. Joseph McClernonEmail author
  • F. Berry Hiott
  • Eric C. Westman
  • Jed E. Rose
  • Edward D. Levin
Original Investigation



Despite established links between nicotine dependence and depression, little research has examined the effects of nicotine on depression symptoms.


This study evaluated the acute and chronic effects of transdermal nicotine in nonsmokers with baseline depression symptoms during a 4-week, double-blind, placebo-controlled trial.


Nonsmokers with scores ≥10 on the Center for Epidemiological Studies Depression scale (CES-D) were recruited from the community. Mood and cognitive performance were measured at baseline (day 0) and at 1, 8, 21, and 28 days. Participants were randomly assigned to wear a placebo or nicotine patch for 4 weeks (3.5 mg/day during weeks 1 and 4; 7 mg/day during weeks 2 and 3). The final sample consisted of 11 nonsmokers with a mean baseline CES-D score of 27.36 (SD=10.53).


Salivary nicotine levels indicated the majority of participants were compliant with treatment. Acute nicotine did not alter mood. After adjusting for baseline values, chronic nicotine resulted in a significant decline in CES-D scores at day 8 (3.5 mg/day), but returned to placebo levels by the last visit. This return to baseline levels was coincident with a decrease in nicotine administration from 7 to 3.5 mg/day. A similar trend for improved response inhibition as measured by the Conners Continuous Performance Task was also observed. Reported side effects were infrequent and minimal.


These findings suggest a role for nicotinic receptor systems in the pathophysiology of depression and that nicotinic compounds should be evaluated for treating depression symptoms.


Cognitive performance Depression Nicotine Mood 



This research was supported by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression. Dr. Rose is an inventor named on several nicotine patch patents and receives royalties from sales of certain nicotine patches.


  1. Anda RF, Williamson DF, Escobedo LG, Mast EE, Giovino GA, Remington PL (1990) Depression and the dynamics of smoking. A national perspective. JAMA 264:1541–1545PubMedCrossRefGoogle Scholar
  2. Audrain-McGovern J, Lerman C, Wileyto EP, Rodriguez D, Shields PG (2004) Interacting effects of genetic predisposition and depression on adolescent smoking progression. Am J Psychiatry 161:1224–1230PubMedCrossRefGoogle Scholar
  3. Bearden CE, Glahn DC, Monkul ES, Barrett J, Najt P, Villarreal V, Soares JC (2006) Patterns of memory impairment in bipolar disorder and unipolar major depression. Psychiatry Res 142:139–150PubMedCrossRefGoogle Scholar
  4. Belluardo N, Blum M, Mudo G, Andbjer B, Fuxe K (1998) Acute intermittent nicotine treatment produces regional increases of basic fibroblast growth factor messenger RNA and protein in the tel- and diencephalon of the rat. Neuroscience 83:723–740PubMedCrossRefGoogle Scholar
  5. Belluardo N, Mudo G, Blum M, Amato G, Fuxe K (2000) Neurotrophic effects of central nicotinic receptor activation. J Neural Transm Suppl:227–245Google Scholar
  6. Belluardo N, Olsson PA, Mudo G, Sommer WH, Amato G, Fuxe K (2005) Transcription factor gene expression profiling after acute intermittent nicotine treatment in the rat cerebral cortex. Neuroscience 133:787–796PubMedCrossRefGoogle Scholar
  7. Castagnoli K, Steyn SJ, Magnin G, Van Der Schyf CJ, Fourie I, Khalil A, Castagnoli N Jr (2002) Studies on the interactions of tobacco leaf and tobacco smoke constituents and monoamine oxidase. Neurotox Res 4:151–160PubMedCrossRefGoogle Scholar
  8. Conners CK (1994) The Conners Continuous Performance Test. Multi-Health Systems, Inc., Toronto, CanadaGoogle Scholar
  9. Conners CK, Levin ED, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J (1996) Nicotine and attention in adult attention deficit hyperactivity disorder (ADHD). Psychopharmacol Bull 32:67–73PubMedGoogle Scholar
  10. Covey LS, Glassman AH, Stetner F (1997) Major depression following smoking cessation. Am J Psychiatry 154:263–265PubMedGoogle Scholar
  11. Cox LS, Patten CA, Krahn LE, Hurt RD, Croghan IT, Wolter TD, Schroeder DR, Tri D, Offord KP (2003) The effect of nicotine patch therapy on depression in nonsmokers: a preliminary study. J Addict Dis 22:75–85PubMedCrossRefGoogle Scholar
  12. Djuric VJ, Dunn E, Overstreet DH, Dragomir A, Steiner M (1999) Antidepressant effect of ingested nicotine in female rats of Flinders resistant and sensitive lines. Physiol Behav 67:533–537PubMedCrossRefGoogle Scholar
  13. Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127PubMedCrossRefGoogle Scholar
  14. Dursun SM, Kutcher S (1999) Smoking, nicotine and psychiatric disorders: evidence for therapeutic role, controversies and implications for future research. Med Hypotheses 52:101–109PubMedCrossRefGoogle Scholar
  15. Ferguson SM, Brodkin JD, Lloyd GK, Menzaghi F (2000) Antidepressant-like effects of the subtype-selective nicotinic acetylcholine receptor agonist, SIB-1508Y, in the learned helplessness rat model of depression. Psychopharmacology (Berl) 152:295–303CrossRefGoogle Scholar
  16. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Shea C, Schlyer D, Wolf AP, Warner D, Zezulkova I, Cilento R (1996a) Inhibition of monoamine oxidase B in the brains of smokers. Nature 379:733–736PubMedCrossRefGoogle Scholar
  17. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, Shea C, Alexoff D, MacGregor RR, Schlyer DJ, Zezulkova I, Wolf AP (1996b) Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci USA 93:14065–14069PubMedCrossRefGoogle Scholar
  18. Gilbert DG, McClernon FJ, Rabinovich NE, Plath LC, Jensen RA, Meliska CJ (1998) Effects of smoking abstinence on mood and craving in men: influences of negative-affect-related personality traits, habitual nicotine intake and repeated measurements. Pers Individ Differ 25:399–423CrossRefGoogle Scholar
  19. Gilbert DG, Crauthers DM, Mooney DK, McClernon FJ, Jensen RA (1999) Effects of monetary contingencies on smoking relapse: influences of trait depression, personality, and habitual nicotine intake. Exp Clin Psychopharmacol 7:174–181PubMedCrossRefGoogle Scholar
  20. Gilbert DG, McClernon FJ, Rabinovich NE, Plath LC, Masson CL, Anderson AE, Sly KF (2002) Mood disturbance fails to resolve across 31 days of cigarette abstinence in women. J Consult Clin Psychol 70:142–152PubMedCrossRefGoogle Scholar
  21. Glassman AH, Covey LS, Stetner F, Rivelli S (2001) Smoking cessation and the course of major depression: a follow-up study. Lancet 357:1929–1932PubMedCrossRefGoogle Scholar
  22. Hannay HJ, Levin HS (1985) Selective Reminding Test: an examination of the equivalence of four forms. J Clin Exp Neuropsychol 7:251–263PubMedGoogle Scholar
  23. Heishman SJ (1998) What aspects of human performance are truly enhanced by nicotine? Addiction 93:317–320PubMedCrossRefGoogle Scholar
  24. Heishman SJ, Henningfield JE (2000) Tolerance to repeated nicotine administration on performance, subjective, and physiological responses in nonsmokers. Psychopharmacology (Berl) 152:321–333CrossRefGoogle Scholar
  25. Heishman SJ, Taylor RC, Henningfield JE (1994) Nicotine and smoking: a review of effects on human performance. Exp Clin Psychopharmacol 2:345CrossRefGoogle Scholar
  26. Jacob P 3rd, Wilson M, Benowitz NL (1981) Improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluids. J Chromatogr 222:61–70PubMedGoogle Scholar
  27. Jamner LD, Shapiro D, Jarvik ME (1999) Nicotine reduces the frequency of anger reports in smokers and nonsmokers with high but not low hostility: an ambulatory study. Exp Clin Psychopharmacol 7:454–463PubMedCrossRefGoogle Scholar
  28. Kelton MC, Kahn HJ, Conrath CL, Newhouse PA (2000) The effects of nicotine on Parkinson’s disease. Brain Cogn 43:274–282PubMedGoogle Scholar
  29. Kendler KS, Neale MC, MacLean CJ, Heath AC, Eaves LJ, Kessler RC (1993) Smoking and major depression. A causal analysis. Arch Gen Psychiatry 50:36–43PubMedGoogle Scholar
  30. Kleykamp BA, Jennings JM, Blank MD, Eissenberg T (2005) The effects of nicotine on attention and working memory in never-smokers. Psychol Addict Behav 19:433–438PubMedCrossRefGoogle Scholar
  31. Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH (2000) Smoking and mental illness: a population-based prevalence study. JAMA 284:2606–2610PubMedCrossRefGoogle Scholar
  32. Lerman C, Caporaso N, Main D, Audrain J, Boyd NR, Bowman ED, Shields PG (1998) Depression and self-medication with nicotine: the modifying influence of the dopamine D4 receptor gene. Health Psychol 17:56–62PubMedCrossRefGoogle Scholar
  33. Levin ED, Conners CK, Silva D, Canu W, March J (2001) Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder. Exp Clin Psychopharmacol 9:83–90PubMedCrossRefGoogle Scholar
  34. Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 184:523–539CrossRefGoogle Scholar
  35. Lorr M, McNair D (1984) Manual: Profile of Mood States. Educational and Industrial Testing Service, San Diego, CAGoogle Scholar
  36. Maggio R, Riva M, Vaglini F, Fornai F, Molteni R, Armogida M, Racagni G, Corsini GU (1998) Nicotine prevents experimental parkinsonism in rodents and induces striatal increase of neurotrophic factors. J Neurochem 71:2439–2446PubMedCrossRefGoogle Scholar
  37. Malberg JE, Duman RS (2003) Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28:1562–1571PubMedCrossRefGoogle Scholar
  38. McClernon FJ, Gilbert DG, Radtke R (2003) Effects of transdermal nicotine on lateralized identification and memory interference. Hum Psychopharmacol 18:339–343PubMedCrossRefGoogle Scholar
  39. Perkins KA, Gerlach D, Vender J, Grobe J, Meeker J, Hutchison S (2001) Sex differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli. Nicotine Tob Res 3:141–150PubMedCrossRefGoogle Scholar
  40. Poltavski DV, Petros T (2006) Effects of transdermal nicotine on attention in adult non-smokers with and without attentional deficits. Physiol Behav 85:833–843Google Scholar
  41. Potter A, Corwin J, Lang J, Piasecki M, Lenox R, Newhouse PA (1999) Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer’s disease. Psychopharmacology (Berl) 142:334–342CrossRefGoogle Scholar
  42. Radloff LS (1977) The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1:385–401Google Scholar
  43. Reeves D, Kane R, Winter K (1995) Automated Neuropsychological Assessment Metrics (ANAM): test administrators guide version 3.11. National Cognitive Recovery Foundation, San Diego, CAGoogle Scholar
  44. Rose JE, Levin ED, Benowitz N (1993) Saliva nicotine as an index of plasma levels in nicotine skin patch users. Ther Drug Monit 15:431–435PubMedGoogle Scholar
  45. Salin-Pascual RJ (2002) Relationship between mood improvement and sleep changes with acute nicotine administration in non-smoking major depressed patients. Rev Invest Clin 54:36–40PubMedGoogle Scholar
  46. Salin-Pascual RJ, Drucker-Colin R (1998) A novel effect of nicotine on mood and sleep in major depression. Neuroreport 9:57–60PubMedGoogle Scholar
  47. Salin-Pascual RJ, Rosas M, Jimenez-Genchi A, Rivera-Meza BL, Delgado-Parra V (1996) Antidepressant effect of transdermal nicotine patches in nonsmoking patients with major depression. J Clin Psychiatry 57:387–389PubMedGoogle Scholar
  48. Smith RC, Singh A, Infante M, Khandat A, Kloos A (2002) Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology 27:479–497PubMedCrossRefGoogle Scholar
  49. Terracciano A, Costa PT Jr (2004) Smoking and the five-factor model of personality. Addiction 99:472–481PubMedCrossRefGoogle Scholar
  50. Tizabi Y, Overstreet DH, Rezvani AH, Louis VA, Clark E Jr, Janowsky DS, Kling MA (1999) Antidepressant effects of nicotine in an animal model of depression. Psychopharmacology (Berl) 142:193–199CrossRefGoogle Scholar
  51. Watkins SS, Koob GF, Markou A (2000) Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine Tob Res 2:19–37PubMedCrossRefGoogle Scholar
  52. Watson D, Clark LA, Tellegen A (1988) Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 54:1063–1070PubMedCrossRefGoogle Scholar
  53. White HK, Levin ED (1999) Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease. Psychopharmacology (Berl) 143:158–165CrossRefGoogle Scholar
  54. White HK, Levin ED (2004) Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment. Psychopharmacology (Berl) 171:465–471CrossRefGoogle Scholar
  55. Wilens TE, Biederman J, Spencer TJ, Bostic J, Prince J, Monuteaux MC, Soriano J, Fine C, Abrams A, Rater M, Polisner D (1999) A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder. Am J Psychiatry 156:1931–1937PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • F. Joseph McClernon
    • 1
    Email author
  • F. Berry Hiott
    • 1
  • Eric C. Westman
    • 2
  • Jed E. Rose
    • 1
  • Edward D. Levin
    • 1
  1. 1.Department of Psychiatry and Behavioral SciencesDuke University Medical CenterDurhamUSA
  2. 2.Department of MedicineDuke University Medical CenterDurhamUSA

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