Skip to main content

Cognitive Effects of Long-Term Benzodiazepine Use

A Meta-Analysis

CNS Drugs volume 18, pages 37–48 (2004)Cite this article

Abstract

Introduction: While benzodiazepines are the most widely used psychotropic drugs, there are relatively few studies that have examined deficits in cognitive functioning after long-term use. The literature that is available is difficult to interpret due to conflicting results as well as a variety of methodological flaws.

Objective: To systematically evaluate and integrate the available research findings to determine the effect of long-term benzodiazepine use on cognitive functioning using meta-analytical techniques.

Methods: Thirteen research studies that employed neuropsychological tests to evaluate cognitive performance after long-term use of benzodiazepine medication met inclusion criteria. The neuropsychological tests employed in these 13 studies were each categorised as measuring one of 12 cognitive domains. Separate effect sizes were calculated for each of the 12 cognitive categories. Each study was only allowed to contribute one effect size to each cognitive category by averaging together the effect sizes from the same study if more than one type of test was used to measure a particular category. This strategy resulted in equal weight being given to each study per category, regardless of the number of tests in that category.

Results: The overall mean number of patients who were benzodiazepine users was 33.5 (SD ± 28.9) and the mean number of controls was 27.9 (SD ± 19.6). The duration of benzodiazepine use ranged from 1 to 34 (mean 9.9) years. Long-term benzodiazepine users were consistently more impaired than controls across all cognitive categories examined, with effect sizes ranging in magnitude from −1.30 to −0.42. The mean weighted effect size was −0.74 (SD ± 0.25). None of the effect sizes had 95% CIs that spanned zero and, therefore, all of these effects were significant and different to zero.

Conclusion: Moderate-to-large weighted effect sizes were found for all cognitive domains suggesting that long-term benzodiazepine users were significantly impaired, compared with controls, in all of the areas that were assessed. However, this study has several limitations, one being that it includes a relatively small number of studies. Further studies need to be conducted; ideally, well designed, controlled studies that thoroughly investigate certain areas of cognitive functioning and present data in such a way so as to be amenable to inclusion in a meta-analysis. Incorporating the information from these studies into a larger meta-analysis would allow for a more thorough and statistically sound investigation of the effects of moderator variables. The observation that long-term benzodiazepine use leads to a generalised effect on cognition has numerous implications for the informed and responsible prescription of these drugs.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 49.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Table I
Table II
Table III
Fig. 1

References

  1. Lader M, Petursson H. Long term effects of benzodiazepines. Neuropharmacology 1983; 22(4): 527–33

    CAS  PubMed  Google Scholar 

  2. Lucki I, Rickeis K. The behavioral effects of benzodiazepines following long-term use. Psychopharmacol Bull 1986; 22(2): 424–33

    CAS  PubMed  Google Scholar 

  3. Balter MB, Manheimer DI, Mellinger GD, et al. A cross-national comparison of anti-anxiety/sedative drug use. Curr Med Res Opin 1984; 8 Suppl. 4: 5–20

    Google Scholar 

  4. Chen Y. Long-term benzodiazepine treatment: is it ever justified? Hum Psychopharmacol Clin Exp 1990; 5(4): 301–12

    Google Scholar 

  5. Mellinger GD, Balter BB, Uhlenhuth EH. Prevalence and correlates of the long-term regular use of anxiolytics. JAMA 1984; 251(3): 375–9

    CAS  PubMed  Google Scholar 

  6. Zandstra SM, Furer JW, van de Lisdonk EH, et al. Different study criteria affect the prevalence of benzodiazepine use. Soc Psychiatry Psychiatr Epidemiol 2002; 37: 139–44

    CAS  PubMed  Google Scholar 

  7. Pollack MH. Innovative uses of benzodiazepines in psychiatry. Can J Psychiatry 1993; 38(9 Suppl. 4): 122–6

    Google Scholar 

  8. McEvoy GK, Welsh OH, Litvak K. American Hospital Formulary Service (AHFS) drug information 2002. Bethesda (MD): American Society of Health System Pharmacists, 2002

    Google Scholar 

  9. Gudex C. Adverse effects of benzodiazepines. Soc Sci Med 1991; 33(5): 587–96

    CAS  PubMed  Google Scholar 

  10. Ashton H. Toxicity and adverse consequences of benzodiazepine use. Psychiatr Ann 1995; 25(3): 158–65

    Google Scholar 

  11. Ashton H. Adverse effects of prolonged benzodiazepine use. Adverse Drug React Bull 1986; 118: 440–3

    Google Scholar 

  12. Lader MH. Psychological effects of buspirone. J Clin Psychiatry 1982; 43(12): 62–7

    CAS  PubMed  Google Scholar 

  13. Birzele HJ. Benzodiazepine induced amnesia after long-term medication and during withdrawal. Eur Rev Appl Psychol 1992; 42(4): 277–82

    Google Scholar 

  14. Tata PR, Rollings J, Collins M, et al. Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med 1994; 24(1): 203–13

    CAS  PubMed  Google Scholar 

  15. Golombok S, Moodley P, Lader M. Cognitive impairment in long-term benzodiazepine users. Psychol Med 1988; 18(2): 365–74

    CAS  PubMed  Google Scholar 

  16. Lucki I, Rickeis K, Geller AM. Chronic use of benzodiazepines and psychomotor and cognitive test performance. Psychopharmacology 1986; 88(4): 426–33

    CAS  PubMed  Google Scholar 

  17. Sakol MS, Power KG. The effects of long-term benzodiazepine treatment and graded withdrawal on psychometric performance. Psychopharmacology 1988; 95(1): 135–8

    CAS  PubMed  Google Scholar 

  18. Golombok S. Causes, effects and treatment of long-term benzodiazepine use: a review of psychological perspectives. Hum Psychopharmacol Clin Exp 1989; 4(1): 15–20

    Google Scholar 

  19. Petursson H, Gudjonsson GH, Lader MH. Psychometric performance during withdrawal from long-term benzodiazepine treatment. Psychopharmacology 1983; 81: 345–9

    CAS  PubMed  Google Scholar 

  20. Bergman H, Borg S, Engelbrektson K, et al. Dependence on sedative-hypnotics: neuropsychological impairment, field dependence and clinical course in a 5-year follow-up study. Br J Addict 1989; 84: 547–53

    CAS  PubMed  Google Scholar 

  21. Bergman H, Borg S, Holm S. Neuropsychological impairment and exclusive abuse of sedatives or hypnotics. Am J Psychiatry 1980; 137(2): 215–7

    CAS  PubMed  Google Scholar 

  22. Gorenstein C, Bernik MA, Pompeia S, et al. Impairment of performance associated with long-term use of benzodiazepines. J Psychopharmacol 1995; 9(4): 313–8

    CAS  PubMed  Google Scholar 

  23. Brosan L, Broadbent D, Nutt D, et al. Performance effects of diazepam during and after prolonged administration. Psychol Med 1986; 16: 561–71

    CAS  PubMed  Google Scholar 

  24. Aranko K, Mattila MJ, Bordignon D. Psychomotor effects of alprazolam and diazepam during acute and subacute treatment, and during follow-up phase. Acta Pharmacol Toxicol (Copenh) 1985; 56: 364–72

    CAS  Google Scholar 

  25. Allen D, Curran HV, Lader M. The effects of repeated doses of clomipramine and alprazolam on physiological, psychomotor and cognitive functions in normal subjects. Eur J Clin Pharmacol 1991; 40: 355–62

    CAS  PubMed  Google Scholar 

  26. Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the epidemiology of vascular aging study. J Clin Psychopharmacol 2002; 22: 285–93

    CAS  PubMed  Google Scholar 

  27. Chaves ML, Bianchin M, Peccin S, et al. Chronic use of benzodiazepines and cognitive deficit complaints: a risk factor study. Ital J Neurol Sci 1993; 14(6): 429–35

    CAS  PubMed  Google Scholar 

  28. Gorenstein C, Bernik MA, Pompeia S. Differential acute psychomotor and cognitive effects of diazepam on long-term benzodiazepine users. Int Clin Psychopharmacol 1994; 9(3): 145–53

    CAS  PubMed  Google Scholar 

  29. Crowe SF. Neuropsychological effects of the psychiatric disorders. Melbourne (VIC): Hardwood Academic, 1998

    Google Scholar 

  30. Gladsjo JA, Rapaport MH, McKinney R, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord 1998; 49(2): 123–31

    CAS  PubMed  Google Scholar 

  31. Chavez EL, Trautt GM, Brandon A, et al. Effects of test anxiety and sex of subject on neuropsychological test performance: finger tapping, trail making, digit span and digit symbol tests. Percept Motor Skills 1983 Jun; 56(3): 923–9

    CAS  PubMed  Google Scholar 

  32. Curran HV. Memory functions, alertness and mood of long-term benzodiazepine users: a preliminary investigation of the effects of a normal daily dose. J Psychopharmacol 1992; 6(1): 69–75

    CAS  PubMed  Google Scholar 

  33. Toenne U, Hiltunen AJ, Vikander B, et al. Neuropsychological changes during steady-state drug use, withdrawal and abstinence in primary benzodiazepine-dependent patients. Acta Psychiatr Scand 1995; 91(5): 299–304

    Google Scholar 

  34. Hendler N, Cimini C, Ma T, et al. A comparison of cognitive impairment due to benzodiazepines and to narcotics. Am J Psychiatry 1980; 137(7): 828–30

    CAS  PubMed  Google Scholar 

  35. Rickels K, Lucki I, Schweizer E, et al. Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation. J Clin Psychopharmacol 1999; 19(2): 107–13

    CAS  PubMed  Google Scholar 

  36. Salzman C, Fisher J, Nobel K, et al. Cognitive improvement following benzodiazepine discontinuation in elderly nursing home residents. Int J Geriatr Psychiatry 1992; 7(2): 89–93

    Google Scholar 

  37. Vignola A, Lamoureux C, Bastion CH, et al. Effects of chronic insomnia and use of benzodiazepines on daytime performance in older adults. J Gerontol B Psychol Sci Soc Sei 2000; 55B: 54–62

    Google Scholar 

  38. Lezak MD. Neuropsychological assessment. 3rd ed. New York: Oxford University Press, 1995

    Google Scholar 

  39. Spreen O, Strauss E. A compendium of neuropsychological tests: administration, norms, and commentary. 2nd ed. New York: Oxford University Press, 1998

    Google Scholar 

  40. Graf P, Squire LR, Mandler G. The information that amnesic patients do not forget. J Exp Psychol 1984; 10(1): 164–78

    CAS  Google Scholar 

  41. Graf P, Mandler G. Activation makes words more accessible, but not necessarily more retrievable. J Verbal Learn Verbal Behav 1984; 23: 553–68

    Google Scholar 

  42. Ryan JJ, Lopez SJ, Paolo AM. Digit span performance of persons 75–96 years of age: base rates and associations with selected demographic variables. Psychol Assess 1996; 8(3): 324–7

    Google Scholar 

  43. Brown J, Packham DW. The effect of prior recall on multiple response recognition. Q J Exp Psychol 1967; 19(4): 356–61

    CAS  PubMed  Google Scholar 

  44. Curran S, Hindmarch I, Wattis JP, et al. Critical flicker fusion in normal elderly subjects: a cross-sectional community study. Curr Psychol Res Rev 1990; 9(1): 25–34

    Google Scholar 

  45. Wechsler D. Wechsler adult intelligence scale: revised manual. San Antonio (TX): Psychological Incorporation, 1981

    Google Scholar 

  46. Cooper AJ. Benzodiazepines: toward more logical use. Scott Med J 1982; 27: 297–304

    CAS  PubMed  Google Scholar 

  47. Rosenthal R. Meta-analytic procedures of social research. Rev. ed. London: Sage Publications, 1991

    Google Scholar 

  48. Cohen J. Statistical power analyses for the behavioral sciences. 2nd ed. Hillsdale (NJ): Lawrence Erlbaum Associates, 1988

    Google Scholar 

  49. Hedges LV, Olkin I. Statistical methods for meta-analysis. New York: Academic Press, 1985

    Google Scholar 

  50. Kilic C. Long-term effects of alprazolam on memory: a 3.5 year follow-up of agoraphobia/panic patients. Psychol Med 1999; 29(1): 225–31

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript. The results reported in this manuscript form part of M. Barker’s doctoral thesis.

Author information

Authors and Affiliations

  1. School of Psychological Science, La Trobe University, Bundoora, Victoria, 3086, Australia

    Melinda J. Barker, Kenneth M. Greenwood, Martin Jackson &  Simon F. Crowe

Authors
  1. Melinda J. Barker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth M. Greenwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simon F. Crowe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Simon F. Crowe.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Barker, M.J., Greenwood, K.M., Jackson, M. et al. Cognitive Effects of Long-Term Benzodiazepine Use. CNS Drugs 18, 37–48 (2004). https://doi.org/10.2165/00023210-200418010-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-200418010-00004

Keywords

  • Verbal Memory
  • Psychomotor Speed
  • Visuospatial Ability
  • High Effect Size
  • Weighted Effect Size