A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features

Abstract

Rationale

Although reports of caffeine withdrawal in the medical literature date back more than 170 years, the most rigorous experimental investigations of the phenomenon have been conducted only recently.

Objectives

The purpose of this paper is to provide a comprehensive review and analysis of the literature regarding human caffeine withdrawal to empirically validate specific symptoms and signs, and to appraise important features of the syndrome.

Methods

A literature search identified 57 experimental and 9 survey studies on caffeine withdrawal that met inclusion criteria. The methodological features of each study were examined to assess the validity of the effects.

Results

Of 49 symptom categories identified, the following 10 fulfilled validity criteria: headache, fatigue, decreased energy/activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and foggy/not clearheaded. In addition, flu-like symptoms, nausea/vomiting, and muscle pain/stiffness were judged likely to represent valid symptom categories. In experimental studies, the incidence of headache was 50% and the incidence of clinically significant distress or functional impairment was 13%. Typically, onset of symptoms occurred 12–24 h after abstinence, with peak intensity at 20–51 h, and for a duration of 2–9 days. In general, the incidence or severity of symptoms increased with increases in daily dose; abstinence from doses as low as 100 mg/day produced symptoms. Research is reviewed indicating that expectancies are not a prime determinant of caffeine withdrawal and that avoidance of withdrawal symptoms plays a central role in habitual caffeine consumption.

Conclusions

The caffeine-withdrawal syndrome has been well characterized and there is sufficient empirical evidence to warrant inclusion of caffeine withdrawal as a disorder in the DSM and revision of diagnostic criteria in the ICD.

This is a preview of subscription content, log in to check access.

References

  1. Adams D, Ditzler T, Haning WF (1993) Primary caffeine dependence: a case report. Hawaii Med J 52:190–191 (see also page 194)

    Google Scholar 

  2. Alsene K, Deckert J, Sand P, de Wit H (2003) Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 28:1694–1702

    Article  CAS  PubMed  Google Scholar 

  3. American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn. American Psychiatric Association, Washington (revised)

    Google Scholar 

  4. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington

    Google Scholar 

  5. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington (text revision)

    Google Scholar 

  6. Ammon HP, Bieck PR, Mandalaz D, Verspohl EJ (1983) Adaptation of blood pressure to continuous heavy coffee drinking in young volunteers: a double-blind crossover study. Br J Clin Pharmacol 15:701–706

    CAS  PubMed  Google Scholar 

  7. Barone JJ, Roberts HR (1996) Caffeine consumption. Food Chem Toxicol 34:119–129

    Article  CAS  PubMed  Google Scholar 

  8. Bernstein GA, Carroll ME, Dean NW, Crosby RD, Perwien AR, Benowitz NL (1998) Caffeine withdrawal in normal school-age children. J Am Acad Child Adolesc Psychiatry 37:858–865

    Article  CAS  PubMed  Google Scholar 

  9. Bernstein GA, Carroll ME, Thuras PD, Cosgrove KP, Roth ME (2002) Caffeine dependence in teenagers. Drug Alcohol Depend 66:1–6

    Article  PubMed  Google Scholar 

  10. Bigal ME, Sheftell FD, Rapoport AM, Tepper SJ, Lipton RB (2002) Chronic daily headache: identification of factors associated with induction and transformation. Headache 42:575–581

    Article  PubMed  Google Scholar 

  11. Brauer LH, Buican B, de Wit H (1994) Effects of caffeine deprivation on taste and mood. Behav Pharmacol 5:111–118

    CAS  PubMed  Google Scholar 

  12. Brice CF, Smith AP (2002) Effects of caffeine on mood and performance: a study of realistic consumption. Psychopharmacology (Berl) 164:188–192

    Article  CAS  Google Scholar 

  13. Bridge N (1893) Coffee-drinking as a frequent cause of disease. Trans Assoc Am Physicians 8:281–288

    Google Scholar 

  14. Bruce M, Scott N, Lader M, Marks V (1986) The psychopharmacological and electrophysiological effects of single doses of caffeine in healthy human subjects. Br J Clin Pharmacol 22:81–87

    CAS  PubMed  Google Scholar 

  15. Bruce M, Scott N, Shine P, Lader M (1991) Caffeine withdrawal: a contrast of withdrawal symptoms in normal subjects who have abstained from caffeine for 24 hours and for 7 days. J Psychopharmacol 5:129–134

    Google Scholar 

  16. Cacciatore R, Helbling A, Jost C, Hess B (1996) Episodic headache, diminished performance and depressive mood. Schweiz Rundsch Med Prax 85:727–729

    CAS  PubMed  Google Scholar 

  17. Cobbs LW (1982) Lethargy, anxiety, and impotence in a diabetic. Hosp Pract (Off Ed) 17:67 (see also pages 70 and 73)

    CAS  Google Scholar 

  18. Comer SD, Haney M, Foltin RW, Fischman MW (1997) Effects of caffeine withdrawal on humans living in a residential laboratory. Exp Clin Psychopharmacol 5:399–403

    Article  CAS  PubMed  Google Scholar 

  19. Couturier EG, Laman DM, van Duijn MA, van Duijn H (1997) Influence of caffeine and caffeine withdrawal on headache and cerebral blood flow velocities. Cephalalgia 17:188–190

    Article  CAS  PubMed  Google Scholar 

  20. Denaro CP, Benowitz NL (1991) Caffeine metabolism: disposition in liver disease and hepatic-function testing. In: Watson RR (ed) Drug and alcohol abuse reviews. Liver pathology and alcohol, vol 2. The Human, Totowa, pp 513–539

    Google Scholar 

  21. Dews PB, Curtis GL, Hanford KJ, O’Brien CP (1999) The frequency of caffeine withdrawal in a population-based survey and in a controlled, blinded pilot experiment. J Clin Pharmacol 39:1221–1232

    Article  CAS  PubMed  Google Scholar 

  22. Dews PB, O’Brien CP, Bergman J (2002) Caffeine: behavioral effects of withdrawal and related issues. Food Chem Toxicol 40:1257–1261

    Article  CAS  PubMed  Google Scholar 

  23. Driesbach RH, Pfeiffer C (1943) Caffeine-withdrawal headache. J Lab Clin Med 28:1212–1219

    Google Scholar 

  24. Dusseldorp M van, Katan MB (1990) Headache caused by caffeine withdrawal among moderate coffee drinkers switched from ordinary to decaffeinated coffee: a 12 week double blind trial. BMJ 300:1558–1559

    PubMed  Google Scholar 

  25. Edelstein BA, Keaton-Brasted C, Burg MM (1983) The effects of caffeine withdrawal on cardiovascular and gastrointestinal responses. Health Psychol 2:343–352

    Google Scholar 

  26. Evans SM, Griffiths RR (1992) Caffeine tolerance and choice in humans. Psychopharmacology (Berl) 108:51–59

    CAS  Google Scholar 

  27. Evans SM, Griffiths RR (1999) Caffeine withdrawal: a parametric analysis of caffeine dosing conditions. J Pharmacol Exp Ther 289:285–294

    CAS  PubMed  Google Scholar 

  28. Evans SM, Critchfield TS, Griffiths RR (1994) Caffeine reinforcement demonstrated in a majority of moderate caffeine users. Behav Pharmacol 5:231–238

    CAS  PubMed  Google Scholar 

  29. Feinstein AR, Heinemann LA, Dalessio D, Fox JM, Goldstein J, Haag G, Ladewig D, O’Brien CP (2000) Do caffeine-containing analgesics promote dependence? a review and evaluation. Clin Pharmacol Ther 68:457–467

    Article  CAS  PubMed  Google Scholar 

  30. Fennelly M, Galletly DC, Purdie GI (1991) Is caffeine withdrawal the mechanism of postoperative headache? Anesth Analg 72:449–453

    CAS  PubMed  Google Scholar 

  31. Field AS, Laurienti PJ, Yen YF, Burdette JH, Moody DM (2003) Dietary caffeine consumption and withdrawal: confounding variables in quantitative cerebral perfusion studies? Radiology 227:129–135

    PubMed  Google Scholar 

  32. Fillmore MT (1994) Investigating the behavioral effects of caffeine: the contribution of drug-related expectancies. Pharmacopsychoecologia 7:63–73

    Google Scholar 

  33. Fredholm BB, Bättig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133

    CAS  PubMed  Google Scholar 

  34. Galletly DC, Fennelly M, Whitwam JG (1989) Does caffeine withdrawal contribute to postanaesthetic morbidity? Lancet 1:1335

    Article  CAS  Google Scholar 

  35. Garrett BE, Griffiths RR (1998) Physical dependence increases the relative reinforcing effects of caffeine versus placebo. Psychopharmacology (Berl) 139:195–202

    Article  CAS  Google Scholar 

  36. Gibson CJ (1981) Caffeine withdrawal elevates urinary MHPG excretion. N Engl J Med 304:363

    CAS  Google Scholar 

  37. Gilbert RJ (1986) Caffeine, the most popular stimulant. Chelsea House, New York

    Google Scholar 

  38. Gilbert RM (1984) Caffeine consumption. In: Spiller GA (ed) The methylxanthine beverages and foods: chemistry, consumption, and health effects. Alan R. Liss, New York, pp 185–213

    Google Scholar 

  39. Goldstein A (1964) Wakefulness caused by caffeine. Arch Exp Pathol Pharmakol 248:269–278

    CAS  Google Scholar 

  40. Goldstein A, Kaizer S (1969) Psychotropic effects of caffeine in man. III. A questionnaire survey of coffee drinking and its effects in a group of housewives. Clin Pharmacol Ther 10:477–488

    CAS  PubMed  Google Scholar 

  41. Goldstein A, Wallace ME (1997) Caffeine dependence in schoolchildren? Exp Clin Psychopharmacol 5:388–392

    Article  CAS  PubMed  Google Scholar 

  42. Goldstein A, Kaizer S, Whitby O (1969) Psychotropic effects of caffeine in man. IV. Quantitative and qualitative differences associated with habituation to coffee. Clin Pharmacol Ther 10:489–497

    CAS  PubMed  Google Scholar 

  43. Greden JF (1974) Anxiety or caffeinism: a diagnostic dilemma. Am J Psychiatry 131:1089–1092

    CAS  PubMed  Google Scholar 

  44. Greden JF, Fontaine P, Lubetsky M, Chamberlin K (1978) Anxiety and depression associated with caffeinism among psychiatric inpatients. Am J Psychiatry 135:963–966

    CAS  PubMed  Google Scholar 

  45. Greden JF, Victor BS, Fontaine P, Lubetsky M (1980) Caffeine-withdrawal headache: a clinical profile. Psychosomatics 21:411–413 (see also pages 417 and 418)

    CAS  PubMed  Google Scholar 

  46. Griffiths RR, Mumford GK (1996) Caffeine reinforcement, discrimination, tolerance, and physical dependence in laboratory animals and humans. In: Schuster CR, Kuhar MJ (eds) Pharmacological aspects of drug dependence: toward an integrated neurobehavioral approach (Handbook of Experimental Pharmacology). Springer, Berlin Heidelberg New York, pp 315–341

    Google Scholar 

  47. Griffiths RR, Woodson PP (1988) Caffeine physical dependence: a review of human and laboratory animal studies. Psychopharmacology (Berl) 94:437–451

    CAS  Google Scholar 

  48. Griffiths RR, Bigelow GE, Liebson IA (1986) Human coffee drinking: reinforcing and physical dependence producing effects of caffeine. J Pharmacol Exp Ther 239:416–425

    CAS  PubMed  Google Scholar 

  49. Griffiths RR, Evans SM, Heishman SJ, Preston KL, Sannerud CA, Wolf B, Woodson PP (1990) Low-dose caffeine physical dependence in humans. J Pharmacol Exp Ther 255:1123–1132

    CAS  PubMed  Google Scholar 

  50. Griffiths RR, Juliano LM, Chausmer AL (2003) Caffeine pharmacology and clinical effects. In: Graham AW, Schultz TK, Mayo-Smith M, Ries RK, Wilford BB (eds) Principles of addiction medicine, 3rd edn. American Society of Addiction Medicine, Chevy Chase, pp 193–224

    Google Scholar 

  51. Hale KL, Hughes JR, Oliveto AH, Higgins ST (1995) Caffeine self-administration and subjective effects in adolescents. Exp Clin Psychopharmacol 3:364–370

    Article  CAS  Google Scholar 

  52. Hampl KF, Stotz G, Schneider MC (1994) Postoperative transient hemihypaesthesia and severe headache associated with caffeine withdrawal. Anaesthesia 49:266–267

    CAS  Google Scholar 

  53. Hampl KF, Schneider MC, Ruttimann U, Ummenhofer W, Drewe J (1995) Perioperative administration of caffeine tablets for prevention of postoperative headaches. Can J Anaesth 42:789–792

    CAS  PubMed  Google Scholar 

  54. Hindmarch I, Quinlan PT, Moore KL, Parkin C (1998) The effects of black tea and other beverages on aspects of cognition and psychomotor performance. Psychopharmacology (Berl) 139:230–238

    Article  CAS  Google Scholar 

  55. Höfer I, Bättig K (1994a) Cardiovascular, behavioral, and subjective effects of caffeine under field conditions. Pharmacol Biochem Behav 48:899–908

    Article  PubMed  Google Scholar 

  56. Höfer I, Bättig K (1994b) Psychophysiological effects of switching to caffeine tablets or decaffeinated coffee under field conditions. Pharmacopsychoecologia 7:169–177

    Google Scholar 

  57. Horst K, Buxton RE, Robinson WD (1934) The effect of the habitual use of coffee or decaffeinated coffee upon blood pressure and certain motor reactions of normal young men. J Pharmacol Exp Ther 52:322–337

    CAS  Google Scholar 

  58. Hughes JR (1994) Caffeine withdrawal, dependence, and abuse. In: American psychiatric association: diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, pp 129–134

    Google Scholar 

  59. Hughes JR, Oliveto AH (1997) A systematic survey of caffeine intake in Vermont. Exp Clin Psychopharmacol 5:393–398

    Article  CAS  PubMed  Google Scholar 

  60. Hughes JR, Higgins ST, Bickel WK, Hunt WK, Fenwick JW, Gulliver SB, Mireault GC (1991) Caffeine self-administration, withdrawal, and adverse effects among coffee drinkers. Arch Gen Psychiatry 48:611–617

    CAS  PubMed  Google Scholar 

  61. Hughes JR, Hunt WK, Higgins ST, Bickel WK, Fenwick JW, Pepper SL (1992) Effect of dose on the ability of caffeine to serve as a reinforcer in humans. Behav Pharmacol 3:211–218

    CAS  PubMed  Google Scholar 

  62. Hughes JR, Oliveto AH, Bickel WK, Higgins ST, Badger GJ (1993) Caffeine self-administration and withdrawal: incidence, individual differences and interrelationships. Drug Alcohol Depend 32:239–246

    Article  CAS  PubMed  Google Scholar 

  63. Hughes JR, Oliveto AH, Bickel WK, Higgins ST, Badger GJ (1995) The ability of low doses of caffeine to serve as reinforcers in humans: A replication. Exp Clin Psychopharmacol 3:358–363

    Article  CAS  Google Scholar 

  64. Hughes JR, Oliveto AH, Liguori A, Carpenter J, Howard T (1998) Endorsement of DSM-IV dependence criteria among caffeine users. Drug Alcohol Depend 52:99–107

    Article  CAS  PubMed  Google Scholar 

  65. James JE (1997) Understanding caffeine. Sage, Thousand Oaks

    Google Scholar 

  66. James JE (1998) Acute and chronic effects of caffeine on performance, mood, headache, and sleep. Neuropsychobiology 38:32–41

    Article  CAS  PubMed  Google Scholar 

  67. Jones HE, Herning RI, Cadet JL, Griffiths RR (2000) Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity. Psychopharmacology (Berl) 147:371–377

    Article  CAS  Google Scholar 

  68. Juliano LM, Brandon TH (2002) Effects of nicotine dose, instructional set, and outcome expectancies on the subjective effects of smoking in the presence of a stressor. J Abnorm Psychol 111:88–97

    Article  PubMed  Google Scholar 

  69. Kendler KS, Prescott CA (1999) Caffeine intake, tolerance, and withdrawal in women: a population-based twin study. Am J Psychiatry 156:223–228

    CAS  PubMed  Google Scholar 

  70. Kenemans JL, Wieleman JS, Zeegers M, Verbaten MN (1999) Caffeine and stroop interference. Pharmacol Biochem Behav 63:589–598

    Article  CAS  PubMed  Google Scholar 

  71. Kingdon (1883) Effects of tea and coffee drinking. Lancet II:47–48

    Google Scholar 

  72. Lader M, Cardwell C, Shine P, Scott N (1996) Caffeine withdrawal symptoms and rate of metabolism. J Psychopharmacol 10:110–118

    CAS  Google Scholar 

  73. Lane JD (1994) Neuroendocrine responses to caffeine in the work environment. Psychosom Med 56:267–270

    CAS  PubMed  Google Scholar 

  74. Lane JD (1997) Effects of brief caffeinated-beverage deprivation on mood, symptoms, and psychomotor performance. Pharmacol Biochem Behav 58:203–208

    Article  CAS  PubMed  Google Scholar 

  75. Lane JD, Phillips-Bute BG (1998) Caffeine deprivation affects vigilance performance and mood. Physiol Behav 65:171–175

    Article  CAS  PubMed  Google Scholar 

  76. Lieberman HR, Wurtman RJ, Emde GG, Coviella IL (1987) The effects of caffeine and aspirin on mood and performance. J Clin Psychopharmacol 7:315–320

    CAS  PubMed  Google Scholar 

  77. Liguori A, Hughes JR (1997) Caffeine self-administration in humans: 2. A within-subjects comparison of coffee and cola vehicles. Exp Clin Psychopharmacol 5:295–303

    Article  CAS  PubMed  Google Scholar 

  78. Liguori A, Hughes JR, Grass JA (1997a) Absorption and subjective effects of caffeine from coffee, cola and capsules. Pharmacol Biochem Behav 58:721–726

    Article  CAS  PubMed  Google Scholar 

  79. Liguori A, Hughes JR, Oliveto AH (1997b) Caffeine self-administration in humans: 1. Efficacy of cola vehicle. Exp Clin Psychopharmacol 5:286–294

    Article  CAS  PubMed  Google Scholar 

  80. Mackenzie TB, Popkin MK, Dziubinski J, Sheppard JR (1981) Effects of caffeine withdrawal on isoproterenol-stimulated cyclic adenosine monophosphate. Clin Pharmacol Ther 30:436–438

    CAS  PubMed  Google Scholar 

  81. Marlatt GA, Rohsenow DJ (1980) Cognitive processes in alcohol use: expectancy and the balanced placebo design. In: Mello NK (ed) Advances in substance abuse: behavioral and biological research. JAI, Greenwich, pp 159–199

    Google Scholar 

  82. Martin WR (1977) Drug addiction I: morphine, sedative/hypnotic and alcohol dependence. Springer, New York Berlin Heidelberg

    Google Scholar 

  83. Mathew RJ, Wilson WH (1985) Caffeine consumption, withdrawal and cerebral blood flow. Headache 25:305–309

    CAS  PubMed  Google Scholar 

  84. McGowan JD, Altman RE, Kanto WP (1988) Neonatal withdrawal symptoms after chronic maternal ingestion of caffeine. South Med J 81:1092–1094

    CAS  PubMed  Google Scholar 

  85. Mitchell SH, de Wit H, Zacny JP (1995) Caffeine withdrawal symptoms and self-administration following caffeine deprivation. Pharmacol Biochem Behav 51:941–945

    Article  CAS  PubMed  Google Scholar 

  86. Mumford GK, Benowitz NL, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR (1996) Absorption rate of methylxanthines following capsules, cola and chocolate. Eur J Clin Pharmacol 51:319–325

    Article  CAS  PubMed  Google Scholar 

  87. Naismith DJ, Akinyanju PA, Szanto S, Yudkin J (1970) The effect, in volunteers, of coffee and decaffeinated coffee on blood glucose, insulin, plasma lipids and some factors involved in blood clotting. Nutr Metab 12:144–151

    CAS  PubMed  Google Scholar 

  88. Nehlig A (1999) Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev 23:563–576

    Article  CAS  PubMed  Google Scholar 

  89. Nikolajsen L, Larsen KM, Kierkegaard O (1994) Effect of previous frequency of headache, duration of fasting and caffeine abstinence on perioperative headache. Br J Anaesth 72:295–297

    CAS  PubMed  Google Scholar 

  90. Oberstar JV, Bernstein GA, Thuras PD (2002) Caffeine use and dependence in adolescents: one-year follow-up. J Child Adolesc Psychopharmacol 12:127–135

    Article  PubMed  Google Scholar 

  91. Oliveto AH, Hughes JR, Higgins ST, Bickel WK, Pepper SL, Shea PJ, Fenwick JW (1992a) Forced-choice versus free-choice procedures: caffeine self-administration in humans. Psychopharmacology (Berl) 109:85–91

    CAS  Google Scholar 

  92. Oliveto AH, Hughes JR, Pepper SL, Bickel WK, Higgins ST (1992b) Low doses of caffeine can serve as reinforcers in humans. In: Problems of drug dependence, 1990 NIDA research monograph no. 178. U.S. Government Printing Office, Washington, p 442

    Google Scholar 

  93. Patrick G, Reeves RR, Struve FA (1996) Does caffeine cessation increase firing rates of diffuse paroxysmal slowing dysrhythmia? A serendipitous observation. Clin Electroencephalogr 27:78–83

    CAS  PubMed  Google Scholar 

  94. Phillips-Bute BG, Lane JD (1998) Caffeine withdrawal symptoms following brief caffeine deprivation. Physiol Behav 63:35–39

    Article  CAS  Google Scholar 

  95. Rainey JT (1985) Headache related to chronic caffeine addiction. Tex Dent J 102:29–30

    CAS  PubMed  Google Scholar 

  96. Reeves RR, Struve FA, Patrick G, Bullen JA (1995) Topographic quantitative EEG measures of alpha and theta power changes during caffeine withdrawal: preliminary findings from normal subjects. Clin Electroencephalogr 26:154–162

    CAS  PubMed  Google Scholar 

  97. Reeves RR, Struve FA, Patrick G (1997) Somatic dysfunction increase during caffeine withdrawal. J Am Osteopath Assoc 97:454–456

    CAS  PubMed  Google Scholar 

  98. Reeves RR, Struve FA, Patrick G (1999) The effects of caffeine withdrawal on cognitive P300 auditory and visual evoked potentials. Clin Electroencephalogr 30:24–27

    CAS  PubMed  Google Scholar 

  99. Reeves RR, Struve FA, Patrick G (2002) Topographic quantitative EEG response to acute caffeine withdrawal: a comprehensive analysis of multiple quantitative variables. Clin Electroencephalogr 33:178–188

    PubMed  Google Scholar 

  100. Richardson NJ, Rogers PJ, Elliman NA, O’Dell RJ (1995) Mood and performance effects of caffeine in relation to acute and chronic caffeine deprivation. Pharmacol Biochem Behav 52:313–320

    Article  CAS  PubMed  Google Scholar 

  101. Rippere V (1984) Some varieties of food intolerance in psychiatric patients: an overview. Nutr Health 3:125–136

    CAS  PubMed  Google Scholar 

  102. Rizzo AA, Stamps LE, Fehr LA (1988) Effects of caffeine withdrawal on motor performance and heart rate changes. Int J Psychophysiol 6:9–14

    Article  CAS  PubMed  Google Scholar 

  103. Robelin M, Rogers PJ (1998) Mood and psychomotor performance effects of the first, but not of subsequent, cup-of-coffee equivalent doses of caffeine consumed after overnight caffeine abstinence. Behav Pharmacol 9:611–618

    CAS  PubMed  Google Scholar 

  104. Robertson D, Wade D, Workman R, Woosley RL, Oates JA (1981) Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest 67:1111–1117

    CAS  PubMed  Google Scholar 

  105. Rogers PJ, Richardson NJ, Elliman NA (1995) Overnight caffeine abstinence and negative reinforcement of preference for caffeine-containing drinks. Psychopharmacology (Berl) 120:457–462

    CAS  Google Scholar 

  106. Rogers PJ, Martin J, Smith C, Heatherley SV, Smit HJ (2003) Absence of reinforcing, mood and psychomotor performance effects of caffeine in habitual non-consumers of caffeine. Psychopharmacology (Berl) 167:54–62

    CAS  Google Scholar 

  107. Roller L (1981) Caffeinism: subjective quantitative aspect of withdrawal syndrome. Med J Aust 1:146

    CAS  Google Scholar 

  108. Rubin GJ, Smith AP (1999) Caffeine withdrawal and headaches. Nutr Neurosci 2:123–126

    Google Scholar 

  109. Schuh KJ, Griffiths RR (1997) Caffeine reinforcement: the role of withdrawal. Psychopharmacology (Berl) 130:320–326

    Article  CAS  Google Scholar 

  110. Silverman K, Evans SM, Strain EC, Griffiths RR (1992) Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 327:1109–1114

    CAS  PubMed  Google Scholar 

  111. Sjaastad O, Bakketeig LS (2004) Caffeine-withdrawal headache: the Vaga study of headache epidemiology. Cephalalgia 24:241–249

    CAS  PubMed  Google Scholar 

  112. Smit HJ, Rogers PJ (2000) Effects of low doses of caffeine on cognitive performance, mood and thirst in low and higher caffeine consumers. Psychopharmacology (Berl) 152:167–173

    Article  CAS  Google Scholar 

  113. Smith AP (1996) Caffeine dependence: an alternative view. Nat Med 2:494

    Article  CAS  PubMed  Google Scholar 

  114. Smith R (1987) Caffeine withdrawal headache. J Clin Pharm Ther 12:53–57

    CAS  PubMed  Google Scholar 

  115. Strain EC, Griffiths RR (1998) Characteristics of patients with chronic use of OTC analgesics containing caffeine. In: Problems of drug dependence, 1997 NIDA research monograph no. 178. U.S. Government Printing Office, Washington, p 286

    Google Scholar 

  116. Strain EC, Mumford GK, Silverman K, Griffiths RR (1994) Caffeine dependence syndrome. Evidence from case histories and experimental evaluations. J Am Med Assoc 272:1043–1048

    Article  CAS  Google Scholar 

  117. Streufert S, Pogash R, Miller J, Gingrich D, Landis R, Lonardi L, Severs W, Roache JD (1995) Effects of caffeine deprivation on complex human functioning. Psychopharmacology (Berl) 118:377–384

    CAS  Google Scholar 

  118. Stringer KA, Watson WA (1987) Caffeine withdrawal symptoms. Am J Emerg Med 5:469

    Article  CAS  Google Scholar 

  119. Swerdlow NR, Eastvold A, Gerbranda T, Uyan KM, Hartman P, Doan Q, Auerbach P (2000) Effects of caffeine on sensorimotor gating of the startle reflex in normal control subjects: impact of caffeine intake and withdrawal. Psychopharmacology (Berl) 151:368–378

    Article  CAS  Google Scholar 

  120. Thomas DB (1988) Neonatal abstinence syndrome. Med J Aust 148:598

    CAS  Google Scholar 

  121. Tinley EM, Yeomans MR, Durlach PJ (2003) Caffeine reinforces flavour preference in caffeine-dependent, but not long-term withdrawn, caffeine consumers. Psychopharmacology (Berl) 166:416–423

    CAS  Google Scholar 

  122. Van Soeren MH, Graham TE (1998) Effect of caffeine on metabolism, exercise endurance, and catecholamine responses after withdrawal. J Appl Physiol 85:1493–1501

    PubMed  Google Scholar 

  123. Verhoeff FH, Millar JM (1990) Does caffeine contribute to postoperative morbidity? Lancet 336:632

    Article  CAS  PubMed  Google Scholar 

  124. Victor BS, Lubetsky M, Greden JF (1981) Somatic manifestations of caffeinism. J Clin Psychiatry 42:185–188

    CAS  PubMed  Google Scholar 

  125. Watson JM, Lunt MJ, Morris S, Weiss MJ, Hussey D, Kerr D (2000) Reversal of caffeine withdrawal by ingestion of a soft beverage. Pharmacol Biochem Behav 66:15–18

    Article  CAS  PubMed  Google Scholar 

  126. Weber JG, Ereth MH, Danielson DR (1993) Perioperative ingestion of caffeine and postoperative headache. Mayo Clin Proc 68:842–845

    CAS  PubMed  Google Scholar 

  127. Weddington WW, Brown BS, Haertzen CA, Cone EJ, Dax EM, Herning RI, Michaelson BS (1990) Changes in mood, craving, and sleep during short-term abstinence reported by male cocaine addicts. A controlled, residential study. Arch Gen Psychiatry 47:861–868

    CAS  PubMed  Google Scholar 

  128. Weil A, Rosen W (1993) From chocolate to morphine: everything you need to know about mind-altering drugs. Houghton Mifflin, Boston

    Google Scholar 

  129. Winstead DK (1976) Coffee consumption among psychiatric inpatients. Am J Psychiatry 113:1447–1450

    Google Scholar 

  130. World Health Organization (1992a) The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. World Health Organization, Geneva

    Google Scholar 

  131. World Health Organization (1992b) International statistical classification of diseases and related health problems, 10th revision. World Health Organization, Geneva

    Google Scholar 

  132. World Health Organization (1993) The ICD-10 classification of mental and behavioural disorders: diagnostic criteria for research. World Health Organization, Geneva

    Google Scholar 

  133. Yeomans MR, Spetch H, Rogers PJ (1998) Conditioned flavour preference negatively reinforced by caffeine in human volunteers. Psychopharmacology (Berl) 137:401–409

    Article  CAS  Google Scholar 

  134. Yeomans MR, Jackson A, Lee MD, Nesic J, Durlach PJ (2000a) Expression of flavour preferences conditioned by caffeine is dependent on caffeine deprivation state. Psychopharmacology (Berl) 150:208–215

    Article  CAS  Google Scholar 

  135. Yeomans MR, Jackson A, Lee MD, Steer B, Tinley E, Durlach P, Rogers PJ (2000b) Acquisition and extinction of flavour preferences conditioned by caffeine in humans. Appetite 35:131–141

    Article  CAS  PubMed  Google Scholar 

  136. Yeomans MR, Ripley T, Lee MD, Durlach PJ (2001) No evidence for latent learning of liking for flavours conditioned by caffeine. Psychopharmacology (Berl) 157:172–179

    Article  CAS  Google Scholar 

  137. Yeomans MR, Pryke R, Durlach PJ (2002a) Effect of caffeine-deprivation on liking for a non-caffeinated drink. Appetite 39:35–42

    Article  CAS  PubMed  Google Scholar 

  138. Yeomans MR, Ripley T, Davies LH, Rusted JM, Rogers PJ (2002b) Effects of caffeine on performance and mood depend on the level of caffeine abstinence. Psychopharmacology (Berl) 164:241–249

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Preparation of this manuscript was supported, in part, by National Institute on Drug Abuse grant R01 DA03890. Roland Griffiths has been a consultant to pharmaceutical companies, International Food Information Counsel, International Life Sciences Institute, and the legal profession on issues related to caffeine effects, withdrawal, and dependence. The authors thank Kristen McCausland and Kimberly Mudd for their assistance with data management.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Roland R. Griffiths.

Appendix A—Studies that did not statistically document symptom or sign

Appendix A—Studies that did not statistically document symptom or sign

Symptom or sign Studiesa
Alertness/attentiveness 10, 14, 16, 22, 23, 28, 38, 46, 55
Anger/hostility 4, 6, 9, 10, 15, 18, 22, 25, 26, 27, 28, 33, 34, 35, 36, 37, 46, 55
Anxiety/nervousness 4, 5, 6, 10, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 33, 34, 35, 36, 37, 41, 44, 45, 46, 55, 56
Blood pressure 3, 13, 38, 43, 44, 45, 54
Blurred vision 5, 19, 21, 25, 26, 37, 46, 55, 56
Calm/relaxedb 16, 17, 18, 21, 27, 31, 39
Chills 21
Circular lights taskb 4
Confusion–bewilderment 4, 5, 10, 15, 17, 18, 21, 25, 28, 33, 35, 36, 37, 46, 55
Constipationb 5, 6
Contentedness/well-being 4, 10, 14, 15, 20, 27, 28, 29, 37, 39, 46
Depression 2, 4, 10, 18, 19, 20, 21, 22, 23, 24, 25, 28, 29, 33, 34, 35, 36, 37, 46, 55
Desire to socialize 15, 18, 19, 21, 23, 24, 25, 26, 27, 28, 29, 35, 36
Diaphoresis 5, 6, 9, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26, 37, 46, 55, 56
Diarrheab 5, 6, 14, 15, 22, 23, 24
Difficulty sleeping/insomniab 9, 14, 15, 19, 21, 22, 23, 24, 46, 55
Difficulty concentrating 21, 25, 28, 46
Digit symbol substitution task 9, 14, 15, 20, 21, 22, 28, 37, 55
Divided attentionb 21
Drowsiness/sleepiness 5, 10, 18, 22, 25, 37
Energy/activeness 10, 14, 16, 17, 25, 36, 42, 46
Flu-like symptoms 19, 21, 26, 28, 35, 37, 46, 56
Frequent urinationb 9, 14, 15, 19, 22, 23, 24, 25, 26, 37, 46, 55, 56
Grammatical/logical reasoningb 28, 55
Hand tremor (objectively measured)b 14, 15, 17, 20, 22, 23, 24
Headache 14, 19, 22, 24, 26, 28, 29, 31, 37, 40, 41
Heart pounding/palpitations 9, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26, 37, 46, 55, 56
Heart rate 3, 13, 19, 38, 43, 45, 54, 55
Heavy feelings in arms and legs 19, 21, 25, 26, 56
Hot and cold spells 19, 25, 26, 37, 46, 55
Hunger/appetiteb 17, 18, 20, 21, 22, 23, 24, 29, 31, 42
Irregular heartbeat 14, 15, 22, 23, 24
Irritability 4, 10, 14, 15, 16, 20, 21, 23, 24, 25, 28, 29, 37, 46, 55
Jittery/shakyb 5, 6, 9, 28, 31, 37, 40, 41, 42, 46, 55
Lightheaded/dizzy 5, 9, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26, 37, 46, 56
Limb tremorb 5, 6, 9, 19, 25, 26, 37, 46, 55, 56
Loss of sex driveb 9, 19, 25, 26, 37, 46, 55, 56
Memory/recallb 9, 21, 28, 37
Muscle crampsb 9, 19, 25, 26, 37, 46, 55, 56
Muscle pain/stiffness 9, 19, 20, 21, 25, 26, 37, 44, 46, 55, 56
Muscle twitchesb 14, 15, 22, 23, 24
Muzzy/foggy/not clearheaded 5, 8, 19, 25, 26, 28, 29, 31, 37, 42, 46
Nausea/vomiting/upset stomach 2, 4, 5, 6, 9, 10, 14, 15, 19, 20, 21, 25, 26, 37, 45, 46, 55, 56
Numbing or tingling in extremities 21
Numerical Stroop taskb 9
Problem solving tasks 19
Reaction time 9, 17, 28, 41, 55
Restlessb 21, 22, 23, 24
Rhinorrhea 5, 6, 9, 19, 21, 25, 26, 37, 46, 55, 56
Ringing in earsb 14, 15, 22, 23, 24
Self-confidence 17, 18, 19, 22, 25, 26, 29, 37, 55, 56
Shaky/weaknessb 22, 23, 24
Symbol copy testb 20
Tapping speed 17, 20, 28, 29, 55
Thirst/thirstyb 17, 18, 29, 31, 42
Tiredness/fatigue 10, 22, 27, 31, 37, 42
Total mood disturbance 10, 25, 33, 37, 41, 46
Unmotivated for work 14, 19, 25, 26, 28, 37, 46, 55
Urinary epinephrine or norepinephrine 3
Yawning 5, 25, 26, 37, 46
Visual vigilance 20, 21
  1. aNumbers in table refer to the entry number in Tables 1 and 2
  2. bSymptom or sign was not documented in any study

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Juliano, L.M., Griffiths, R.R. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology 176, 1–29 (2004). https://doi.org/10.1007/s00213-004-2000-x

Download citation

Keywords

  • Caffeine
  • Abstinence
  • Cessation
  • Deprivation
  • Withdrawal
  • Headache
  • Physical dependence
  • DSM
  • ICD
  • Humans