Abstract
Rationale
Although the subjective effects of caffeine abstinence, acute and chronic administration, and tolerance are well described, the corresponding neurophysiological effects are not.
Objectives
Caffeine withdrawal, acute caffeine effects, caffeine tolerance, and net beneficial effects of chronic caffeine administration were investigated using cerebral blood flow velocity, quantitative electroencephalography (EEG), and subjective effects.
Materials and methods
Sixteen regular caffeine users participated in this double-blind, within-subject study during which they received acute caffeine and placebo challenges (1) while maintained on 400 mg caffeine daily for ≥14 days and (2) while maintained on placebo for ≥14 days. Blood flow velocity was determined for the middle (MCA) and anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded from 16 scalp sites. Subjective effects were assessed with questionnaires.
Results
Acute caffeine abstinence (evaluated 24 h after placebo substitution) increased mean, systolic, and diastolic velocity in the MCA and ACA and decreased pulsatility index in the MCA. Acute caffeine abstinence increased EEG theta and decreased beta 2 power. Acute caffeine abstinence also increased measures of Tired, Fatigue, Sluggish, and Weary and decreased ratings of Energetic, Friendly, Lively, and Vigor. Acute caffeine effects were demonstrated across a wide range of measures, including cerebral blood flow, EEG, and subjective effects. Tolerance and “complete” tolerance were observed on subjective but not physiological measures. Chronic caffeine effects were demonstrated only on the measure of EEG beta 2 power.
Conclusion
Acute caffeine abstinence and administration produced changes in cerebral blood flow velocity, EEG, and subjective effects. Tolerance to subjective but not physiological measures was demonstrated. There was almost no evidence for net effects of chronic caffeine administration on these measures. Overall, these findings provide the most rigorous demonstration to date of physiological effects of caffeine withdrawal.
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References
Abreu ME, Griffths RR (1996) Drug tasting may confound human drug discrimination studies. Psychopharmacology 125:255–257
Cameron OG, Modell JG, Hariharan M (1990) Caffeine and human cerebral blood flow: a positron emission tomography study. Life Sci 47:1141–1146
Chamberlin H (1985) Musical application of microprocessors. Hayden, Hasbrouk Heights, NJ, pp 435–458
Childs E, de Wit H (2006) Subjective, behavioral, and physiological effects of acute caffeine in light, nondependent caffeine users. Psychopharmacology 185:514–523
Couturier EGM, Laman DM, van Duijn MAJ, van Duijn H (1997) Influence of caffeine and caffeine withdrawal on headache and cerebral blood flow velocities. Cephalalgia 17:188–190
Debrah K, Haigh R, Sherwin R, Murphy J, Kerr D (1995) Effect of acute and chronic caffeine use on cerebrovascular, cardiovascular and hormonal responses to orthostasis in healthy volunteers. Clin Sci 89:475–480
Denaro CP, Brown CR, Jacob PI, Benowitz NL (1991) Effects of caffeine with repeated dosing. Eur J Clin Pharmacol 40:273–278
Evans SM, Griffiths RR (1992) Caffeine tolerance and choice in humans. Psychopharmacology 108:51–59
Evans SM, Griffiths RR (1999) Caffeine withdrawal: a parametric analysis of caffeine dosing conditions. J Pharmacol Exp Ther 289:285–294
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
Goldstein L, Murphree HB, Pfeiffer CC (1963) Quantitative electroencephalography in man as a measure of CNS stimulation. Ann N Y Acad Sci 107:1045–1056
Griffiths RR, Mumford GK (1996) Caffeine reinforcement, discrimination, tolerance and physical dependence in laboratory animals and humans. In: Schuster CR, Gust SW, Kuhar MJ (eds) Pharmacological aspects of drug dependence—toward an integrated neurobehavioral approach—handbook of experimental pharmacology. Springer, New York, pp 315–341
Griffiths RR, Woodson PP (1988) Reinforcing effects of caffeine in humans. J Pharmacol Exp Ther 246:21–29
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 225:1123–1132
Haskell CF, Kennedy DO, Wesnes KA, Scholey AB (2005) Cognitive and mood improvements of caffeine in habitual consumers and habitual non-consumers of caffeine. Psychopharmacology 179:813–825
Jacob P, Wilson M, Benowitz NL (1981) Improved gas chromatographic method for the determination of nicotine and cotinine in biological fluids. J Chromatogr B 222:61–70
James JE (1994) Chronic effects of habitual caffeine consumption on laboratory and ambulatory blood pressure levels. J Cardiovasc Risk 1:159–164
James JE (1996) Effects of habitual caffeine consumption on ambulatory blood pressure. Am J Cardiol 78:129
James JE (1998) Acute and chronic effects of caffeine on performance, mood, headache, and sleep. Neuropsychobiology 38:32–41
James JE, Keane MA (2007) Caffeine, sleep and wakefulness: implications of new understanding about withdrawal reversal. Hum Psychopharmacol Clin Exp 22:1–10
James JE, Rogers PJ (2005) Effects of caffeine on performance and mood: withdrawal reversal is the most plausible explanation. Psychopharmacol 182:1–8
James JE, Gregg ME, Kane M, Harte F (2005) Dietary caffeine, performance and mood: enhancing and restorative effects after controlling for withdrawal relief. Neuropsychobiology 52:1–10
Jones HE, Herning RI, Cadet JL, Griffiths RR (2000) Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity. Psychopharmacology 147:371–377
Juliano LM, Griffiths RR (2004) A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity and associated features. Psychopharmacology 176:1–29
Keane MA, James JE, Hogan MJ (2007) Effects of dietary caffeine on topographic EEG after controlling for withdrawal and withdrawal reversal. Neuropsychobiology 56:197–207
Lader M, Cardwell C, Shine P, Scott N (1996) Caffeine withdrawal symptoms and rate of metabolism. J Psychopharmacol 10:110–118
Lovallo WR, Wilson MF, Vincent AS, Sung BH, McKey BS, Whitsett TL (2004) Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension 43:769–765
Mathew RJ, Wilson WH (1985) Caffeine consumption, withdrawal and cerebral blood flow. Headache 25:305–309
Mathew RJ, Barr DL, Weinman ML (1983) Caffeine and cerebral blood flow. Br J Psychiatry 143:604–608
McNair DM, Lorr M, Droppleman LF (1971) EITS manual for the profile of mood states. Educational and Industrial Service, San Diego
Muhonen MG, Loftus CM, Heistad DD (1995) Effects of adenosine and 2-chloroadenosine on cerebral collateral vessels. J Cereb Blood Flow Metab 15:1075–1081
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 Electroencephal 26:154–162
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
Rogers PJ, Dernoncourt C (1998) Regular caffeine consumption: a balance of adverse and beneficial effects for mood and psychomotor performance. Pharmacol Biochem Behav 59:1039–1045
Rogers PJ, Heatherley SV, Hayward RC, Seers HE, Hill J, Kane M (2005) Effects of caffeine and caffeine withdrawal on mood and cognitive performance degraded by sleep restriction. Psychopharmacology 179:742–752
Saletu B, Anderer P, Kinsperger K, Grünberger J (1987) Topographic brain mapping of EEG in neuropsychopharmacology—Part II. Clinical applications (pharmaco EEG imaging). Methods Find Exp Clin Pharmacol 9:385–408
Acknowledgments
This research was supported in part by research grant R01 DA-03890 and training grant T32-DA07209 from the National Institute on Drug Abuse. The authors thank John Yingling for computer programming assistance, Allison Chausmer, Tiffany Tomlin, and Krista Powell for their help with data collection, and Paul Nuzzo for assistance with statistical analysis. This study complies with current laws of the United States and the authors report no conflicting interests.
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Sigmon, S.C., Herning, R.I., Better, W. et al. Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. Psychopharmacology 204, 573–585 (2009). https://doi.org/10.1007/s00213-009-1489-4
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DOI: https://doi.org/10.1007/s00213-009-1489-4