, Volume 204, Issue 4, pp 573–585 | Cite as

Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects

  • Stacey C. Sigmon
  • Ronald I. Herning
  • Warren Better
  • Jean L. Cadet
  • Roland R. GriffithsEmail author
Original Investigation



Although the subjective effects of caffeine abstinence, acute and chronic administration, and tolerance are well described, the corresponding neurophysiological effects are not.


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.


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.


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.


Cerebral blood flow velocity EEG Caffeine Withdrawal Physical dependence Tolerance Subjective effects Humans 



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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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Stacey C. Sigmon
    • 1
  • Ronald I. Herning
    • 2
  • Warren Better
    • 2
  • Jean L. Cadet
    • 2
  • Roland R. Griffiths
    • 3
    Email author
  1. 1.Department of PsychiatryUniversity of Vermont College of Medicine, SATC-UHCBurlingtonUSA
  2. 2.Molecular Neuropsychiatry Section, Division of Intramural ResearchNational Institute on Drug AbuseBaltimoreUSA
  3. 3.Departments of Psychiatry and NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

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