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Controlled Clinical Trial
. 2009 Jul;204(4):573-85.
doi: 10.1007/s00213-009-1489-4. Epub 2009 Feb 25.

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  1 , Ronald I Herning, Warren Better, Jean L Cadet, Roland R Griffiths
Affiliations
Controlled Clinical Trial

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 et al. Psychopharmacology (Berl). 2009 Jul.

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 > or =14 days and (2) while maintained on placebo for > or =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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Figures

Figure 1
Figure 1
Effects of the four drug conditions on cerebral blood flow velocities for middle cerebral artery (top panel) and anterior cerebral artery (bottom panel). Mean, systolic and diastolic blood flow velocities, averaged over left and right sides, are presented. Dark grey bars show the caffeine maintenance condition (caff/caff); solid bars show the acute caffeine abstinence condition (caff/plac), open bars show the placebo maintenance condition (plac/plac), and light grey bars show the acute caffeine administration condition (plac/caff). The y-axis is presented on a smaller scale (40-120 cm/s) that represents a physiologically reasonable range for cerebral blood flow velocity and allows more detailed inspection of the data (normative range is 29-176 cm/s for MCA and 16-124 cm/s for ACA). Brackets indicate +1SEM. Asterisks (*) indicate that the condition was significantly different from the acute abstinence condition (caff/plac); the letter “a” indicates that the acute abstinence condition (caff/plac) was significantly different from the two chronic maintenance conditions combined (caff/caff and plac/plac).
Figure 2
Figure 2
Effects of the four drug conditions (caff/caff, caff/plac, plac/plac, plac/caff) on EEG relative power for theta (top panel) and beta 2 (bottom panel). The y-axis is presented on a smaller scale that represents a physiologically reasonable range for cerebral blood flow velocity and allows more detailed inspection of the data (normative range is .10-.35 for relative theta and .05-.20 for relative beta). Other details are as in Figure 1.
Figure 3
Figure 3
Effects of the four drug conditions (caff/caff, caff/plac, plac/plac, plac/caff) on subjective measures. Other details are as in Figure 1.
Figure 4
Figure 4
Effects of the four drug conditions (caff/caff, caff/plac, plac/plac, plac/caff) on two illustrative subjective measures that did not show withdrawal effects but did show acute caffeine effects and tolerance to caffeine. Brackets indicate significant effects. Acute caffeine effects were demonstrated by a significant difference between the plac/caff and plac/plac conditions (a). Tolerance was demonstrated by a significant difference between the plac/caff and caff/caff conditions (b).
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