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

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 EEG and subjective effects. 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 hours 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.

Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption

“…If caffeine was consumed, the adverse effects of lowered alertness and headache were avoided, but even after 100 + 150 mg of caffeine their alertness was not raised above the level of alertness showed by nonconsumers of caffeine (group N) who received placebo (Figure 1, middle panel). This result is similar to that from an early study comparing responses to caffeine of coffee drinkers and abstainers (Goldstein et al, 1969), and is consistent with the claim, supported by a variety of subsequent findings, that regular caffeine consumption provides little or no net benefit for alertness or performance on tests of vigilance (James and Rogers, 2005;Sigmon et al, 2009). Another interpretation could be that frequent caffeine consumers are 'constitutionally' less alert or more fatigued, and they use caffeine to remedy this state of affairs.…”

“…However, although frequent consumers feel alerted by caffeine, especially by their morning tea, coffee, or other caffeine-containing drink, evidence suggests that this is actually merely the reversal of the fatiguing effects of acute caffeine withdrawal (James and Rogers, 2005;Sigmon et al, 2009). That is, little or perhaps no net benefit for alertness is gained.…”

Cerebral blood flow and behavioural effects of caffeine in habitual and non-habitual consumers of caffeine: A near infrared spectroscopy study

“…Methodologies have included PET (Cameron, Modell, & Hariharan, 1990), Trans-cranial Doppler (Jones, Herning, Cadet, & Griffiths, 2000;Sigmon, Herning, Better, Cadet, & Griffiths, 2009) and MRI Perthen ). The current study utilised NIRS to confirm the previous observation of caffeine related reductions in CBF and this gave the added advantage of continuous recording from pre-dose until 66 minutes post-dose.…”

“…This has been seen in the modulation of putative indices of CBF using a number of methodologies. These include Positron Emission Tomography (PET) (Cameron, Modell, & Hariharan, 1990); Xenon Clearance (Lunt, Ragab, Birch, Schley, & Jenkinson, 2004), Trans-cranial Doppler (Jones, Herning, Cadet, & Griffiths, 2000;Sigmon, Herning, Better, Cadet, & Griffiths, 2009) and Magnetic Resonance Imaging (MRI) . With regards the latter method, Field et al (2003), using quantitative perfusion MRI undertaken approximately 60 to 90 minutes postdose of placebo or caffeine, found that habitual high consumers (>300mg/day) had greater placebo CBF in comparison to lower consumers (<125mg/day) following abstention for 30 hours.…”

Repeated administration of caffeine induces either sensitization or tolerance of locomotor stimulation depending on the environmental context

“…Also, Lau and Falk [24] showed evidence of caffeine tolerance following a long period of daily intraperitoneal (ip) drug injections. Development of tolerance has been related to neuroadaptations responsible for withdrawal symptoms when the repeated administration of psychostimulants is discontinued [29,41]. In contrast, it has been shown that an ip injection of caffeine on alternate days for two weeks induces sensitization to its psychomotor stimulation [7,42].…”