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J Pharmacol Exp Ther
1999;289(1):285-294
Caffeine withdrawal:
a parametric analysis of caffeine dosing conditions
Evans SM, Griffiths RR
Department of Psychiatry, The Johns Hopkins University School of Medicine
Baltimore, Maryland, USA.

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Although caffeine is the most widely used behaviorally active drug in the world, caffeine physical dependence has been only moderately well characterized in humans. Four double-blind experiments were conducted in independent groups of healthy participants to assess the conditions under which withdrawal symptoms occur upon cessation of low to moderate doses of caffeine.
 
In experiment 1, there was no evidence that the range or magnitude of caffeine withdrawal symptoms differed when 300 mg of caffeine was consumed as a single dose in the morning versus 100 mg at three time points across the day.
 
In experiment 2, both the range and severity of withdrawal increased as a function of caffeine maintenance dose (100, 300, and 600 mg/day), with even the lowest dose (100 mg) producing significant caffeine withdrawal.
 
Experiment 3 showed that when individuals were maintained on 300 mg caffeine/day and tested with a range of lower doses (200, 100, 50, 25, and 0 mg/day), a substantial reduction in caffeine consumption (</=100 mg/day) was necessary for the manifestation of caffeine withdrawal.
 
Experiment 4 manipulated duration of exposure to caffeine (1, 3, 7, or 14 days of 300 mg/day) and showed that caffeine withdrawal occurred after as little as 3 days of caffeine exposure, with a somewhat increased severity of withdrawal observed after 7 or 14 days of exposure.
 
As a whole, this set of experiments provides the most complete parametric characterization of caffeine withdrawal to date and suggests that caffeine physical dependence can occur under more modest conditions (i.e., fewer doses per day, lower daily dose, shorter duration of exposure) than previously recognized.
 
Discussion
The present study provides the most comprehensive parametric experimental analysis to date of the dosing conditions necessary for the development of caffeine physical dependence as expressed by caffeine withdrawal symptoms upon abrupt cessation of caffeine administration. A particular strength of the present study is that each of the four parametric experiments was conducted using the same general procedure in a different group of moderate daily caffeine consumers.
Caffeine Withdrawal Symptoms.
 
The present studyconfirms and extends previous findings regarding the symptoms associated with the cessation of caffeine consumption. The major symptom clusters that were affected significantly in each of the four experiments were increases in Headache, Headache/Poor Mood (including irritability, anxiety, feelings of depression), Tiredness (drowsy, yawning, lethargy), Fatigue (POMS), and Total Mood Disturbance (POMS) and decreases in Activity/Alertness (alertness, well being, desire to socialize, urge to do task-related activities, concentration, energy, satisfaction, self-confidence) and Vigor (POMS).
 
These symptom clusters overlap with the four most prominent symptom clusters summarized in a recent comprehensive review by Griffiths and Mumford (1995) of the caffeine withdrawal literature: headache, drowsiness, work difficulty (decreased motivation for work/tasks, impaired concentration), and decreased well being/contentment (including decreased self-confidence, increased irritability). The present results also provide weak support for two less prominent symptom clusters cited in the Griffiths and Mumford (1995) review: decreased friendliness and flu-like symptoms. As shown in Table 2, decreased Friendly (POMS) and Flu-Like Symptoms were intermittently sensitive to the caffeine withdrawal manipulations across the four experiments.
 
In summary, the present series of parametric experiments confirms and extends previous studies of caffeine withdrawal (see reviews by Griffiths and Woodson, 1988a; Griffiths and Mumford, 1995) and suggests that caffeine physical dependence can occur under more modest conditions (i.e., fewer doses per day, lower daily dose, and shorter duration of exposure) than previously recognized. Significant caffeine withdrawal symptoms can occur reliably when individuals are maintained on as little as 100 mg caffeine each day, and the severity of caffeine withdrawal is an increasing function of the caffeine maintenance dose.
 
Administration of caffeine as a single daily dose produces physical dependence similar to that produced by three divided doses over the day, suggesting that the daily dose of caffeine consumed is more relevant to the development of caffeine dependence than the pattern of caffeine intake within the day. Furthermore, caffeine withdrawal occurs after as little as 3 consecutive days of caffeine exposure, with a somewhat increased severity ofwithdrawal observed after a week of caffeine exposure.
 
A final experiment showed that, when individuals were maintained on 300 mg caffeine/day, a substantial reduction in caffeine consumption, or complete elimination, is necessary for the manifestation of the full, classic withdrawal syndrome.
 
As a whole, this set of experiments provides the most complete parametric characterization of caffeine withdrawal to date.
 
-Evans SM, Griffiths RR. Caffeine withdrawal: a parametric analysis of caffeine dosing conditions. J Pharmacol Exp Ther. 1999;289(1):285-294.
-Phillips-Bute BG, Lane JD.Caffeine withdrawal symptoms following brief caffeine deprivation. Physiol Behav 199763(1):35-39
-Lane JD Effects of brief caffeinated-beverage deprivation on mood, symptoms, and psychomotor performance. Pharmacol Biochem Behav. 1997;58(1):203-208
-Lane JD, Phillips-Bute BG Caffeine deprivation affects vigilance performance and mood. Physiol Behav.1998;65(1):171-175