Although reports of caffeine with-drawal in the medical literature date back more than 170 years, the most rigorous experimental investigations of the phenomenon have been conducted only recently.
The purpose of this paper is to provide a comprehensive review and analysis of the literature regarding human caffeine withdrawal to empiricallyvalidate specific symptoms and signs, and to appraise important features of the syndrome.
A literature search identified 57 experimental and 9 survey studies on caffeine withdrawal that met inclusion criteria. The methodological features of each study were examined to assess the validity of the effects.
Of 49 symptom categories identified, the following 10 fulfilled validity criteria: headache, fatigue, decreased energy/ activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and foggy/not clearheaded. In addition, flu-like symptoms, nausea/vomiting, and muscle pain/stiffness were judged likely to represent valid symptom categories. In experimental studies, the incidence of headache was 50% and the incidence of clinically significant distress or functional impairment was 13%. Typically, onset of symptoms occurred 12–24 h after abstinence, with peak intensity at 20–51 h, and for a duration of 2–9 days. In general, the incidence or severity of symptoms increased with increases in daily dose; abstinence from doses as low as 100 mg/day produced symptoms. Research is reviewed indicating that expectancies are not a prime determinant of caffeine withdrawal and that avoidance of withdrawal symptoms plays a central role in habitual caffeine consumption.
The caffeine-withdrawal syndrome has been well characterized and there is sufficient empirical evidence to warrant inclusion of caffeine withdrawal as a disorder in the DSM and revision of diagnostic criteria in the ICD.
Caffeine is the most widely used behaviorally active drug in the world (Gilbert 1984). In North America, 80–90% ofadults report regular use of caffeine (Gilbert 1984; Hughes and Oliveto 1997). Mean daily intake of caffeine among caffeine consumers in the United States is about 280 mg, with higher intakes estimated in some European countries (Gilbert 1984; Barone and Roberts 1996). In the United States, coffee and soft drinks are the most common sources of caffeine, with almost half of caffeine consumers ingesting caffeine from multiple sources, including tea (Hughes and Oliveto 1997).
After oral ingestion, caffeine is rapidly and completely absorbed, with peak blood levels generally reached in 30–45 min (Denaro and Benowitz 1991; Mumford et al. 1996; Liguori et al. 1997a), and is quickly eliminated, with a typical half-life of 4–6 h (Denaroand Benowitz 1991). The primary mechanism of action of caffeine is competitive antagonism at A1and A2A adenosine receptors (Fredholm et al. 1999). Caffeine produces a variety of physiological effects, including effects on the cerebral vascular system, blood pressure, respiratory functioning, gastric and colonic activity, urine volume, and exercise performance (James 1997). Low to moderate doses of caffeine (20–200 mg) produce reports of increased well- being, happiness, energy, alertness, and sociability, whereas higher doses are more likely to produce reports of anxiety, jitteriness, and upset stomach (Griffiths et al. 2003). Chronic administration of caffeine results in tolerance to a number of its physiological, subjective, and behavioral effects (Griffiths and Mumford 1996). Caffeine has been shown to function as a reinforcer in humans (e.g. Hughes et al.1991; Evans et al.1994), and some individuals become clinically dependent on caffeine as indicated by being unable to quit and continuing use despite having medical problems made worse by caffeine (Strain et al. 1994; Hughes et al.1998).
Regular use of caffeine also produces physical dependence, evidenced as time-limited withdrawal symptoms upon the termination or reduction of one’s usual caffeine dose. Physical dependence on caffeine has been documented in both pre-clinical and clinical research, and the biological basis has been hypothesized to be increased functional sensitivity to endogenous adenosine (Griffiths and Mumford 1996). Symptoms of caffeine withdrawal have been described in the medical literature for more than 170 years. In 1988, the first comprehensive review of clinical reports and experimental studies on caffeine withdrawal was published (Griffiths and Woodson 1988), which provided evidence for caffeine withdrawal as a discrete clinical syndrome. Since that time, the research literature on caffeine withdrawal has increased substantially. For example, of 48 blind caffeine-withdrawal studies identified for this review, only five were published before 1988.
The present review was inspired by this emergent research literature, which has not been comprehensively reviewed, as well as by the practical need to develop empirically based diagnostic criteria for caffeine withdrawal. In 1994, a tentative research diagnosis of caffeine withdrawal was proposed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) to encourage research on diagnostic criteria and the utility of the diagnosis (American Psychiatric Association 1994). Only one-quarter of the blind studies identified for this review were available to the DSM-IV Work Group (Hughes 1994). The review also addresses the previous suggestions (Rubin and Smith 1999; Dews et al. 2002) that caffeine withdrawal is not clinically significant and is primarily determined by expectancies.