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A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features

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Abstract

Rationale

Although reports of caffeine withdrawal in the medical literature date back more than 170 years, the most rigorous experimental investigations of the phenomenon have been conducted only recently.

Objectives

The purpose of this paper is to provide a comprehensive review and analysis of the literature regarding human caffeine withdrawal to empirically validate specific symptoms and signs, and to appraise important features of the syndrome.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

Preparation of this manuscript was supported, in part, by National Institute on Drug Abuse grant R01 DA03890. Roland Griffiths has been a consultant to pharmaceutical companies, International Food Information Counsel, International Life Sciences Institute, and the legal profession on issues related to caffeine effects, withdrawal, and dependence. The authors thank Kristen McCausland and Kimberly Mudd for their assistance with data management.

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Corresponding author

Correspondence to Roland R. Griffiths.

Appendix A—Studies that did not statistically document symptom or sign

Appendix A—Studies that did not statistically document symptom or sign

Symptom or sign

Studiesa

Alertness/attentiveness

10, 14, 16, 22, 23, 28, 38, 46, 55

Anger/hostility

4, 6, 9, 10, 15, 18, 22, 25, 26, 27, 28, 33, 34, 35, 36, 37, 46, 55

Anxiety/nervousness

4, 5, 6, 10, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 33, 34, 35, 36, 37, 41, 44, 45, 46, 55, 56

Blood pressure

3, 13, 38, 43, 44, 45, 54

Blurred vision

5, 19, 21, 25, 26, 37, 46, 55, 56

Calm/relaxedb

16, 17, 18, 21, 27, 31, 39

Chills

21

Circular lights taskb

4

Confusion–bewilderment

4, 5, 10, 15, 17, 18, 21, 25, 28, 33, 35, 36, 37, 46, 55

Constipationb

5, 6

Contentedness/well-being

4, 10, 14, 15, 20, 27, 28, 29, 37, 39, 46

Depression

2, 4, 10, 18, 19, 20, 21, 22, 23, 24, 25, 28, 29, 33, 34, 35, 36, 37, 46, 55

Desire to socialize

15, 18, 19, 21, 23, 24, 25, 26, 27, 28, 29, 35, 36

Diaphoresis

5, 6, 9, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26, 37, 46, 55, 56

Diarrheab

5, 6, 14, 15, 22, 23, 24

Difficulty sleeping/insomniab

9, 14, 15, 19, 21, 22, 23, 24, 46, 55

Difficulty concentrating

21, 25, 28, 46

Digit symbol substitution task

9, 14, 15, 20, 21, 22, 28, 37, 55

Divided attentionb

21

Drowsiness/sleepiness

5, 10, 18, 22, 25, 37

Energy/activeness

10, 14, 16, 17, 25, 36, 42, 46

Flu-like symptoms

19, 21, 26, 28, 35, 37, 46, 56

Frequent urinationb

9, 14, 15, 19, 22, 23, 24, 25, 26, 37, 46, 55, 56

Grammatical/logical reasoningb

28, 55

Hand tremor (objectively measured)b

14, 15, 17, 20, 22, 23, 24

Headache

14, 19, 22, 24, 26, 28, 29, 31, 37, 40, 41

Heart pounding/palpitations

9, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26, 37, 46, 55, 56

Heart rate

3, 13, 19, 38, 43, 45, 54, 55

Heavy feelings in arms and legs

19, 21, 25, 26, 56

Hot and cold spells

19, 25, 26, 37, 46, 55

Hunger/appetiteb

17, 18, 20, 21, 22, 23, 24, 29, 31, 42

Irregular heartbeat

14, 15, 22, 23, 24

Irritability

4, 10, 14, 15, 16, 20, 21, 23, 24, 25, 28, 29, 37, 46, 55

Jittery/shakyb

5, 6, 9, 28, 31, 37, 40, 41, 42, 46, 55

Lightheaded/dizzy

5, 9, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26, 37, 46, 56

Limb tremorb

5, 6, 9, 19, 25, 26, 37, 46, 55, 56

Loss of sex driveb

9, 19, 25, 26, 37, 46, 55, 56

Memory/recallb

9, 21, 28, 37

Muscle crampsb

9, 19, 25, 26, 37, 46, 55, 56

Muscle pain/stiffness

9, 19, 20, 21, 25, 26, 37, 44, 46, 55, 56

Muscle twitchesb

14, 15, 22, 23, 24

Muzzy/foggy/not clearheaded

5, 8, 19, 25, 26, 28, 29, 31, 37, 42, 46

Nausea/vomiting/upset stomach

2, 4, 5, 6, 9, 10, 14, 15, 19, 20, 21, 25, 26, 37, 45, 46, 55, 56

Numbing or tingling in extremities

21

Numerical Stroop taskb

9

Problem solving tasks

19

Reaction time

9, 17, 28, 41, 55

Restlessb

21, 22, 23, 24

Rhinorrhea

5, 6, 9, 19, 21, 25, 26, 37, 46, 55, 56

Ringing in earsb

14, 15, 22, 23, 24

Self-confidence

17, 18, 19, 22, 25, 26, 29, 37, 55, 56

Shaky/weaknessb

22, 23, 24

Symbol copy testb

20

Tapping speed

17, 20, 28, 29, 55

Thirst/thirstyb

17, 18, 29, 31, 42

Tiredness/fatigue

10, 22, 27, 31, 37, 42

Total mood disturbance

10, 25, 33, 37, 41, 46

Unmotivated for work

14, 19, 25, 26, 28, 37, 46, 55

Urinary epinephrine or norepinephrine

3

Yawning

5, 25, 26, 37, 46

Visual vigilance

20, 21

  1. aNumbers in table refer to the entry number in Tables 1 and 2
  2. bSymptom or sign was not documented in any study

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Juliano, L.M., Griffiths, R.R. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology 176, 1–29 (2004). https://doi.org/10.1007/s00213-004-2000-x

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