Food and Chemical Toxicology 40 (2002) 1257–1261 www.elsevier.

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Caffeine: behavioral effects of withdrawal and related issues
P.B. Dewsa,*, C.P. O’Brienb, J. Bergmanc
a

New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, MA 01772-9102, USA b Department of Psychiatry, University of Pennsylvania/VA Med. Center, 3900 Chestnut St, Philadelphia, PA 19104-6178, USA c McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02178-9106, USA Accepted 28 August 2001

Abstract Acquired tolerance to some behavioral effects of caffeine in humans is widely assumed to occur but is poorly documented and appears, at most, to be of low magnitude. Withdrawal from regular consumption of caffeine has been reported to result in a variety of symptoms, including: irritability, sleepiness, dysphoria, delerium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains and flushed face. Some of these same symptoms have been reported following excess intake of caffeine. The prevalence of symptoms reported on withdrawal in different studies also covers a wide range from 11% or less to 100%. It is suggested that the evidence leads to the conclusion that non pharmacological factors related to knowledge and expectation are the prime determinants of symptoms and their reported prevalence on withdrawal of caffeine after regular consumption. # 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Acquired tolerance; Adaptive changes; Alcohol; ‘Binge’ mode; Cocaine; Double-blind; Heroin; Locomotor activity; Non-pharmacological factors; Observer rating; Prevalence of symptoms; Prospective clinical type study; Questionnaires; Retrospective survey study; Tolerance; Withdrawal symptoms

1. Introduction Tolerance, withdrawal symptoms and dependence will be discussed. They are related phenomena of wide occurrence in pharmacology. Tolerance is the reduced effect of an agent that often results from regular administration of the agent over a period of time, a few days or a week or two, depending on the agent, so that larger doses are needed to produce the original effect. Withdrawal symptoms are symptoms that can occur when such regular administration is discontinued. Withdrawal symptoms often occur when tolerance has developed, but the quantitative relationship between degree of tolerance and consistency of occurrence and intensity of withdrawal symptoms is usually not strong and, again, depends on the agent. There is no universally accepted definition of dependence, but a widely accepted definition is that dependence on an agent is present during regular administration of an agent if discontinuance precipitates withdrawal symptoms (O’Brien, 1995).

* Corresponding author. Tel.: +1-508-624-8144; fax: +1-508-6248197. E-mail address: peter_dews@hms.harvard.edu (P.B. Dews).

Dependence is thus defined in terms of withdrawal symptoms. Reasons for the poor relationship between tolerance and withdrawal are clear if tolerance is recognized as an adaptive phenomenon. Adaptive changes are usual when physiological systems are subjected to continuing external influence. As an example, consider the adaptive changes that take place when a subject moves from sea level to an altitude of 5000 m and stays there. The partial pressure of oxygen at 5000 m is about 80 mmHg, down from 150 mmHg at sea level. A partial pressure of 80 mmHg is too low for full oxygenation of blood as it passes through the lungs. Adaptive changes occur. For example, respiration increases, cardiac output increases and the concentration of red cells in the blood is increased by cellular proliferation in bone marrow. The first two changes can take place quite quickly, but the last is slower. When the subject returns to sea level the changes in respiration and circulation can regress rather quickly, although if the stay at 5000 m has been prolonged and the heart has hypertrophied that takes some time to regress. The return of the concentration of red cells to normal takes many days. During that time, the subject has blood with a higher viscosity than normal, making circulation more difficult: withdrawal symptoms

0278-6915/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0278-6915(02)00095-9

they started giving the rats a series of doses of caffeine from 3 to 100 mg/kg assessing the effects on locomotor activity. Not only are reported withdrawal symptoms variegated but the frequency of occurrence reported by subjects in different studies also varies widely. lethargy. After a week. no dose caused an increase of more than about 25% in the caffeine drinking rats.. The difference could be related to factors determining whether an individual chose to be a coffee drinker and not to tolerance to caffeine due to the regular consumption of coffee. While in rats that had not been drinking caffeine. Tolerance to caffeine That tolerance to caffeine can develop in some species and under some regimes is beyond doubt. The regular administration of the agent produces changes in the physiological systems affected by the agent. muscle pains and flushed face. Intake of 50 mg/kg per day is about half a log unit above what the heaviest human users obtain from dietary sources. 2. weakness. Thus the tolerance to caffeine was great and was not surmountable by increasing the dose. sleepiness. To obtain dose–effect curves for tolerance. a month. insomnia. Finn and Holtzman (1986) exposed rats to more than 50 mg/kg per day of caffeine. nature and intensity of withdrawal symptoms related to the different physiological systems can likewise vary. the degree of tolerance seen for the different systems can vary. It is interesting that some of these same symptoms have also been reported in the opposite situation. For completeness. restlessness. 3 mg/kg caused about a 50% increase in locomotor activity. It should be noted that although the phenomenon of tolerance has fascinated many pharmacologists and others. and the adaptive changes in the different systems will differ in kind and effectiveness and in the rate at which they disappear when administration of the agent is discontinued.B. While the demonstration that tolerance can develop to a particular effect of an agent is relatively easy and has been done innumerable times. In any case. there seem to have been no subsequent studies that challenge the conclusion of the authors of the study that ‘‘ tolerance to [behavioral effects of] caffeine in man appears to be of low magnitude’’. and the frequency. such as headache. Withdrawal symptoms A review of caffeine dependence studies by Griffiths and Woodson (1988) listed a wide variety of withdrawal symptoms that had been reported when consumers abruptly discontinued caffeine consumption. a year. Whether the adjustment of dosage is made necessary by development of tolerance or by other changes in the patient may be of importance in indicating changes in progress of the disease. but dosage of regularly taken therapeutically important drugs is determined by assessing the desired effects and adjusting dosage to optimize. insomnia. directly and indirectly. nausea. and then the determination of changes in effects of acute doses to assess tolerance can be made usually only at the rate of one per day. muscle tension.1258 P. self-antagonism) quantitative assessments often could be made on isolated tissues at the rate of one determination every 2 or 3 min. The homology to adaptation to regularly administered chemical agents is obvious. . rhinorrhea. nervousness. dysphoria. delirium. It was shown many years ago that 150 mg caffeine taken 30–40 min before retiring delayed sleep in non-coffee drinkers but not in coffee drinkers. and much fine work has been done. it is logistically difficult to generate a pharmacologically satisfactory quantitative account of tolerance. a matter commonly of 1 week or more. There are two general ways of investigating withdrawal phenomena. . nervousness. For a more recent account of the subject. It is thus unreasonable to expect to be able to make generally applicable quantitative statements about tolerance to an agent. obtained from the drinking water. hand or limb tremor. certainly for a drug with the pharmacokinetics of caffeine: and does not appear to have been done even in outline. tremor. a week. . all the determinations should be repeated for different initial periods of developed tolerance: say. Tolerance to some behavioral effects of caffeine in human users in the range that people consume caffeine is widely assumed to occur but has been surprisingly little documented. that of excess consumption of caffeine. As an example. Agents modify. 3 years. As with altitude. Clinicians are aware of the existence of tolerance. psychomotor impairment. The symptoms are reported by the subject. and often little or nothing can be confirmed by physical examination by a physician. (1999). irritability. The completion of the matrix of different levels of exposures and dose–effect curves at each level thus is a formidable undertaking. 1968). a quantitative account of tolerance to the agent would not be much help in diagnosis. When administration of the agent is discontinued the countervailing adaptations are unopposed and the result can be symptoms. first tolerance must be developed by exposure to agent. at best. Adaptive changes take place to reduce the changes caused by the agent. the pressure of the clinic for quantitative information has been lacking. 3. nausea. Dews et al.. the demonstration lacks a quantitative context. see Fredholm et al. restlessness and flushed face (DSM IV). anxiety. mental confusion. Even when attention is focused on a single effect of an agent. namely mental confusion. vomiting. but the difference between the groups was small (Colten et al. / Food and Chemical Toxicology 40 (2002) 1257–1261 from being withdrawn from high altitude if you will. more than one physiological system. In classical studies of drug antagonisms (and tolerance is a special case of antagonism.

These subjects were further asked: ‘‘ Have you had problems or symptoms on stopping caffeine in the past?’’ Some 752 (11%) self reported withdrawal symptoms.. 10 (23%) reported somatic symptoms on withdrawal. (1986) reported symptoms on withdrawal (100%). (1992). Another questionnaire study was conducted on the wives of 183 graduate students by Goldstein and Kaizer (1969).. The second way is to select a sample of regular drinkers and switch them to a caffeine-free diet. / Food and Chemical Toxicology 40 (2002) 1257–1261 1259 One way is to survey a sample of individuals who regularly drink caffeinated beverages and ask them whether they have ever omitted their beverage and. also conducted by Harris. mental depression. A large survey of daily caffeine consumers was conducted by telephone by Harris Laboratories of Lincoln. but 19 (42%) reported more headache while only five (11%) reported less when on decaffeinated coffee. shaky. drowsy. also on hospitalized subjects. blindly. In a later study.211 subjects queried answered affirmatively. nervous. average of 6. what they were. Other symptoms reported were nausea. (1978) on 83 hospitalized subjects. The range of reported incidence of symptoms in prospective clinical trials is even greater than in the survey studies. All seven subjects in a study by Griffiths et al. When decaffeinated coffee was substituted for caffeinated coffee. Of the 11 subjects. In studies of post-operative headache in subjects withdrawn from caffeine as part of pre. For a study of experimental headache. The survey study previously mentioned on 11. Nine of the 11 (82%) gave descriptions of symptoms that were diagnosed as due to withdrawal. 1999). irritable. such that neither subject nor rater know when the switch is made. Of 34 patients estimated to be consuming more than 500 mg/day caffeine. In a non-blind study by Naismith et al. Among regular consumers of 2 or more cups of coffee per day. Next morning. but where the object of the study was physiological .g. drowsiness. nausea. Dreisbach and Pfeiffer (1943) recruited 22 subjects.B. 70 (38%) responded affirmatively to ‘‘Feel half awake’’ A questionnaire was completed by 135 psychiatric patients in a study by Winstead (1976). Dews et al. Forty-two (20%) checked headache on abstention from coffee (53 ‘‘did not know’’). In a questionnaire study by Greden et al. despite the fact that coffee is a richer source of caffeine than soft drinks. The self-reported withdrawal symptoms included sleepy. In this series of survey studies. only five of 18 (28%) actually reported symptoms on withdrawal in spite of the fact that all 18 had reported that they had had withdrawal symptoms in the past. Then. Both approaches have been used to assess caffeine withdrawal. van Dusseldorp and Katan (1990) report that 38 of 45 (84%) subjects in a double-blind withdrawal study did not realize when their coffee was switched to decaffeinated. as did all 62 subjects in a study by Silverman et al. 14 of 67 (21%) reported headache after lactose the night before but only four out of 74 (5%) after caffeine the night before. 30 min before retiring. no energy. Some of the headache. Finally. 18 h after their last caffeine for lactose subjects and 8 h after for caffeine subjects.. of 233 patients 22% of coffee drinkers reported symptoms but only 7% of non-caffeine drinkers (Weber et al. in a couple of studies that involved regular dosing of caffeine and then abrupt withdrawal. They were asked to discontinue caffeine beverages and were given capsules containing caffeine or lactose. stressed. seven had coffee and four had soft drinks as their usual source of caffeine. 18 were considered high consumers of caffeine ( > 750 mg/day): two (11%) reported they got a headache if they omitted their morning coffee.7 cups coffee per day. 1980). yawning and disinclination to work. Subjects were asked ‘‘do you consume caffeinated beverages (e.P. colas) on a regular daily basis?’’: some 6839 of 11. The following paragraphs discuss representative studies and do not constitute an exhaustive review. Goldstein (1964) deprived subjects of caffeine-containing beverages from lunchtime for the rest of the day. if so.. When the caffeine capsules were replaced by lactose only capsules. In this study. being given caffeine on one day and not the other. the prevalence of symptoms on abstinence from caffeine ranged from 11 to 76%. they were asked if they had a headache. In a study on medical students. 1994). but 26 (76%) reported anxiety. The two subjects who had no symptoms on withdrawal were coffee drinkers.operative fasting. usually striving to make the switch double-blind. they took a capsule containing either 150 mg caffeine or lactose.211 subjects was followed by a controlled experiment. stomach upset and headache. coffee. NE (Dews et al. that is. 205 were questioned (Greden et al. Out of 99 subjects self-diagnosed as ‘‘caffeinedependent’’ 11 were selected and completed a 2-day study. and directed specifically at withdrawal headache. vomiting. nausea and vomiting could have been due to migraine. 32 (52%) reported headache compared with 2% under baseline conditions. blindly (Strain et al. tea. insomnia. One item on questionnaire was:’’ How do you think you would feel if you did not have any coffee at all in the morning?’’ While only 11 (6%) responded yes to ‘‘Get a headache’’. (1970) all 20 subjects (100%) reported withdrawal symptoms. This is a prospective clinical type study. They took the same number of capsules daily but the proportion containing caffeine was progressively increased until after 6 or 7 days they were taking around 780 mg/day caffeine. on some 55 of the subjects who had reported symptoms on withdrawal from caffeine. This is a retrospective survey study. whether they had symptoms and. 1993). 14 (82%) reported headache. if so. including five who ‘‘had had typical periodic migraine headaches for at least 2 years’’. diarrhea. rhynorrhea.

even at times when rating scales showed the changes noted above. 1999) (28%). however. which are prone to cause withdrawal symptoms. Once headache had been highlighted as a consequence of withdrawal. cardiovascular. but only 0. in the non-blind study compared to the low prevalence (0%) in studies not directed towards withdrawal. 1993). a noxebo indisposes. (1986) (100%).5% of women. The focus of the studies ranged from withdrawal symptoms in general to particular interest in headache. A placebo pleases. Studies have been made to obtain more objective assessment of performance decline in caffeine withdrawal. (1981) in 18 subjects and Ammon et al. is the high prevalence reported. They report their lower (non-caffeine) level of performance at times as continuance of ‘‘withdrawal symptoms’’. All these factors must contribute to the variability of symptoms and their prevalence. 76% were made by women. In general..B. 1997. 1998).9% of men complained of symptoms upon withdrawal that interfered with their normal daily activities (although. however. Workers agree that coffee with caffeine has discernible effects and therefore can be distinguished from the non-caffeinated state. 1998). the declines have been surprisingly small and nonsignificant. (1992). Silverman et al. / Food and Chemical Toxicology 40 (2002) 1257–1261 measures. for example. In the light of the vast experience of aspartame since. Thus the incidence of withdrawal symptoms in the clinical studies ranged from 22% (0% in studies not on symptoms of withdrawal) to 100% in a study when subjects knew when they were withdrawn. Such a conclusion is by no means novel. are the differences between prevalence reported from studies conducted in laboratories identified as concerned with caffeine withdrawal problems in the literature and by the institutional press office. including epileptiform convulsions. Unfortunately. Severe reactions were reported to ingestion of aspartame. Of the 4000 complaints of symptoms after consumption of aspartame received by the FDA between 1985 and 1993.1260 P. reports of headache on withdrawal became more frequent. close to ‘background noise’ with symptoms and prevalence primarily determined by non-pharmacological factors. within the range of the ‘noise level’. as many as 2/3 of even this population may have failed to report symptoms in a clinical trial). The subjects ranged from hospitalized psychiatric patients to healthy people going about their daily business. as was subsequently found. nor is it seen for withdrawal of other agents such as heroin or phenytoin. Consider the following example. Such a high ratio of women to men is not generally seen for complaints not related to physical sex characteristics. in complaints of ‘‘noxebo’’ effects after consumption of behaviorally inert substances such as aspartame. Following Dreisbach and Pfeiffer’s 1943 description of severe headache on withdrawal.211 subjects (Dews et al. It has been seen. . Even more striking. There are many differences between these different studies. The foregoing discussion is not intended to make the case that caffeine withdrawal symptoms do not occur but rather to put them in the context of symptoms and complaints by people in the course of their everyday lives. The subjects in some studies were recruited without regard to reported history of withdrawal symptoms. The demographics of reports of caffeine withdrawal symptoms are interesting. even dependence. weeks or even months raise the possibility that some individuals may miss the enhancement of performance they customarily receive at appropriate times from consumption of caffeine (Smith et al. some 10 of 16 studies reported headaches on withdrawal. Reports on symptoms were obtained by questionnaires completed by subject. by observer rating and by telephone. the evidence will remain anecdotal. (1993). both without pharmacogical basis). Lane and Phillips-Bute. 1999) 5. the studies of Griffiths et al. In the review of caffeine dependence by Griffiths and Woodson (1988).. Dews et al. the results are presented as a composite of the 30 subjects so it is not possible to see how many subjects were measurably affected or how large the effect was in individual subjects. (1994) (82%). In the Harris survey of 11. but still striking. Obviously. other studies recruited subjects who reported a history of withdrawal symptoms. (1983) in 10 subjects reported no complaints on withdrawal. the anecdotal reports no longer command credence. blindness and incapacitating nervousness. only one of eight reports published prior to 1943 mentioned headache. in which the proportion of targets detected declined and reaction time increased (Lane and Philips-Bute. rather than reported symptoms both Robertson et al. The most parsimonious explanation of much of the variability is that caffeine withdrawal causes a subtle syndrome. see for example. Smith et al. Harris Laboratory had not been linked to caffeine withdrawal studies and so subjects had no reason to expect that such a study was being conducted. 100%. One test that has shown significant declines is a vigilance task. (100%) and Strain et al. Until a reasonable number of individuals have been documented as exhibiting severe caffeine withdrawal symptoms under controlled conditions. The reports of caffeine withdrawal symptoms continuing for days. Less extreme. (Noxebo is a neologism coined to designate the opposite of placebo. such a state of plain normalcy scarcely qualifies as a withdrawal syndrome. so that double-blind cannot be maintained in knowledgeable subjects with some focus on withdrawal. for example on psychomotor tests (Phillips-Bute and Lane. and the report from the Harris study (Dews et al. There are anecdotal accounts of severe caffeine withdrawal symptoms with prostration..

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