Caffeine is widely consumed throughout the world in behaviorally active doses. Most of the data suggest that caffeine, in the doses that are commonly consumed, acts primarily by blocking adenosine A1 and A2A receptors. The possibility that some, as yet unidentified, additional mechanism contributes, cannot be excluded, however. Caffeine thus has a unique mechanism of action among all centrally stimulating drugs. It does interact with the dopaminergic transmission, but the mechanism is very different from that of other drugs such as cocaine and amphetamine. Caffeine does not markedly increase the release of dopamine, and it does not lead to any substantial increase in activation of D1 dopaminergic neurotransmission in nucleus accumbens, in contrast to the other central stimulants. Instead it increases transmission via cells equipped with dopamine D2 receptors in this nucleus as well as elsewhere in the basal ganglia. The effect of caffeine in nucleus accumbens is manifested as a decrease in activity of the cells involved, whereas the effects of cocaine and amphetamine are associated with an increased activity of the relevant cellular targets. Accordingly, the overall activity of the nucleus accumbens is much less affected by caffeine than by cocaine, nicotine, and amphetamine. Furthermore, the cells activated by cocaine possess particularly dopamine D1 receptors, whereas those affected by caffeine possess D2 and adenosine A2A receptors. There is, however, very good evidence that D1 and D2 receptor-stimulating drugs interact and potentiate each other's actions. Thus, the unique molecular and cellular actions of caffeine in the brain do not a priori rule out a potential as an addictive drug, they only indicate that its stimulant effects are different from those exerted by drugs such as cocaine and amphetamine.
There is good experimental evidence that i.v. caffeine can act as a reinforcing agent in several paradigms. The reinforcing properties of caffeine are, however, very much weaker and less consistent than those of cocaine and amphetamine. In some studies, the effects of caffeine are even weaker in this regard than those of nicotine, which is notoriously unreliable as a reinforcing drug.
Another important issue relates to the mode of administration. The studies concerning caffeine reinforcement in animals have generally examined the effect of i.v. administered drug, despite the fact that this mode of administration is hardly ever used by humans. If caffeine is administered i.v., human subjects report a higher liking than after oral use.
One important aspect of caffeine use is that the margin for dose increases may be limited by the biphasic effects of the drug. It is important to remember that the doses of caffeine that cause reinforcement in animals are low and that high doses are aversive. Thus, reinforcement is observed with doses even below 1 mg/kg, and doses above 10 to 15 mg/kg are usually aversive. Similarly, doses that are behaviorally stimulant (increasing motor behavior) are below about 30 mg/kg, and doses above 50 mg/kg are generally depressant in these paradigms. A similar biphasic dose-response curve is observed in humans, with low doses being perceived as stimulant and pleasant, whereas higher doses frequently are associated with dysphoria or in extreme cases with clear-cut toxic effects. The exact reasons for these biphasic responses are unknown (even though some possibilities are outlined above), but the fact that the response curve is inverted U-shaped has very important implications for the possibilities of dose increases.
Caffeine has important effects on alertness, and there is no doubt that caffeine is widely consumed by subjects who need to stay awake. Caffeine also has some poorly investigated analgesic actions that contribute to its use. In some contexts there are performance-enhancing actions.
Tolerance develops to some caffeine effects but not to others. For example the blood pressure increase that is observed with acute administration of caffeine, and which is most likely centrally mediated, shows a rapid tolerance development. Other effects, including susceptibility to seizures and ischemic brain damage, actually demonstrate a complete effect reversal. By contrast, tolerance to discriminative stimulant effects, motor stimulant effects, and alerting actions develops more slowly and to a variable extent.
Withdrawal effects are observed after long-term caffeine use. The exact frequency may be debatable, but most studies indicate that the majority of subjects exhibit some withdrawal symptoms after acute discontinuation of caffeine. Withdrawal symptoms typically characterize physical drug dependence. It is, however, less clear if these withdrawal effects are a significant factor in continued caffeine use, at least for the majority of subjects (but see Garrett and Griffiths, 1998). The available evidence should probably be interpreted to indicate that, for some individuals and in some circumstances, caffeine can be used to alleviate withdrawal symptoms, but this is not the case for all subjects and the urge to re-administer caffeine is nowhere near as strong as in several other cases of drugs of addiction. Hence, despite the fact that individuals exist who profess a wish to stop using caffeine because of real or perceived detrimental effects and who yet persist in their caffeine use, the continued use "despite adverse psychological or physical effects" (Rang et al., 1995) does not appear to be a major issue in caffeine use (but see Hughes et al., 1998).
This leads naturally to another major consideration, namely, if caffeine use leads to major negative consequences. Because the drug is consumed by a majority of the adult population in most countries, it is clear that caffeine use does not introduce major social problems. In fact, there is even some, albeit weak, evidence to suggest that caffeine can improve social interactions. It is also widely accepted that compared with other widely used drugs such as nicotine (in smoked tobacco) or alcohol the social consequences of caffeine use are negligible. Thus, caffeine does not impose a potential health hazard or a polluted environment on fellow citizens as does smoking. Similarly, the behavioral changes are not nearly as great as those seen after use of ethanol.
Also there really is very little evidence that caffeine used in moderation leads to any significant negative effects on the health of the individual. Thus, initial concerns that coffee drinking may lead to increases in cancer incidence have now largely vanished. Similarly, concerns that coffee use is a cardiovascular risk factor have lessened. Instead there has been an increasing realization that some of the effects of caffeine use may be beneficial. The alerting actions, for example, have been shown to be important in reducing accidents during driving or night time work. There is accumulating evidence that caffeine use may reduce suicidal tendencies, perhaps by being antidepressant. And performance of some types of activities is facilitated by caffeine use. For other stimulant drugs such as amphetamine and cocaine, as well as for opiates, the reason why many subjects eventually relapse into drug use is not the physical withdrawal effects (even though they may be more severe than observed with caffeine) but rather is brought about by drug-associated cues (O'Brien, 1995; Rang et al., 1995). We have found little evidence that this is a major factor in continued caffeine use.
From the above considerations it is clear that caffeine cannot really be considered a "model drug of dependence" (Holtzman, 1990), at least not if by "model" is meant "typical". Its weak reinforcing properties are due to a unique and atypical mechanism of action. The drug is self-limiting and subjects do not gradually increase the dose, because tolerance development to both the reinforcing and aversive effects is limited. There are few negative consequences of caffeine use in moderation and the withdrawal affects are modest and transient in the individuals that experience them. Because caffeine will, according to current drug classification schemes, be designated a drug of dependence, and that it will not, in this respect, be different from drugs such as amphetamine, morphine, ethanol, or nicotine, it is possible that, in addition to the qualitative criteria, some quantitative criteria of relative abuse potential and negative health consequences would be useful in a modified drug classification scheme. This is particularly true for a drug whose use is so entrenched in normal societal activities.
We are grateful to Drs. François Gonon, Björn Johansson, Alexander Kuzmin, George G. Nomikos, and Per Svenningsson for helpful comments and suggestions and for providing access to unpublished information. Original studies reported here have been supported inter alia by the Swedish Medical Research Council, the Wallenberg Foundation, the Swedish Heart Lung Foundation and Karolinska Institutet (B.B.F. and J.H.), and by Institut National de la Santé et de la Recherche Médicale (A.N.). All the authors have received support from the Physiological Effects of Caffeine Group at the Institute for Scientific Information on Caffeine.
1 Address for correspondence: Bertil B. Fredholm, Section of Molecular Neuropharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm. E-mail: Bertil.Fredholm@fyfa.ki.se
2 Professor Karl Bättig died on 27 December 1996 and has not been able to assess the later versions of this review.
AP-1, activator protein 1; APEC, 2-[(2-aminoethylamino)carbonylethylphenylethylamino]-5'-N-ethylcarboxamidoadenosine; CGS 15943, 9-chloro-2-(2-furanyl)-5,6-dihydro-[1,2,4]-triazolo[1,5]quinazolin-5-imine; CGS 21680, 2-[p-(2-carbonylethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine; CHO, Chinese hamster ovary; CNS, central nervous system; CREB, cyclic AMP response element-binding protein; CRE, cyclic AMP response element; DA, dopamine; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; DSM, Diagnostic and Statistical Manual of Mental Disorders; EEG, electroencephalogram; ICD, International Classification of Diseases; IEG, immediate early gene; MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine; NGFI-A/B, nerve growth factor-induced genes A and B (NGFI-A is also called zif/268 and egr1); NMDA, N-methyl-D-aspartate; PCP, phencyclidine; REM, rapid eye movement; SCH 58261, 5-amino-2-(2-furyl)-7-phenylethylpyraxolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; SKF 38393, 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; VTA, ventral tegmental area.