Caffeine is the most widely used psychoactive substance and has been considered occasionally as a drug of abuse. The present paper reviews available data on caffeine dependence, tolerance, reinforcement and withdrawal. After sudden caffeine cessation, withdrawal symptoms develop in a small portion of the population but are moderate and transient. Tolerance to caffeine-induced stimulation of locomotor activity has been shown in animals. In humans, tolerance to some subjective effects of caffeine seems to occur, but most of the time complete tolerance to many effects of caffeine on the central nervous system does not occur. In animals, caffeine can act as a reinforcer, but only in a more limited range of conditions than with classical drugs of dependence. In humans, the reinforcing stimuli functions of caffeine are limited to low or rather moderate doses while high doses are usually avoided. The classical drugs of abuse lead to quite specific increases in cerebral functional activity and dopamine release in the shell of the nucleus accumbens, the key structure for reward, motivation and addiction. However, caffeine doses that reflect the daily human consumption, do not induce a release of dopamine in the shell of the nucleus accumbens but lead to a release of dopamine in the prefrontal cortex, which is consistent with caffeine reinforcing properties. Moreover, caffeine increases glucose utilization in the shell of the nucleus accumbens only at rather high doses that stimulate most brain structures, non-specifically, and likely reflect the side effects linked to high caffeine ingestion. That dose is also 5–10-fold higher than the one necessary to stimulate the caudate nucleus, which mediates motor activity and the structures regulating the sleep-wake cycle, the two functions the most sensitive to caffeine. In conclusion, it appears that although caffeine fulfils some of the criteria for drug dependence and shares with amphetamines and cocaine a certain specificity of action on the cerebral dopaminergic system, the methylxanthine does not act on the dopaminergic structures related to reward, motivation and addiction.
