affeine is the most consumed psychoactive drug in the world. As a psychostimulant, it shows all the pharmacological properties of classical psychostimulants, such as cocaine and amphetamine. Those properties include arousal, motor activation, and reinforcing effects. Nevertheless, those effects are milder for caffeine, which depends on its unique mechanism of action, adenosine receptor antagonism. Classical psychostimulants produce a direct potentiation of central dopaminergic, noradrenergic, and serotoninergic neurotransmission, by acting on catecholamine and serotonin transporters. Caffeine, instead, indirectly activates those and several other ascending neurotransmitter systems (cholinergic, histaminergic, and orexinergic) by removing an inhibitory presynaptic adenosinergic tone, mediated by the effect of endogenous adenosine on adenosine A 1 receptors. Caffeine-induced modulation of the dopaminergic system also depends on postsynaptic mechanisms that depend on assemblies of adenosine and dopamine receptors (A 1 -D 1 and A 2A -D 2 receptor heteromers) (for review see Ref. 1).The same as for classical psychostimulants, the effects of caffeine on the dopaminergic system are largely responsible for its relatively mild motor activating and reinforcing effects.1 However, it has been difficult to definitively show a psychostimulant-like biochemical profile of caffeine in the experimental animal. The hallmark of that profile is a significant increase in the striatal extracellular concentration of dopamine, and this has only been clearly seen in a distinct region of the ventral striatum.1 In this issue, Ferre et al. 2 review recent results that indicate that paraxanthine, the main metabolite of caffeine in man, produces stronger motor activating effects and a more significant striatal dopamine-releasing effect than caffeine. This unique pharmacological profile of paraxanthine depends on an additional selective mechanism, other than adenosine receptor antagonism: inhibition of cGMP-preferring phosphodiesterases. These results open up the possibility that a part of the reinforcing effects of caffeine might depend on paraxanthine, which can reach significant plasma levels upon chronic caffeine intake.The overwhelming caffeine consumption all over the world basically demonstrates its reinforcing effects. Several epidemiological studies indicate that regular caffeine intake creates dependence, which in part depends on withdrawal symptoms. But should we consider caffeine as a drug with potential abuse liability? Researchers and clinicians have been debating about the addictive potential and clinical importance of caffeine use. In this issue, Budney et al.3 present the results of a survey among addiction professionals (members of six clinical/scientific organizations that focus on addiction) about the clinical importance of caffeine withdrawal and dependence. The survey indicates that most professionals believe that caffeine withdrawal and dependence exist and are clinically relevant. However, there was no consensus about t...