Caffeine, the psychoactive ingredient of coffee and of many soft drinks, is frequently abused by humans especially during stressful live events. The endocannabinoid system is involved in the central effects of many psychoactive compounds and of stress. Whether caffeine alters the cannabinoid system and interferes with stress-induced synaptic alterations is however unknown. We have studied electrophysiologically the sensitivity of cannabinoid receptors modulating synaptic transmission in the striatum of mice exposed to caffeine in their drinking solution. Chronic caffeine assumption sensitized GABAergic synapses to the presynaptic effect of cannabinoid CB1 receptor stimulation by exo- and endocannabinoids. Caffeine was conversely unable to affect the sensitivity of cannabinoid receptors modulating glutamate transmission. The synaptic effects of caffeine were slowly reversible after its removal from the drinking solution. Furthermore, although exposure to caffeine for only 24h did not produce measurable changes of the sensitivity of cannabinoid CB1 receptors, it was able to contrast the down-regulation of CB1 receptor-mediated responses after social defeat stress. Our data suggest that the cannabinoid system is implicated in the psychoactive properties of caffeine and in the ability of caffeine to reduce the pathological consequences of stress.