Gamma-hydroxybutyric acid (GHB) is a recreational drug, as well as a treatment for narcolepsy and against substance dependence. Recent animal research suggests that at recreational doses GHB may increase mesocorticolimbic dopamine (DA) signaling by reducing inhibitory influence from GABAergic interneurons on DA neurons in the substantia nigra/ ventral tegmental area (SN/VTA). Here, we used functional MRI to test how enhanced SN/ VTA DA transmission after GHB administration affects the neural processing of rewards in healthy humans while they played a gambling-like task. In trials associated with rewards, GHB increased ventral striatum activity with parallel increases in behavioral impulsivity. Moreover, fMRI signal in the SN/VTA positively correlated with individual doses of GHB. By contrast, during feedback processing, GHB mostly reduced response in the orbitofrontal cortex and across a salience network which is involved in identifying relevant internal and extrapersonal stimuli in order to guide behavior (including the amygdala, anterior cingulate cortex, insula, habenula), and with distinct effects for actual gains and losses. These data are consistent with increased phasic response of DA neurons in the SN/VTA, affecting reward processing at remote target regions of the mesocorticolimbic DA circuit. Moreover, reduced reactivity to feedbacks (rewards and losses) across a salience network might also explain why GHB has only a weak reinforcing capacity. These findings do not only provide unprecedented insights into the mechanisms of action of GHB in humans at the macroscopic systems level, but may also have important implications for understanding the multifaceted actions of GHB as both a recreational and therapeutic drug.