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The individual risk of developing drug addiction is highly determined by the epigenetic landscape1,2. Chromatin remodeling regulates drug-induced transcriptional and behavioral effects and the consequent development of addictive behaviors2,3. Several chromatin modifications in the ventral tegmental area and nucleus accumbens, including histone H3 methylation, H3 and H4 acetylation, have been implicated in drug addiction. Still, the contribution of other histones and their post-translational modifications (PTMs), such as monoubiquitination is unknown4–8. Here we found that H2A monoubiquitination in the paraventricular thalamus (PVT) plays a major role in cocaine-adaptive behaviors and local cocaine-evoked transcriptional repression. Mice undergoing chronic cocaine administration showed a specific increased monoubiquitination of H2A. Furthermore, we showed that this histone PTM is controlled, in the PVT, by an interaction between melanoma-associated antigen D1 (Maged1), a scaffold protein involved in drug addiction9, and USP7, a deubiquitinase10. Accordingly, Maged1 specific inactivation in thalamic vGluT2 neurons, or USP7 inhibition, blocked cocaine-evoked H2A monoubiquitination and abolished cocaine locomotor sensitization. Finally, we identified genetic variations ofMAGED1andUSP7associated with modified transition to cocaine addiction and cocaine-induced aggressive behavior in human subjects. These findings identified a new epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factor for drug addiction in human.