Cannabinoid receptors (CBRs) are widely distributed in the brain, including the inferior colliculus (IC). Here, we aim to study whether endocannabinoids influence a specific type of neuronal adaptation, namely, stimulus-specific adaptation (SSA) found in some IC neurons. SSA is important because it has been found as early as the level of the midbrain and therefore it may be a neuronal correlate of early indices of deviance detection. Furthermore, recent studies have demonstrated a direct link between SSA and MMN, that is widely used as an outcome measure in a variety of human neurodegenerative disorders. SSA is considered a form of short-term plasticity, and CBRs have been shown to play a role in short-term neural plasticity. Therefore, it is reasonable to hypothesize that endocannabinoids may play a role in the generation or modulation of SSA. We recorded single units in the IC under an oddball paradigm stimulation. The results demonstrate that cannabinoid agonists lead to a reduction in the neuronal adaptation. This change is due to a differential increase of the neuronal firing rate to the standard tone alone. Furthermore, we show that the effect is mediated by the cannabinoid receptor 1 (CBR1). Thus, cannabinoid agonists down-modulate SSA in IC neurons.