Cannabinoids affect positive and negative affective experience and emotional perception, possibly by modulating limbic brain reactivity. In this double-blind crossover, placebo-controlled functional magnetic resonance imaging study in humans, an acute oral dose of ∆(9)-tetrahydrocannabinol (THC) attenuated subgenual anterior cingulate cortex (sgACC) reactivity during the induction of negative affect. This observation extends prior findings implicating a cortico-limbic, emotion-related central mechanism underlying cannabinoid function.