Unraveling the role of cigarette use in neural cannabis cue reactivity in heavy cannabis users

Cue reactivity is an important biomarker of cannabis use disorder (CUD). Despite high rates of cigarette and cannabis co-use, its role in cannabis cue reactivity remains unclear. Using a visual functional magnetic resonance imaging cue reactivity paradigm, we investigated interactive effects of cannabis and cigarette use on cannabis cue relative to cigarette and neutral cue reactivity in a priori regions of interest-the amygdala, striatum, anterior cingulate cortex (ACC), ventral tegmental area (VTA), and orbitofrontal cortex-and a whole-brain analysis. In our sample of cannabis users and controls closely matched on cigarette use, significant interactions between cannabis and cigarette use status emerged in the amygdala, striatum, ACC, frontal pole, and inferior frontal gyrus. Cannabis-only users showed heightened cue reactivity in the amygdala compared with nonusing controls. Co-users did not show heightened cue reactivity compared with cigarette smoking controls, although cue-induced VTA activity was positively correlated with grams per week of cannabis. Cigarette smoking controls showed unexpectedly heightened cue reactivity compared to co-users and nonsmoking controls. These findings and the high prevalence of cannabis and cigarette co-use underscore the importance of considering cigarette smoking status when investigating the role of cue reactivity in heavy cannabis use.