INTRODUCTION: The salience network may be linked to addiction. Evidence suggests less salience network resting state functional connectivity (rsFC) from heavy alcohol use, but higher rsFC within and between brain networks from regular cannabis use. Given the rise in alcohol-cannabis co-use, the present study sought to elucidate rsFC between regions within the salience network and regions across the whole brain in individuals who use no drugs regularly, those who use alcohol only heavily, and those who co-use alcohol-cannabis. METHODS: This is a secondary analysis of three clinical laboratory studies. A total of sixty individuals were classified into one of three groups based on their drug use: control (n = 16), heavy alcohol use only (n = 27), and heavy alcohol and regular cannabis co-use (n = 17). All participants completed resting state fMRI scans. Seed regions from the salience network were used to examine group differences in rsFC. RESULTS: Main effects of group on rsFC emerged between the anterior cingulate cortex, left and right anterior insula, and left supramarginal gyrus seeds and regions associated with motor, sensory, visual, and executive control functioning (all ps <
0.05). Post-hoc analyses revealed less rsFC between alcohol-only and co-use groups as compared to controls (all ps <
0.05), but no differences between alcohol-only and co-use groups (all ps >
0.05). CONCLUSIONS: This preliminary study suggests that co-using alcohol-cannabis may not be associated with any additive or contrasting effects on rsFC compared to using alcohol alone. Thus, in individuals who co-use alcohol-cannabis, alcohol may drive neural alterations associated with inhibitory control and substance craving.