This study aimed to investigate the relationship between navigational strategies and the use of abused substances in a sample of healthy young adults. Navigational strategies were assessed with the 4-on-8 virtual maze (4/8VM), a task previously shown to dissociate between hippocampal-dependent spatial navigational strategies and caudate nucleus-dependent stimulus-response navigational strategies. Spatial strategies involve learning the spatial relationships between the landmarks in an environment, while response learning strategies involve learning a rigid set of stimulus-response type associations, e.g., see the tree, turn left. We have shown that spatial learners have increased gray matter and fMRI activity in the hippocampus compared with response learners, while response learners have increased gray matter and fMRI activity in the caudate nucleus. We were interested in the prevalence of use of substances of abuse in spatial and response learners because of the evidence that people who score high on traits such as novelty seeking, sensation seeking, reward seeking, and impulsivity, are more cue-responsive and more likely to use substances of abuse. Since response learners show increased activity and gray matter in the caudate nucleus of the striatum, which is a brain area involved in addiction, we hypothesized that response learners would have a greater use of abused substances than spatial learners. Fifty-five young adults were tested on the 4/8VM and completed a time-line follow-back assessment of drug and alcohol use. We found that response learners had smoked a significantly greater number of cigarettes in their lifetime than spatial learners, were more likely to have used cannabis, and had double the lifetime alcohol consumption. We discuss the possible relationship between substance abuse and response strategies as well as the implications for the hippocampus, risks of neurological and psychiatric disorders, and healthy cognition.