© 2017 Elsevier Inc. All rights reserved.Evidence that long-term cannabis use may be hazardous to white matter in the developing brain has been accumulating, with early onset use in particular thought to impair structural morphology and integrity, during the critical neurodevelopment occurring in adolescence. We found specific localized axonal connectivity disturbances in adult long-term heavy cannabis users, with 84-88% reductions in streamlines in the fimbria of the hippocampus, and commissural fibers extending to the precuneus. White matter integrity within these fiber bundles was associated with the age of onset of cannabis use. The endocannabinoid system is critically involved in axonal growth in the developing brain; mechanisms underlying axonal morphological alterations following exposure to cannabis in utero have been identified. Mechanisms that may be specifically perturbed by cannabis use impacting the neurodevelopment and brain maturational processes that occur during adolescence require further research. Dysfunctional connectivity may underlie a wide range of cognitive disturbances and psychological symptoms, including vulnerability to psychosis, depression, and anxiety disorders, all of which are significant public health concerns.