Several laboratories have reported that chronic exposure to delta-9-tetrahydrocannabinol (THC) or marijuana extracts persistently altered the structure and function of the rat hippocampus, a paleocortical brain region involved with learning and memory processes in both rats and humans. Certain choices must be made in designing experiments to evaluate cannabis neurotoxicity, such as dose, route of administration, duration of exposure, age at onset of exposure, species of subjects, whether or how long to allow withdrawal, and which endpoints or biomarkers of neurotoxicity to measure. A review of the literature suggests that both age during exposure and duration of exposure may be critical determinants of neurotoxicity. Cannabinoid administration for at least three months (8-10% of a rat's lifespan) was required to produce neurotoxic effects in peripubertal rodents, which would be comparable to about three years exposure in rhesus monkeys and seven to ten years in humans. Studies of monkeys after up to 12 months of daily exposure have not consistently reported neurotoxicity, and the results of longer exposures have not yet been studied.