The objective of this study was to evaluate the effect of the acute administration of marijuana (MJ) on cardiovascular (CV) function and CNS pharmacokinetics (PK) of[15O]water in occasional (O) versus chronic (C) MJ users. Each subject received four injections of [15O]water (one prior and three postsmoking) on two occasions in which they received active or placebo MJ. For each injection, measures of CV function and CNS PK [15O]water were made. Postsmoking, MJ influenced all measured CV and [15 O]water PK parameters. C users reported significantly lower “highness” and smaller heart rate (HR) changes, which resulted in reduced rate pressure product (RPP) changes compared to O users, even though Δ9-tetrahydrocannabinol levels were higher, whereas changes in blood pressure (BP), arrival time, and [15O]water concentration were not significantly different between the groups. Significant CV changes resulted in changes in the whole-body distribution of cardiac output rather than changes in cerebral blood flow. Chronic MJ use produces tolerance to the HR increases induced by acute MJ smoking compared to changes observed in occasional users, without changing the effects on BP and [15O]water PK.