Regular cannabis users develop tolerance to the drug's impairing and rewarding effects, but the underlying brain changes are unclear. In a double-blind, placebo-controlled study, 12 occasional and 12 chronic cannabis users received acute doses of cannabis (300 μg/kg delta-9-tetrahydrocannabinol) or placebo. In occasional users, cannabis decreased functional connectivity and increased striatal glutamate levels in reward circuitry, linked to greater subjective high and worse attention performance. Chronic users showed none of these changes, indicating reduced responsiveness of reward circuitry to cannabis intoxication, suggesting a pharmacodynamic mechanism for tolerance development.
Regular cannabis users develop tolerance to the drug's impairing and rewarding effects, but the underlying brain changes are unclear. In a double-blind, randomized, placebo-controlled crossover study, 12 occasional and 12 chronic cannabis users received acute doses of cannabis (300 μg/kg THC) and placebo, then underwent ultra-high field fMRI and magnetic resonance spectroscopy. In occasional users, cannabis caused decreased functional connectivity and increased striatal glutamate concentrations in reward circuitry, linked to greater subjective high and worse sustained attention. These changes were absent in chronic users, suggesting reduced responsiveness of reward circuitry to cannabis intoxication and a pharmacodynamic mechanism for tolerance development.