Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users
Natasha L. Mason, Eef L. Theunissen, Nadia R. P. W. Hutten, Desmond H. Y. Tse, Stefan W. Toennes, Jacobus F.A. Jansen, Peter Stiers, Johannes G. Ramaekers
Addiction Biology December 22, 2019 DOI: 10.1111/adb.12870 via OpenAlex
Summary
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.
Study at a glance
| Characteristics | Double-blind, randomized, placebo-controlled, cross-over study Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Occasional and chronic cannabis users |
| Intervention | Placebo |
| Dose | 300 μg/kg delta-9-tetrahydrocannabinol |
| Topics | Cannabis |
| Keywords | Context archaeology Dronabinol Effects of cannabis Psychology Drug tolerance |
| Citations | 58 |
| Key finding | Cannabis altered reward circuitry and behavior in occasional users but not chronic users, suggesting reduced responsiveness to intoxication in chronic users. |
Abstract
Cannabis is the most commonly used illicit drug in the world. However, because of a changing legal landscape and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly cannabis impairment. Importantly, a growing body of evidence suggests that regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo-controlled, cross-over study assessed the acute influence of cannabis on the brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional and 12 chronic cannabis users received acute doses of cannabis (300-μg/kg delta-9-tetrahydrocannabinol) and placebo and underwent ultrahigh field functional magnetic resonance imaging and magnetic resonance spectroscopy. In occasional users, cannabis induced significant neurometabolic alterations in reward circuitry, namely, decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in chronic users. The finding that cannabis altered circuitry and distorted behavior in occasional, but not chronic users, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users. Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment, of which is important to understand in the context of the long-term therapeutic use of cannabis-based medications, as well as in the context of public health and safety of cannabis use when performing day-to-day operations.