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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind, randomized, placebo-controlled, cross-over study Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Occasional and chronic cannabis users |
| Dose | 300-μg/kg delta-9-tetrahydrocannabinol |
| Measures | functional magnetic resonance imaging, magnetic resonance spectroscopy, sustained attention task |
| Topics | Cannabis CBD |
| Keywords | Context archaeology Dronabinol Effects of cannabis Drug tolerance Delta-9-tetrahydrocannabinol Placebo Cannabinoid |
| Citations | 58 |
| Key points | 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.
Comparable studies
Other randomized controlled trials on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Healthy participants | 2012 | Randomized controlled trial | n = 48 |
| Distinct Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing Healthy, English-native, right-handed men who had used cannabis 15 times or less in... | 2009 | Double-blind, randomized, placebo-controlled crossover trial | n = 15 |
| Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers Healthy male subjects | 2012 | Randomized controlled trial | n = 16 |
| Modulation of Mediotemporal and Ventrostriatal Function in Humans by Δ9-Tetrahydrocannabinol Healthy, native English-speaking, right-handed men of white race/ethnicity who had used... | 2009 | Randomized controlled trial | n = 15 |
| Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition Healthy volunteers with a history of light cannabis use | 2019 | Randomized, double-blind, within-subjects crossover | n = 14 |
Citations in the library
Cited by 18
- Spontaneous and deliberate creative cognition during and after psilocybin exposure Translational Psychiatry April 8, 2021
- Functional brain connectomes reflect acute and chronic cannabis use Scientific Reports February 14, 2022
- Cannabis Use and Neuroadaptation: A Call for Δ9-Tetrahydrocannabinol Challenge Studies Frontiers in Psychiatry April 14, 2022
- Metabolomic profiling of cannabis use and cannabis intoxication in humans. Neuropsychopharmacology May 1, 2025
- Cannabis Perturbs Dynamic Brain States Biological Psychiatry October 21, 2025
and 13 more in the library
Cites 13
- Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes Brain Imaging and Behavior December 14, 2015
- Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity. European Neuropsychopharmacology December 1, 2019
- Cannabis use and the development of tolerance: a systematic review of human evidence. Neuroscience & Biobehavioral Reviews October 2018
- Long-term effects of marijuana use on the brain. Proceedings of the National Academy of Sciences November 25, 2014
- A Review of Magnetic Resonance Spectroscopy Studies in Marijuana using Adolescents and Adults. Journal of Addiction Research & Therapy April 24, 2013
and 8 more in the library