Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users

Mason, Natasha L.; Theunissen, Eef L.; Hutten, Nadia R. P. W.; Tse, Desmond H. Y.; Toennes, Stefan W.; Jansen, Jacobus F.A.; Stiers, Peter; Ramaekers, Johannes G. · 2019 · OpenAlex-citations

DOI: 10.1111/adb.12870

archive: archived pipeline: cataloged verified

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Summary

This study investigates the neurobiological mechanisms underlying tolerance to cannabis impairment in chronic users. While it is established that regular cannabis users develop tolerance to both the rewarding and impairing effects of the drug, the specific neuroadaptations responsible for this phenomenon remain unclear. The research aimed to determine if reduced responsiveness of the brain’s reward system explains this tolerance by comparing acute cannabis effects in occasional versus chronic users. The researchers conducted a double-blind, randomized, placebo-controlled, cross-over study involving 24 male participants: 12 occasional cannabis users and 12 chronic users. Each participant received either a placebo or an acute dose of cannabis containing 300 μg/kg of delta-9-tetrahydrocannabinol (THC) on separate days. The study utilized ultrahigh-field (7T) multimodal brain imaging, including functional magnetic resonance imaging (fMRI) to assess functional connectivity (FC) within the reward circuitry and magnetic resonance spectroscopy (MRS) to measure neurometabolite concentrations (glutamate, GABA, NAA, myo-inositol, and choline) in the striatum and anterior cingulate cortex (ACC). Behavioral outcomes were assessed using a psychomotor vigilance task to measure sustained attention and visual analog scales to rate subjective feelings of intoxication. The results demonstrated distinct differences between the two groups. In occasional users, acute cannabis exposure induced significant neurometabolic alterations in the reward circuitry, specifically increased striatal glutamate concentrations and decreased functional connectivity between the nucleus accumbens and cortical areas. These neural changes correlated with increased subjective high and decreased performance on the sustained attention task. In contrast, chronic users exhibited no such changes in functional connectivity or striatal glutamate levels following cannabis administration. Furthermore, chronic users did not show significant impairments in sustained attention performance compared to placebo, although they still reported a subjective high, albeit to a lesser degree than occasional users. Exploratory analyses controlling for baseline serum cannabinoid levels found no significant long-term differences between groups in placebo conditions, suggesting that the observed tolerance is pharmacodynamic rather than due to persistent baseline neurochemical deficits. The findings suggest that chronic cannabis use leads to neuroadaptations in the reward circuitry, likely involving the downregulation or desensitization of CB1 receptors, which reduces the system's responsiveness to acute THC intoxication. This reduced neural responsiveness underlies the behavioral tolerance to cannabis-induced impairment. The study provides evidence for a pharmacodynamic mechanism of tolerance, which has important implications for understanding the safety of cannabis use in daily operations and for the therapeutic dosing of cannabis-based medications.

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• cannabis