Reduced responsiveness of the reward system underlies tolerance to cannabis impairment in chronic users

Abstract

words)Cannabis is the most commonly used illicit drug in the world. However due to 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 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 brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional (OUs) and 12 chronic (CUs) cannabis users received acute doses of cannabis (300 μg/kg THC) and placebo, and underwent ultra-high field functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS). In OUs, 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 CUs. The finding that cannabis altered circuitry and distorted behavior in OUs, but not CUs, 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. regions of interest (ROI) in the NAc and remote cortical areas, as an indirect measure of dopaminergic stimulation (10, 29, 30). Furthermore a priori ROI-to-ROI analysis assessed differences in connectivity strength between areas of the reward circuit. Finally, subjective high and sustained attention, two outcome variables shown to be modulated by (acute) cannabis exposure (10, 31, 32), were assessed.The second goal was exploratory in nature, to evaluate long-term effects of repeated cannabis exposure, by comparing the placebo condition of each group. Overall, we hypothesized that THC would induce behavioral, functional, and metabolic changes in the OUs, but not the CUs, indicative of (neuroadaptive) tolerance. Furthermore, based on previous studies with chronic cannabis users, we hypothesized that during placebo, CUs would show decreased concentrations of metabolites compared to OUs. MethodsParticipants. In total, 27 healthy cannabis users entered the study. Three participants were excluded due to poor fMRI data, resulting in a total of 12 occasional and 12 chronic users (male N= 14, female N= 10). For further details see SI Methods.This study was conducted according to the code of ethics on human experimentation established by the declaration of Helsinki (1964) and amended in Fortaleza (Brazil, October 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and was approved by the Academic Hospital and University's Medical Ethics committee. All participants were full...

Digital Medical Cannabis as Market Differentiator: Second-Generation Artificial Intelligence Systems to Improve Response

“…In occasional users, cannabis induced significant neurometabolic alterations in reward circuitry, decreased functional connectivity, and increased striatal glutamate concentrations, along with increases in subjective high and decreases in sustained attention. Similar changes were not observed in chronic users, suggesting reduced reward circuitry responsiveness to cannabis intoxication in chronic users ( 2 , 3 ).…”

“…Partial and complete loss of response to chronic medication is a common problem with multiple drugs ( 24 ) when regular cannabis users develop tolerance to its effect ( 2 ). Cannabis tolerance models imply neurobiological or behavioral adaptation following repeated cannabis exposure ( 25 ).…”

“…The active constituents of the product were described several decades ago ( 1 ). The changing legal landscape and rising interest in its potential therapeutic utilities have opened new opportunities for therapy ( 2 ). Multiple cannabis products are increasingly used in countries that have legalized their use.…”