Cannabis reshapes brain dynamics and may explain tolerance

The impact of acute cannabis exposure on brain function and cognitive performance varies among individuals. Acute effects of cannabis on behavior may be absent or benign in chronic users, while occasional users experience significant impairment in day-to-day operations. It is hypothesized that repeated cannabis use induces neuroadaptations leading to tolerance and desensitization, although the precise mechanisms underlying these adaptations remain unclear. In this study, we investigated acute and persistent effects of vaporized cannabis on brain dynamics in a placebo-controlled neuroimaging trial involving occasional (n = 23) and chronic (n = 20) cannabis users. Functional resting-state data were collected to assess dynamic functional connectivity changes during intoxication and their association with attentional performance and normative cannabinoid CB1 receptor density. Cannabis intoxication induced significant acute alterations in the dynamics of brain network organization, as shown by a reduced occurrence of a hyperconnected brain state in both user groups. Chronic users also displayed decreased segregation of brain networks independent of treatment condition, suggesting persisting neuroadaptations. Dynamic reconfiguration of hyperconnected brain motifs correlated with attentional performance, which was most impaired in occasional users, indicating tolerance in chronic users. Both the acute and persistent effects of cannabis on dynamic brain state organization were significantly associated with spatial CB1 receptor density. Acute cannabis-induced cognitive impairment is influenced by (persistent) network reconfigurations and CB1 receptor density. These findings emphasize the relevance of neural dynamics and individual neuroadaptations to (prolonged) cannabis use when assessing the behavioral effects of cannabis in therapeutic, legal, and societal settings.