Cue-elicited prefrontal gamma-aminobutyric acid (GABA) dynamics in cannabis use disorder

Chronic cannabis use drives neuroadaptations in reward and stress-related circuits that condition the brain to the drug and its associated cues. These changes underlie craving and heighten its sensitivity to cue- and stress-induced triggers, sustaining drug intake and promoting relapse. Task-based functional magnetic resonance imaging of drug cue reactivity paradigms has shown the dorsolateral prefrontal cortex (dlPFC) as one region commonly activated during cue-elicited craving. However, the state-induced dynamics of critical neurometabolites in cannabis use disorder remain to be investigated. The present study addresses this gap by investigating gamma-aminobutyric acid (GABA) and Glx (glutamate and glutamine) in the dlPFC during cannabis cue reactivity in individuals with cannabis use disorder compared to matched non-cannabis using controls. Magnetic resonance spectroscopy (HERMES) data were acquired from the dlPFC during a cue reactivity paradigm and analyzed using GANNET. We found that, while individuals with cannabis use disorder and controls had similar overall GABA+ levels, they responded differently to cue reactivity, where individuals with cannabis use disorder showed increases in GABA+ during cannabis cue reactivity compared to neutral cue reactivity, irrespective of presentation order. In addition, greater increases in GABA+ during cannabis cue reactivity were positively correlated with subjective craving and cannabis use severity. These findings indicate that cannabis cue reactivity may reveal neurometabolic alterations that are not observable under rest conditions. These findings also establish MRS cue-reactivity paradigms as a valuable tool for probing the neurobiology of cannabis use disorder and identify cue-elicited GABA dynamics as a clinically relevant biomarker amenable to therapeutic intervention.