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 (n = 22; 11 females) compared to matched non-cannabis using controls (n = 19; 9 females). 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 (F_1,16 = 7.31, p = 0.016, n²_p = .31). 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.