Evidence That Cannabis Exposure, Abuse, and Dependence Are Related to Glutamate Metabolism and Glial Function in the Anterior Cingulate Cortex: A ¹ H-Magnetic Resonance Spectroscopy Study

There is evidence that long-term cannabis use is associated with alterations to glutamate neurotransmission and glial function. In this study, 26 long-term cannabis users (males=65.4%) and 47 non-cannabis using healthy controls (males=44.6%) underwent proton magnetic resonance spectroscopy (¹H-MRS) of the anterior cingulate cortex (ACC) in order to characterize neurometabolite alterations in cannabis users and to examine associations between neurometabolites, cannabis exposure, and cannabis use behaviors. Myo-inositol, a marker of glial function, and glutamate metabolites did not differ between healthy controls and cannabis users or cannabis users who met criteria for DSM5 cannabis use disorder (n=17). Lower myo-inositol, a putative marker of glial function, was related to greater problematic drug use (F_1,22 = 11.95, p=.002; Cohen's f=0.59, large effect; Drug Abuse Screening Test) and severity of cannabis dependence (F_1,22 = 6.61, p=.17; Cohen's f=0.44, large effect). Further, past-year cannabis exposure exerted different effects on glutamate and glutamate+glutamine in males and females (glutamate: F_1,21 = 6.31, p=.02; glutamate+glutamine: F_1,21 = 7.20, p=.014), such that greater past-year cannabis exposure was related to higher concentrations of glutamate metabolites in male cannabis users (glutamate: F_1,14 = 25.94, p=.00016; Cohen's f=1.32, large effect; glutamate+glutamine: F_1,14 = 23.24, p=.00027, Cohen's f=1.24, large effect) but not in female cannabis users (glutamate: F_1,6 = 1.37, p=0.78; glutamate+glutamine: F_1,6 = 0.001, p=.97). The present results extend existing evidence of altered glial function and glutamate metabolism with cannabis use by providing evidence linking problematic drug use behaviors with glial function as measured with myo-inositol and recent chronic cannabis exposure to alterations in glutamate metabolism. This provides novel directions for the interrogation of the impact of cannabis use on brain neurochemistry.

Keywords: anterior cingulate cortex; cannabis; glial; glutamate; imaging; magnetic resonance spectroscopy; myo-inositol; substance use disorder.