Neurometabolite Alterations Associated With Cannabis Use: A Proton Magnetic Resonance Spectroscopy Meta-Analysis

Abstract

Little is known about the neurometabolic effects of cannabis use. Using meta-analytic modeling of proton magnetic resonance spectroscopy (1H-MRS) studies, this study aimed to assess the differences in brain metabolite levels associated with cannabis use (PROSPERO: CRD42020209890) to inform treatment development for cannabis use disorder (CUD). Hedge's g with random-effects modeling was used, and heterogeneity and publication bias indices were assessed. A complete literature search was conducted, and 15 studies met the inclusion criteria (e.g., 1H-MRS, cannabis group compared to a control group, brain region-specific results, necessary data to complete modeling). There were 29 models across gray matter regions in the brain. All models had between 2 and 5 studies (k), indicating that results should be interpreted with caution due to the limited number of available studies. Compared to the control groups, the cannabis-using groups showed lower levels of GABA and N-acetylaspartate in the anterior cingulate cortex (k = 3); lower glutamate in the basal ganglia/striatum (k = 2); and lower glutamine and myo-inositol in the thalamus (k = 2; although the two effect sizes came from the same sample). This is the first meta-analysis to consolidate the extant 1H-MRS studies focused on the neurometabolic effects of cannabis. Despite the few studies available, the evidence suggests cannabis use may impact important neural processes, including glutamatergic and GABAergic functioning (glutamate, glutamine, and GABA), neural health (N-acetylaspartate), and glial functioning (myo-inositol). The findings should be interpreted with caution considering the small sample size; the inability to test the impact of demographic, substance use, and methodological factors; and the heterogeneity of studies. Understanding the neurobiological effects of cannabis may inspire novel pharmacotherapy and/or psychosocial interventions for CUD.

Keywords: cannabis use disorder; meta‐analysis; neurometabolites; proton magnetic resonance spectroscopy; substance use disorders.

FIGURE 1

PRISMA flow‐chart of included studies.

FIGURE 2

Significant neurometabolite differences in the ACC between cannabis‐using groups and control groups. Levels of NAA and GABA within the anterior cingulate cortex (ACC) were noted as being lower in the cannabis‐using groups. The diamond markers indicate overall model effect sizes for each metabolite, while the circles indicate individual study effect sizes. Glutamate (Glu), glutamine (Gln), glutamate + glutamine (Glx), gamma‐aminobutyric acid (GABA), N‐acetylaspartate (NAA), choline‐containing metabolites (Cho), creatine‐containing metabolites (Cr), and myo‐inositol (mI).

FIGURE 3

Significant neurometabolite differences in the basal ganglia/striatum between cannabis‐using groups and control groups. Levels of Glu within the basal ganglia/striatum was noted as being lower in the cannabis‐using groups. The diamond markers indicate overall model effect sizes for each metabolite, while the circles indicate individual study effect sizes. Glutamate (Glu), glutamine (Gln), glutamate + glutamine (Glx), gamma‐aminobutyric acid (GABA), N‐acetylaspartate (NAA), choline‐containing metabolites (Cho), creatine‐containing metabolites (Cr), and myo‐inositol (mI).

FIGURE 4

Significant neurometabolite differences in the thalamus between cannabis‐using groups and control groups. Levels of Gln and mI in the thalamus were noted as being lower in the cannabis‐using groups. The diamond markers indicate overall model effect sizes for each metabolite, while the circles indicate individual study effect sizes. Glutamate (Glu), glutamine (Gln), glutamate + glutamine (Glx), gamma‐aminobutyric acid (GABA), N‐acetylaspartate (NAA), choline‐containing metabolites (Cho), creatine‐containing metabolites (Cr), and myo‐inositol (mI).

FIGURE 5

Overview of neurometabolic alterations associated with alcohol, stimulant, and cannabis use. The cannabis specific findings are from the current work. The alcohol‐specific findings are from Kirkland et al. (2022). The stimulant specific findings are from Smucny and Maddock (2023). Anterior Cingulate Cortex (ACC), glutamate (Glu), glutamine (Gln), gamma‐aminobutyric acid (GABA), N‐acetylaspartate (NAA), choline‐containing metabolites (Cho), creatine‐containing metabolites (Cr), and myo‐inositol (mI).