Effects of Gabapentin on Dorsal Anterior Cingulate Cortex GABA and Glutamate Levels and Their Associations With Abstinence in Alcohol Use Disorder: A Randomized Clinical Trial

Abstract

Objective: Although gabapentin has demonstrated efficacy in mitigating alcohol withdrawal symptoms and preventing relapse drinking in individuals with alcohol use disorder (AUD), the neurobiological mechanisms of action underlying these therapeutic effects remain unknown. The present study evaluated changes in GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) as candidate mechanisms of action.

Methods: In a 16-week randomized clinical trial, 68 adults with AUD, including a history of alcohol withdrawal syndrome, received 1,200 mg/day of gabapentin (N=37) or placebo (N=31) and nine medical management visits after ≥72 hours of abstinence. Proton MR spectroscopy (¹H-MRS) estimates of dACC levels of GABA (N=67) and glutamate (N=64) were acquired before start of treatment and again approximately 14 days after randomization. Percent days abstinent was reported via timeline followback interview.

Results: The effects of gabapentin on GABA and glutamate levels were significantly associated with participants' percent days abstinent during early treatment. Specifically, gabapentin was associated with greater increases in glutamate and greater decreases in GABA levels in participants who remained mostly or entirely abstinent, and yet the opposite in participants who drank on more than half of the days preceding the second scan. Furthermore, gabapentin-treated participants with greater increases in glutamate levels during early treatment had significantly more percent days abstinent across the remainder of the study, relative to placebo-treated participants.

Conclusions: In addition to providing insight into the mechanisms through which gabapentin may promote abstinence in individuals with AUD, this study also provides evidence for a biomarker of efficacious treatment that may be used to evaluate other glutamatergic or GABAergic medications for AUD and related conditions.

Trial registration: ClinicalTrials.gov NCT02349477.

Keywords: Alcohol; Anticonvulsants; Neuroimaging; Substance-Related and Addictive Disorders.

Figure 1.

Consort Diagram.

Figure 2.

a) Representative dorsal anterior cingulate cortex (dACC) voxel placement, b) PRESS spectrum fitted in LCModel, and c) MEGA-PRESS GABA difference spectrum (right), along with reference water and creatine signals (left), fitted in Gannet.

Figure 3.

Change in dorsal anterior cingulate cortex (dACC) glutamate (n=64, left) and GABA (n=67, right) (y-axes) levels, normalized to water and expressed in Institutional Units (I.U.), by percent days abstinent between scans (x-axis) by treatment group (red line = placebo, blue line = gabapentin). Error bands represent 95% confidence intervals. Dark and light dotted lines represent the p < 0.05 and p < 0.10 thresholds, respectively, of Johnson-Neyman significance regions.

Figure 4.

Percent days abstinent following scan 2 (i.e., early treatment; y-axis) by change in dorsal anterior cingulate cortex (dACC) glutamate (n=64, left) and GABA (n=67, right) levels (x-axes), normalized to water and expressed in Institutional Units (I.U.), by treatment group (red line = placebo, blue line = gabapentin). Error bands represent 95% confidence intervals. Dark dotted lines represent the p < 0.05 threshold of Johnson-Neyman significance regions.