Gabapentin for Restoring GABA/glutamate Homeostasis in Co-occurring Bipolar and Cannabis Use Disorders: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Clinical MRI Study

Project Summary / Abstract There is an 8-fold increase in the prevalence of cannabis use disorder (CUD) in individuals with bipolar disorder (BD) relative to the general population, and individuals with co-occurring BD and CUD (BD+CUD) have substantially worse clinical outcomes (e.g., elevated rates of suicide) than those with either BD or CUD alone. Response to traditional mood-stabilizing medications is poor, yet little is known about optimal treatment as there have been no randomized medication trials for BD+CUD to date. Convergent evidence supports disrupted brain gamma-Aminobutyric acid (GABA)/glutamate homeostasis as a promising target for pharmacological intervention, and gabapentin as a candidate adjuvant medication to normalize frontal and striatal brain GABA and glutamate levels, in BD+CUD. Against this background, we recently completed an NIH/NIDA-funded (R21DA043917), double-blind, randomized, crossover, MRI (i.e., proton magnetic resonance spectroscopy [1H- MRS], functional MRI [fMRI]) study of gabapentin (1200mg/day) vs. placebo in BD+CUD (n=22) which found that, a) gabapentin increased dorsal anterior cingulate cortex (dACC) and right basal ganglia (rBG) glutamate levels, the latter only in cigarette-smokers, b) relative elevations of rBG glutamate and dACC GABA levels in gabapentin-treated participants were associated with lower cannabis use and mood symptoms, respectively, and c) gabapentin increased activation to visual cannabis cues in the posterior midcingulate (pMCC) gyrus, which was associated with increased rBG glutamate and GABA levels, as well as reduced cannabis use, however only in smokers. Though promising, these findings must be interpreted with caution due to the study's small sample size, observed randomization order effects, and post-hoc identification of statistical moderators, in part guided by a failure of simple randomization to balance condition orders on participant characteristics; effects of gabapentin on brain GABA, as opposed to glutamate, levels were additionally not as robust as anticipated. The proposed randomized, placebo-controlled, double-blind, parallel-group, MRI study aims to evaluate whether gabapentin increases dACC and rBG GABA and glutamate levels in BD+CUD, and whether normalization of these levels will be associated with changes in brain cannabis-cue activation, cannabis use and craving, and mood symptoms. This study will overcome the limitations of our preliminary study via, a) parallel-group study design, b) a larger sample of enrolled BD+CUD individuals (n=68 vs. 22), c) urn-randomization to treatment group, and d) a higher dose of gabapentin (1800mg/day) delivered over a longer period (17 days vs. 5 days/condition) to increase our likelihood of observing gabapentin effects on brain GABA levels. Positive results may support investigation of gabapentin for the adjuvant treatment of BD+CUD in more clinically-focused RCTs. The proposed study will also add to the literature on associations of regional brain GABA/glutamate levels with constructs related to BD+CUD, including cue reactivity, cannabis use/craving, and mood and anxiety symptoms.