Results from a randomized, double-blind, placebo-controlled, crossover, multimodal-MRI pilot study of gabapentin for co-occurring bipolar and cannabis use disorders.

Disrupted brain gamma-aminobutyric acid (GABA)/glutamate homeostasis is a promising target for pharmacological intervention in co-occurring bipolar disorder (BD) and cannabis use disorder (CUD). Gabapentin is a safe and well-tolerated medication, FDA-approved to treat other neurological diseases, that restores GABA/glutamate homeostasis, with treatment studies supporting efficacy in treating CUD, as well as anxiety and sleep disorders that are common to both BD and CUD. The present manuscript represents the primary report of a randomized, double-blind, placebo-controlled, crossover (1-week/condition), multimodal-MRI (proton-MR spectroscopy, functional MRI) pilot study of gabapentin (1200 mg/day) in BD + CUD (n = 22). Primary analyses revealed that (1) gabapentin was well tolerated and adherence and retention were high, (2) gabapentin increased dorsal anterior cingulate cortex (dACC) and right basal ganglia (rBG) glutamate levels and (3) gabapentin increased activation to visual cannabis cues in the posterior midcingulate cortex (pMCC, a region involved in response inhibition to rewarding stimuli). Exploratory evaluation of clinical outcomes further found that in participants taking gabapentin versus placebo, (1) elevations of dACC GABA levels were associated with lower manic/mixed and depressive symptoms and (2) elevations of rBG glutamate levels and pMCC activation to cannabis cues were associated with lower cannabis use. Though promising, the findings from this study should be interpreted with caution due to observed randomization order effects on dACC glutamate levels and identification of statistical moderators that differed by randomization order (i.e. cigarette-smoking status on rBG glutamate levels and pMCC cue activation). Nonetheless, they provide the necessary foundation for a more robustly designed (urn-randomized, parallel-group) future study of adjuvant gabapentin for BD + CUD.

Blunted reward-related activation to food scenes distinguishes individuals with alcohol use disorder in a pilot case-control fMRI pilot study.

BACKGROUND: Alcohol use disorder (AUD) is thought to bias the neurocircuitry underlying reward processing and motivation to preferentially attend to conditioned alcohol cues over natural rewards. The present case-control pilot study evaluated this hypothesis using novel natural reward paradigms. METHODS: Twenty-eight participants (AUD, n = 14, light drinkers, n = 14) were recruited-AUD participants reported 44.0% heavy drinking days (%HDD) and 4.67 drinks/day over the preceding 90 days. Functional magnetic resonance imaging (fMRI) data were acquired during the administration of three separate picture-viewing paradigms of alcohol cues, food scenes, and social reward, respectively. Independent samples t-tests were performed to compare groups' fMRI data and exploratory correlation analyses were performed to examine associations with clinical characteristics of AUD. RESULTS: Food scenes elicited abnormally low reward-related activation, within the superior frontal gyrus and caudate bilaterally, among AUD participants. Lower activation to food scenes within the superior frontal gyrus was, in turn, associated with higher levels of past-month %HDD among AUD participants, specifically, along with craving and alcohol dependence severity when examined across the full sample. Contrasting reward types (e.g., alcohol cues vs. food scenes) did not reveal "preferential" activation to differentiate groups. CONCLUSIONS: Heavy drinking appears associated with reduced responsivity to natural rewards, specifically food rather than social cues. Neural mechanisms underlying the high prevalence of malnutrition among individuals with AUD may involve some combination of blunted approach-related affect and reduced craving-related motivation to eat when food is present, resulting in limited engagement of cortico-striato-thalamic motor circuitry supporting food acquisition. However, given the preliminary nature of this pilot study, such formulations remain tentative until larger follow-up studies can be conducted. From a potential translational standpoint, the ability of promising therapeutics to demonstrate increased responsivity to natural rewards, specifically nutritive reward may serve as a valuable complementary efficacy indicator for future clinical neuroimaging trials in AUD.