Abstract
Background and Aims: Baclofen, a GABAB agonist, is used as a treatment for alcohol dependence. We aimed to examine brain metabolites following administration of baclofen or placebo in alcohol dependent individuals enrolled in a randomized placebo-controlled trial.Methods: Participants included 31 alcohol dependent individuals (recent drinking: N = 16; and abstinent: N = 15) who had received daily baclofen (BAC 30–75 mg = 20) or placebo (PL = 11) for at least 2 weeks (average 17 days). Using in vivo proton magnetic resonance spectroscopy (1H-MRS), spectra from the right parietal lobe were analyzed to obtain measures of GABA, Glutamate (Glu), Glutathione (GSH) and N-Acetyl Apartate (NAA) 120 min following administration of PL or BAC.Results: When weighting alcohol dependent participants according to recent alcohol consumption (within 24 h), there were significant differences between BAC and PL on parietal concentrations of GSH (p < 0.01) and NAA (p < 0.05). Multiple linear regression revealed a significant predictive effect of GSH on heavy drinking days at 12 weeks follow-up (Model: F = 14.28, R2 = 0.85; GSH: B = −1.22, p = 0.01) and also percentage days abstinent at 12 weeks follow-up (Model: F = 6.50, R2 = 0.72; GSH: B = 0.99, p = 0.06).Conclusion: Our data provide preliminary evidence that the effect of baclofen may be mediated by increased parietal concentrations of the antioxidant GSH and NAA in recently drinking alcohol dependent patients. GSH/Cr levels were also predictive of improved drinking outcomes in the trial and suggests a role for neural oxidative stress in alcohol use disorder.
Highlights
Alcohol dependence is a common disorder characterized most often by chronic relapses to heavy alcohol consumption [1]
We have recently demonstrated that baclofen is effective in increasing abstinence in patients with and without alcoholic liver disease [12]
The study involved off-label use of a registered medication in Australia and approval was given under the Clinical Trial Notification (CTN) scheme of the Therapeutics Goods Administration (TGA) (2013/0060) as part of a clinical trial (ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ ct2/show/NCT01711125)
Summary
Alcohol dependence is a common disorder characterized most often by chronic relapses to heavy alcohol consumption [1]. A selective GABAB receptor agonist, has emerged as a potential treatment for alcohol dependence and is thought to counterbalance these processes given that presynaptic GABAB receptors regulate neuronal excitability and neurotransmitter release in many different neuronal pathways including the mesolimbic system [2, 3]. While there has been expanded utilization of baclofen in the treatment of alcohol dependence [4], there remains controversy in the field with mixed results from clinical trials [for example see [5,6,7,8,9,10,11]]. There is significant variation in treatment response and not all individuals with alcohol dependence respond favorably to baclofen. Alcohol dependence is a complex and heterogeneous disorder involving disruption of multiple neurobiological mechanisms whereby advances in the understanding of this heterogeneity and associated variations in response to pharmacotherapies will have clinical appeal for treatment. We aimed to examine brain metabolites following administration of baclofen or placebo in alcohol dependent individuals enrolled in a randomized placebo-controlled trial
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