Raymond F. Anton

With growing knowledge of the neural circuitry involved in alcohol use disorder (AUD), interest in developing neural-circuit-based therapeutic tools, including transcranial magnetic stimulation (TMS), for people with AUD has increased. While mounting evidence supports the efficacy of TMS for AUD, multiple dosing protocols are currently under consideration, and little is known about the neurobiological mechanisms through which TMS leads to clinical improvement. This randomized, sham-controlled, double-blind, crossover study was designed to address this gap by evaluating the impact of a single session of two prominent TMS protocols (each relative to sham), 10 Hz TMS to dorsolateral prefrontal cortex (dlPFC) and continuous theta burst stimulation (cTBS) to medial PFC (mPFC), on levels of excitatory (glutamate, glutamine, glycine) and inhibitory (GABA) neurometabolites, using proton MR spectroscopy (MRS), in the tissue beneath the TMS coil in treatment-naïve individuals with AUD. Seventy men and women, aged 21-40 years, with moderate-severe AUD were enrolled into the study and randomly assigned to complete one of six experimental condition orders, each consisting of three TMS sessions (cTBS, 10 Hz TMS, sham) conducted on three separate days, each immediately followed by MRI/MRS. Whereas cTBS to mPFC was associated with relatively lower levels of excitatory neurometabolites (glutamine and glycine, with additional mixed support for glutamate), 10 Hz TMS to dlPFC was not, and neither protocol was associated with GABA levels. Together, these findings demonstrate acute neurochemical target engagement under the coil with a single session of cTBS to mPFC, pointing to the utility of assaying neurometabolites in further optimizing this and other candidate targets for AUD.

Background: The U.S. Food and Drug Administration (FDA) recommends a minimum duration of 6 months for randomized controlled trials (RCTs) evaluating pharmacotherapies for alcohol use disorder (AUD). The relationship between trial length and treatment effects is not well understood. The current study conducted meta‐regression analyses of RCTs for AUD to examine the association between trial length and observed medication effect sizes in clinical trials. Methods: This secondary data analysis utilized data from a systematic literature review that identified 139 pharmacotherapy RCTs for AUD conducted between 1985 and 2023. Meta‐regressions were conducted using the metafor package in R to examine whether shorter (< 12 weeks) or longer (> 12 weeks) trials differed in observed medication effect sizes for abstinence‐ and drinking‐based endpoints, relative to 12‐week trials, which represented the median trial duration. Publication bias was addressed using a weight‐function model. Results: For abstinence‐based endpoints, neither shorter (< 12 weeks; β = 0.13, SE = 0.21, p = 0.54) nor longer (> 12 weeks; β = 0.11, SE = 0.11, p = 0.30) trials differed significantly from the 12‐week reference group in observed medication effect sizes. Similarly, for drinking‐based endpoints, neither shorter (< 12 weeks; β = −0.07, SE = 0.09, p = 0.39) nor longer (> 12 weeks; β = 0.06, SE = 0.05, p = 0.26) trials differed significantly from 12‐week trials in observed medication effect sizes. All results remained nonsignificant after adjusting for publication bias. In sensitivity analyses restricted to trials with statistically significant effect sizes, trials > 12 weeks showed smaller estimated treatment effects compared to trials ≤ 12 weeks. Conclusions: Observed medication effect sizes did not differ significantly across trial lengths for abstinence and drinking‐based endpoints, except for analyses restricted to trials with significant effect sizes, where there was an advantage for trials that were 12 weeks or shorter. These findings inform efforts to optimize AUD RCT design.

Forty percent of people with bipolar disorder (BD) develop alcohol use disorder (AUD), with co-occurring AUD substantially worsening the course of BD. Though efficacious treatments remain elusive, frontal glutamate and GABA dysregulation represent promising targets for intervention. This study evaluated the ability of two adjunctive medications, N-acetylcysteine (NAC) and gabapentin, to modulate glutamate and GABA (primary) and to reduce heavy drinking and depressive symptoms (exploratory) in people with BD + AUD. Fifty-four individuals meeting DSM-5 criteria for BD + AUD were enrolled in a randomized, double-blind, placebo-controlled, crossover study, with 3, 1-week conditions (NAC, gabapentin, placebo). Medication effects on dorsal anterior cingulate cortex (dACC) glutamate+glutamine (Glx) and GABA levels, via proton MR spectroscopy, and percent heavy drinking days (%HDD) and depressive symptoms were evaluated with linear mixed models. Forty-nine participants (M[SD] age=41.0[12.2], 51% female, 74% white) provided 121-131 posttreatment-MRI scans, depending on analysis. Medications were well-tolerated, and adherence was excellent. DACC Glx (F = 4.76, p = 0.012) but not GABA (F = 0.96, p = 0.388) levels significantly differed across conditions, with only NAC (M[SD] = 21.50[2.55]) demonstrating significantly different(lower) glutamate levels relative to placebo (M[SD] = 22.59[2.56]; p = 0.003; SMD = 0.43). %HDD (F = 3.90, p = 0.025) also significantly differed across conditions, again with only NAC (M[SD] = 31.86[4.60]) demonstrating significantly different(lower) %HDD relative to placebo (M[SD] = 40.94[4.55]; p = 0.015; SMD = 0.33), though neither NAC (p = 0.128) nor gabapentin (p = 0.228) differed from placebo on depressive symptoms. These results support the development of mechanistic clinical trials targeting glutamatergic dysfunction in people with BD + AUD. Trial Registration: https://clinicaltrials.gov/study/NCT03220776.

Reward brain circuitry dysfunction is a hypothesized mechanism of bipolar disorder and alcohol use disorder co-occurrence (BD + AUD) that remains largely untested. This neuroimaging study represents the first investigation of functional connectivity in BD + AUD. Following a two-by-two factorial design ( N = 90), individuals with BD + AUD ( n = 22), AUD alone ( n = 20), BD alone ( n = 23), and healthy control participants ( n = 25) were administered a fMRI alcohol-cue reactivity paradigm. Generalized psychophysiological interaction (PPI) modeling ( p < 0.001; p -FDR < 0.05) was performed for regions of interest, including the right dorsal anterior insula, inferior frontal gyrus, and bilateral amygdala and dorsal striatum (i.e., caudate body). Extracted beta weights were explored for bivariate associations with key behavioral correlates (AUD age of onset, alcohol craving and dependence severity, abstinence duration, and impulsivity) ( p < 0.05). BD + AUD individuals exhibited cue-modulated hyperconnectivity between the left dorsal striatum and right posterior cingulate cortex ( p -FDR = 0.045) versus the AUD and BD groups, who both exhibited hypoconnectivity between these regions versus healthy participants. Additionally, there were main effects of AUD and BD ( p -FDR ≤ 0.040) on cue-modulated functional connectivity of the right dAI (↓ middle frontal gyrus [MFG]) and left amygdala (↑ right superior temporal gyrus, anterior cingulate cortex, and MFG), respectively. Select functional connectivity data were associated with trait characteristics of AUD in BD + AUD ( r ≥±0.50, p ≤ 0.026) but not AUD. A distinct pattern of cortico-striato-limbic functional connectivity and brain-behavior relationships was found to characterize BD + AUD with implications for treatment development. Namely, leveraging neuromodulation techniques that can effectively normalize the identified circuitry disruptions could represent a novel path for treatment advances in BD + AUD.

Background: Partially due to the complexity associated with conducting trials, there have been relatively few regulatory agency‐approved medications for the treatment of alcohol use disorder (AUD). Heterogeneity of study samples, such as participant characteristics (including variation in alcohol consumption) as well as drinking efficacy endpoints, may lead to inconsistency in results and a potential increase in Type II errors. The aim of this study is to begin to fill in the knowledge gap of optimal clinical trial design by analyzing potential predictors of outcomes. Methods: Five federally funded and publicly available multisite randomized pharmacotherapy clinical trials for the treatment of AUD using similar methodologies to assess drinking outcomes were included. Three FDA‐guided drinking efficacy outcomes were calculated for each study independently and combined: abstinence (no drinking days), no heavy drinking days, WHO 2+ risk drinking level (RDL) reduction as well as a measure of study participant completion. These outcomes were analyzed by logistic regression models including a variety of predictors within the full‐study sample as well as among only participants treated with placebo. Results: The number of days abstinent prior to randomization was a strong positive predictor of all three predefined drinking outcomes. Further analysis indicated a cutoff of less than three to five abstinent days before randomization might be optimal. For the WHO 2+ RDL endpoint, those within the “high” or “very‐high” risk categories were more likely to meet criteria for successful two or more risk level reductions than “medium” risk. Across various demographic variables, only age (older participants) was associated with better outcomes. Conclusions: These findings suggest that some important prestudy drinking characteristics (e.g., less abstinence and older age) as well as being in a higher risk drinking category should be considered for inclusion in future alcohol pharmacotherapy trials.

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.

Background Abstinence has historically been considered the preferred goal of alcohol use disorder (AUD) treatment. However, most individuals with AUD do not want to abstain and many are able to reduce their drinking successfully. Craving is often a target of pharmacological and behavioral interventions for AUD, and reductions in craving may signal recovery. Whether reductions in drinking during AUD treatment are associated with reductions in craving has not been well examined.Methods We conducted secondary analyses of data from three AUD clinical trials (N's= 1327, 346, and 200). Drinking reductions from baseline to the end of treatment were measured as changes in World Health Organization (WHO) risk drinking levels; alcohol craving was measured using validated self-report measures. Regression analyses tested whether drinking reductions were associated with end-of-treatment craving reductions; moderation analyses tested whether associations between drinking reduction and end-of-treatment craving differed across AUD severity.Results Reductions of at least 1 or at least 2 WHO risk drinking levels were associated with lower craving (all p's < 0.05). Results were substantively similar after removing abstainers at the end-of-treatment. Associations between drinking reductions and craving were generally not moderated by AUD severity.Conclusions Individuals with WHO risk drinking level reductions reported significantly lower craving, as compared to those who did not achieve meaningful reductions in drinking. The results demonstrate the utility of WHO risk drinking levels as AUD clinical trial endpoints and provide evidence that drinking reductions mitigate craving.

Background: Poor inhibitory control and enhanced subjective response to alcohol are interrelated risk factors for alcohol use disorder (AUD) that share underlying neural substrates, including dopamine signaling in the right prefrontal cortex, a potential target for pharmacological intervention. Cortical dopamine inactivation is primarily regulated by catechol-O-methyltransferase (COMT), an enzyme with large variation in activity as a function of the COMT rs4680 (val158met) single nucleotide polymorphism. In a previous randomized, placebo-controlled trial of the COMT inhibitor tolcapone (200 mg TID) in non-treatment-seeking participants with AUD, we found that tolcapone, relative to placebo, reduced alcohol self-administration only among rs4680 val-allele homozygotes, whose COMT activity is higher than in met-allele carriers.Methods: We conducted secondary analyses of the effects of tolcapone and baseline COMT activity, as indexed by both rs4680 genotype and an enzymatic activity assay, on the subjective response to alcohol in a bar-laboratory paradigm among 60 participants in the previous trial.Results: Tolcapone did not affect alcohol-induced stimulation or sedation more than placebo. However, baseline COMT activity moderated the effects of the drug on both outcomes, such that tolcapone-treated participants with higher baseline COMT activity had less stimulation (p = 0.008) and sedation (p = 0.053) than participants with lower baseline COMT activity and those treated with placebo. Additionally, alcohol-induced stimulation significantly mediated the interacting effects of baseline COMT activity and tolcapone on bar-laboratory self-administration.Conclusions: Tolcapone may reduce subjective response to alcohol more effectively among individuals with preexisting high COMT activity an effect that could account for the drug's reduction of alcohol consumption among these individuals.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone’s effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone. ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934

Polymorphisms in genes associated with opioid signaling and dopamine reuptake and inactivation may moderate naltrexone efficacy in Alcohol Use Disorder (AUD), but the effects of epigenetic modification of these genes on naltrexone response are largely unexplored. This study tested interactions between methylation in the μ-opioid receptor (OPRM1), dopamine transporter (SLC6A3), and catechol-O-methyltransferase (COMT) genes as predictors of naltrexone effects on heavy drinking in a 16-week randomized, placebo-controlled trial among 145 treatment-seeking AUD patients. OPRM1 methylation interacted with both SLC6A3 and COMT methylation to moderate naltrexone efficacy, such that naltrexone-treated individuals with lower methylation of the OPRM1 promoter and the SLC6A3 promoter (p = 0.006), COMT promoter (p = 0.005), or SLC6A3 3’ untranslated region (p = 0.004), relative to placebo and to those with higher OPRM1 and SLC6A3 or COMT methylation, had significantly fewer heavy drinking days. Epigenetic modification of opioid- and dopamine-related genes may represent a novel pharmacoepigenetic predictor of naltrexone efficacy in AUD.