Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models

Naltrexone reduces craving for alcohol and has been found to be most effective in reducing heavy drinking (25). The efficacy of naltrexone in reducing relapse to heavy drinking, in comparison to placebo, has been supported in numerous meta-analyses (23–25), although there is less evidence for its efficacy in supporting abstinence (25). Fewer studies have been conducted with the extended-release formulation, but its effects on heavy drinking, craving, and quality of life are promising (29, 30). Historically, naltrexone’s package insert has been accompanied by a risk of hepatotoxicity, a precaution primarily due to observed liver toxicity in an early clinical trial with administrating a naltrexone dosage of 300 mg per day to obese men (31). However, there is no published evidence of severe liver toxicity at the lower FDA-approved dosage of naltrexone for alcohol use disorder (50 mg per day).

For example, selection of peers is related to substance initiation, influenced by genetics (Kendler et al., 2007; Kendler & Baker, 2007; Tarantino et al., 2014), and can also be targeted in prevention programming (Dodge et al., 2006; Hansen & Graham, 1991; Larimer & Cronce, 2007). Studying theory-driven mediators of GxI effects may enable researchers to further identify factors that could be harnessed to enhance intervention effects. In addition to functional activity studies, hiPSC-derived neurons can be processed for RNAseq to study up and down regulation of transcripts, immunohistochemistry to observe the localization of proteins, and Western analyses to quantitate protein expression levels. Since many alcohol-related variants are believed to be eQTLs (Mamdani et al., 2015; Zhou et al., 2017), genome-wide transcript analysis is likely to reveal regulatory targets and these processes are expected to be cell type specific. With this wide selection of techniques, researchers can elucidate differences in activity in healthy, disease affected, genetically manipulated, and pharmacologically treated human cells.

Advances in research on medications for the treatment of alcohol use disorders: A review

• The differences between twin-based and SNP-based heritabilities (i.e., the ‘missing heritability’) for four of the addictions shown is in line with those observed among other human traits and diseases.
• Therefore, more large-scale, high-quality clinical controlled research is needed to explore and validate baclofen’s role and effectiveness in AUD treatment comprehensively.
• Human tissues of this type with complementary records of maternal alcohol exposure are rarely available.
• Third, if individual variants within a polygenic score are moderated by the environment in different directions, the method of creating aggregate PGS based on GWAS results and then testing for moderation of the environment may miss important interactions.
• All of the communities selected the “Strengthening Families Program” for the family-focused component, whereas three different programs were selected for the in-school component of the study and later controlled for in analyses.
• This article will review the latest research advances in currently available drugs, while focusing on drug classes that are not currently used in the clinic but have been shown in studies to be potential candidates for development, such as phosphodiesterase inhibitors and glucagon-like peptide-1 receptor agonists.

Collectively, the included articles highlight that FASD is a highly complex neurodevelopmental disorder with life-long consequences that calls for concerted efforts of investigation on all fronts, at all levels, and across lifespan, to advance and improve treatment and management of FASD. Although research in this field has indeed come a long way, knowledge gaps remain and must be addressed, potentially utilizing some of the advances described in this Research Topic. Data was collected via structured and semi-structured interviews, paper and pencil self-report measures, computerized assessments, or a combination of these methods. Overall, studies appeared to rely on standardized and validated measures with appropriate steps taken to assure participants of the confidentiality of their substance use data.

Figure 2. Timeline of the GWAS of AUD.

However, because of the lack of efficacy of a-2 agonists and β-blockers in preventing severe alcohol withdrawal syndrome and the risk of masking withdrawal symptoms, these drugs are recommended not as monotherapy, but only as a possible adjunctive treatment. (a) Different definitions of AUD and proxy phenotypes (e.g., AUDIT-P) have shared genetic architecture, resulting in improved power in gene discovery when they are combined from different cohorts (78, 80). Deep phenotyping (either using same definition or focusing on subphenotypes) in larger cohorts could reduce the phenotypic heterogeneity and increase the possibility of identifying trait-specific associations and pathways (92). In summary, clinical studies conducted in the past two years provide preliminary support of NMDA receptor antagonism (ifenprodil), but not agonism (glycine), in AUD treatment.

{His recommendations for remedies and case examples included practicing the Christian religion, experiencing guilt and shame, pairing alcohol with aversive stimuli, developing other passions in life, following a vegetarian diet, taking an oath to not drink alcohol, and sudden and absolute abstinence from alcohol. Through the 1800s and early 1900s, the temperance movement laid the groundwork for mutual help organizations, and the notion of excessive alcohol use as a moral failing. During the same period, inebriate asylums emerged as a residential treatment option for excessive alcohol use, although the only treatment offered was forced abstinence from alcohol (12). The founding of Alcoholics Anonymous (A.A.) in the 1930s (13) and the introduction of the modern disease concept of alcohol use disorder (previously called “alcoholism”) in the 1940s (14) laid the groundwork for many of the existing treatment programs that remain widely available today. And other support groups, such as SMART (Self-Management and Recovery Training)} and medical models of treatment for alcohol use disorder, as well as the development of new pharmacological and behavioral treatment options.|Future research should delve deeper into the value of gabapentin in AUD treatment and how to optimize its treatment protocol to maximize efficacy while minimizing potential side effects. Primarily used as an aid for smoking cessation, varenicline has drawn attention for its ability to reduce the rewarding effects of smoking by activating specific nicotinic acetylcholine receptors. Its mechanism involves binding to α4β2 nicotinic acetylcholine receptors, slowing the dopamine release triggered by receptor activation, similar to the process induced by alcohol.19 Based on this similarity, researchers have begun exploring varenicline’s potential utility in treating AUD. Data are presented as count (n/n; n (%)) or mean (±SD), PMI postmortem interval, pH pH-value of the brain, pp-value of t-Test comparing cases and controls, estimated smoking is the likelihood of smoking estimated based on the methylation data. Two studies used survival analysis (Musci et al., 2018, 2015), and one study used time-varying effect modeling (Russell et al., 2018).|For more than 25 years, advances have been made in developing medications to treat alcohol use disorder (AUD), highlighted by the U.S. Despite this progress, more work remains to be done in this area because these medications, though effective for some people, do not work for everyone. A high priority for the National Institute on Alcohol Abuse and Alcohol (NIAAA) is to put into place a solid infrastructure to aid in the development of medications that are more effective than those currently available, and with few side effects. Medication development, especially for a disorder as complex as AUD, is challenging and involves multiple phases, including discovery of “druggable” targets, preclinical studies, human clinical trials, and the adoption and implementation of the new medication into mainstream medicine.|Baker et al. found that the effects of PAE varied significantly among mouse strains, with some strains showing minimal effects and others displaying substantial changes in hippocampal-dependent behavior. They also noted strain-sex interactions underscoring the complex interplay that determines behavioral outcomes. Furthermore, Bariselli et al. observed in a mouse model of moderate postnatal ethanol exposure (third-trimester equivalent) that female, but not male, mice exhibited mild social impairments and altered extinction of operant responding. However, Wang et al. discovered that heavy PAE mimicking second-trimester exposure in humans resulted in persistent anxiety-like behavior in both male and female rats. Additionally, Lei et al. investigated the combined effects of PAE and Δ-9-tetrahydrocannabinol on cognitive and emotional development, revealing substance- and sex-specific patterns of impairment and highlighting the need for public health policies addressing the use of alcohol and cannabis during pregnancy. The findings of these studies underscore the enduring impact of PAE on mental health and emphasize the significance of considering sex and co-exposures in understanding the risk for development of FASD.}

Promising future behavioral treatments and neuromodulation treatments

• In this review, we provide an evaluation of our understanding of the genetics of AUD in relation to current precision medicine approaches.
• Kember and colleagues again help clarify most of these discrepancies between these genetic correlations between alcohol consumption and use disorder with other traits.
• Genetic literacy is low even among those with high levels of education (Chapman et al., 2018), and genetic essentialism, the notion that genetic effects are immutable and fully determine various outcomes, is prevalent (Dar-Nimrod & Heine, 2011; Pearson & Liu-Thompkins, 2012).
• The difference in findings of the variants’ effects on receptor function by neuron type between these studies could be attributed to differences in iPSC differentiation protocols.
• Forty-five records were found suitable for this review and are outlined in Table 1; selected studies are discussed below.