Medication development for alcohol use disorder (AUD) represents a challenging, costly, and time-consuming process. A typical development trajectory involves testing compounds in animal models, human laboratory studies, and randomized clinical trials (RCTs). This paper reviews a series of data-driven studies seeking to evaluate best practices in medication development for AUD at each of the three levels of analysis. First, we evaluate the role of behavioral pharmacology paradigms in early efficacy testing and highlight the importance of preclinical and human laboratory evidence in making critical “go/no-go” decisions throughout the development process. Second, we discuss a recent translational meta-analytic approach that integrates preclinical, human laboratory, and RCT data to inform AUD medication development. This narrative review synthesizes findings from systematic reviews, meta-regression analyses, and integrated data across stages of medication testing. Findings from this work suggest that factors such as sample characteristics and study design influence the detection of medication effects on AUD outcomes, emphasizing the need for standardized methodologies. Furthermore, findings suggest that early efficacy signals in animal models and human laboratory studies can predict specific clinical trial outcomes, offering valuable insights for data-informed decision making in medication development. Together, these studies bridge the gap between the preclinical and clinical stages, facilitating more efficient medication development for AUD.
Fetal alcohol spectrum disorders (FASD) is an umbrella term used to describe physical, neuropathological, and behavioral alterations caused by prenatal alcohol exposure. Caretakers often report that children with FASD experience sleep problems. However, interventions to improve sleep have not been well-studied in this population. Interestingly, supplementation with the essential nutrient choline can attenuate many behavioral alterations associated with prenatal alcohol exposure. Moreover, choline is a precursor to acetylcholine, a neurochemical that is also involved in sleep–wake modulation. Using an animal model, this study investigated the effects of developmental alcohol exposure on sleep and examined whether postnatal choline supplementation can modulate sleep alterations associated with FASD.
Sprague–Dawley rat pups received ethanol (5.25 g/kg/day, 11.9% v/v) or sham intubations from postnatal days (PD) 4–9, a period of development equivalent to the human third-trimester brain growth spurt. Subjects then received subcutaneous injections with choline chloride (100 mg/kg/day) or saline from PD 10–30. On PD 32–37, subjects were individually housed to measure sleep–wake behaviors using the PiezoSleep Adapt-A-Base System. Sleep parameters, including sleep time, bout length, and number, were recorded.
Ethanol-exposed subjects, particularly females, slept less during the dark cycle. In addition, females exposed to developmental alcohol exhibited more night-to-night variability in sleep duration, consistent with findings from clinical populations. In contrast, choline supplementation increased sleep duration, particularly among males exposed to developmental alcohol. Choline specifically increased sleep bout duration in ethanol-exposed subjects during the dark cycle, suggesting that choline can modify sleep patterns among subjects exposed to prenatal alcohol.
These results illustrate that alcohol exposure during late gestation may lead to sleep disturbances and suggest that postnatal choline supplementation affects sleep quality. Importantly, this nutritional intervention was administered after the alcohol insult, suggesting that nutritional supplements in children with FASD may impact sleep problems.
Friendships become increasingly influential in early adolescence, leading to a greater impact of friends' norms on behavior. However, not all youth conform to norms, suggesting other factors may shape this influence. One such factor is friendship quality, which may shape adolescents' motivation to adopt peer norms, especially when those norms come from close, supportive friendships. This study examined how perceptions of friends' alcohol use and approval predict adolescents' intentions to drink, and whether friendship quality moderates these effects while disaggregating between- and within-person effects using a multilevel, longitudinal design.
Hierarchical linear modeling with a community sample of adolescents (n = 387) across 3 years tested hypotheses by distinguishing within- and between-person associations, capturing both the dynamic nature of friendships and how shifts in perceived norms influence alcohol intentions over time, as well as adolescents' broader tendency to affiliate with peers who approve of or engage in alcohol use. Interactions were tested using cross-product terms.
Results partially supported hypotheses suggesting that friendship quality impacted susceptibility to peer norms regarding perceptions of friends' approval (β = 0.28, p = 0.026) but not use (β = 0.22, p = 0.214). The models supported the decomposition of between- and within-person effects, as both friends' approval (between-person: β = 0.58, p < 0.001; within-person: β = 0.37, p < 0.001) and use (between-person: β = 0.61, p < 0.001; within-person: β = 0.29, p < 0.001) were positively associated with future intentions to drink.
Taken together, results suggest that high-quality friendships amplified the influence of perceived friends' approval on alcohol intentions at the between-person level, but not for perceptions of use. Adolescents may prioritize maintaining their friendships; in turn, they adjust their beliefs and perceptions to preserve these relationships. Furthermore, perceptions of friends' alcohol norms operated similarly at the between- and within-level.
Fetal alcohol spectrum disorders (FASD) describe a spectrum of ethanol-induced developmental defects. Ethanol susceptibility is modulated by genetics, but the underlying mechanisms remain poorly understood. In all vertebrates, complex cellular events give rise to the body plan, including gastrulation and morphogenesis of the endoderm and cranial neural crest (CNC—gives rise to the facial skeleton). These events are crucial for establishing complex signaling interactions that drive embryo development, including the formation of the facial skeleton. In zebrafish, gastrulation occurs between 6 and 10 h postfertilization (hpf), while endoderm/CNC morphogenesis occurs between 10 and 24 hpf. In previous work, planar cell polarity (PCP) mutants are ethanol-sensitive from 6 to 24 hpf (covering both gastrulation and endoderm/CNC morphogenesis), exhibiting multiple defects in the forming head. This raises the question of whether ethanol during both these time windows drives PCP-ethanol defects. We hypothesize that PCP mutants are ethanol-sensitive from 10 to 24 hpf, after gastrulation. We also hypothesize that bone morphogenetic protein (BMP) signaling (ethanol-sensitive 10–18 hpf) interacts with and sensitizes the PCP pathway to ethanol.
We treated PCP/BMP mutants with ethanol over various time windows between 6 and 30 hpf and combined morphometric and linear measurements to examine facial development.
We show that PCP mutants are largely ethanol-sensitive from 10 to 24 hpf. We also show that BMP mutants sensitize PCP mutants to ethanol and lead to novel ethanol-independent midline craniofacial defects. Our results suggest that the ethanol-sensitive role of the PCP pathway occurs after gastrulation, during endoderm/CNC morphogenesis, and that the PCP and BMP pathways genetically interact during the morphogenetic events.
Ultimately, our work builds on a mechanistic paradigm of ethanol-induced birth defects we have been developing, connecting the conceptual framework with concrete cellular events that could be ethanol-sensitive beyond facial development.
Immune medications, including ibudilast, have shown early potential in mitigating alcohol intake in preclinical models and small-scale trials for alcohol use disorder (AUD). To elucidate clinical utility and clinical mechanisms of these novel treatments, research should carefully assess medication-related changes in AUD symptomatology, including craving and negative mood, over time.
This is a secondary analysis of a 12-week randomized clinical trial of ibudilast for AUD. Participants were 102 individuals (40% female, average age 44 years) seeking treatment for AUD and randomized to ibudilast (50 mg twice-daily) or matched placebo. Clinical symptom measures of alcohol craving, depression, and anxiety were collected monthly. Growth models compared rates of change in clinical symptomatology between treatment groups and tested whether changes were moderated by sex. A subsample (n = 25) completed a functional magnetic resonance imaging scan with an alcohol cue-reactivity task at week four to assess a brain-based craving marker.
At pretreatment, participants reported moderate craving symptoms and nonclinically elevated negative mood symptoms, on average. Participants taking ibudilast showed significantly steeper reductions in craving during the trial, as compared with placebo (1.32 vs. 0.52 points lower per month; p = 0.035). At treatment endpoint, female participants taking ibudilast reported lower craving than female participants taking placebo (p < 0.001). Greater cue-elicited brain activation in bilateral insula, bilateral orbitofrontal cortex, and right precuneus (p's < 0.02) was detected among the placebo subsample, compared to ibudilast. Rates of change for depression and anxiety did not differ between medication conditions, nor were they moderated by sex. Depression symptoms decreased during the trial, while anxiety symptoms remained relatively stable.
Consistent with prior research, ibudilast reduced neurobiological and self-report markers of craving, with female participants showing a stronger treatment response by trial endpoint. Despite shared neuroimmune correlates between negative mood and addiction, ibudilast did not alleviate negative mood symptoms beyond placebo effects.
Alcohol intake is widely accepted in diverse cultures around the world, although heavy and prolonged consumption can be harmful. Alcohol influences multiple organs through interorgan and intercellular signaling cascades. The common health conditions associated with alcohol use disorder (AUD) are pancreatitis, liver cirrhosis, neuropathies, cardiomyopathies, and dementia. By virtue of its anatomical orientation and function, the lung continually encounters microbes, and this can be exacerbated by excessive alcohol consumption. Alcohol abuse is a well-known risk factor for bacterial infection in the lung. Increased susceptibility to bacterial pneumonia is caused by impaired immune responses in individuals with AUD. The key cells to defend against pulmonary infections are innate immune cells, including alveolar macrophages, neutrophils, and adaptive immune cells, such as T and B cells. This review highlights recent advances illuminating the roles of innate immune responses in bacterial pneumonia and the effects of alcohol in bacterial pneumonia. Understanding the molecular mechanisms associated with innate immunity in the lung is essential for developing effective strategies to control pneumonia and alcohol-mediated immunosuppression.
Heightened alcohol cue reactivity is associated with alcohol problems and poor alcohol use disorder outcomes. Theory suggests that this reflects a conditioned response, whereby cues repeatedly paired with chronic alcohol use become more salient. However, few studies have investigated the relative emergence of heightened alcohol cue reactivity. It is possible that this response occurs very early in individual drinking trajectories and may play a role in shaping future alcohol use behavior.
We tested this hypothesis in a sample of youth (n = 159; ages 16–19) with limited lifetime alcohol exposure (<100 lifetime drinks). Participants completed a baseline cue reactivity task in which they viewed images of alcoholic beverages, high-calorie foods (reward control), and neutral objects. The late positive potential (LPP), measured using electroencephalography, is a positive-going event-related potential measured 400 ms after a visual cue. The LPP was used to index cue reactivity and scored as the average amplitude from parietal site Pz. At baseline and 12 months, participants completed a retrospective calendar of alcohol use. Participants were classified into groups based on lifetime alcohol exposure: (1) ≤ 10 drinks (n = 50), (2) ≤50 drinks (n = 74), (3) >50 drinks (n = 35).
We ran a repeated measures analysis of variance to compare the effects of task condition (alcohol cues/food cues > neutral) and drink groups on LPP amplitude. Our results revealed a significant condition × drink group interaction. Follow-up analyses revealed that, for alcohol cues only, there was a significant group effect. The highest drink exposure group exhibited greater LPP relative only to the low drink exposure group. Next, we examined whether baseline LPP to alcohol cues predicted total drinks consumed 12 months later, while controlling for baseline drinking behavior. Greater LPP to alcohol cues was associated with an increase in drinks consumed at one year.
Heightened alcohol cue reactivity emerges with limited alcohol use and can be predictive of future drinking behaviors.
Binge drinking peaks during emerging adulthood and is associated with negative developmental outcomes. Within-person changes in cannabis use have been shown to coincide with binge drinking; however, whether within-person changes in binge drinking and cannabis use prospectively predict one another and whether these relations vary by age remain unknown. The current study sought to fill these gaps.
Data come from National Consortium on Alcohol and Neurodevelopment (NCANDA) participants aged 18–25 years reporting alcohol and cannabis use (N = 526). Parallel-process state–trait mixed effect growth models tested whether: (1) binge drinking across emerging adulthood was correlated with cannabis use (random intercepts); (2) steeper growth in binge drinking across emerging adulthood correlated with growth in cannabis use (random slopes); and (3) age-specific, within-person changes in binge drinking/cannabis use reciprocally predicted one another.
Across individuals, more frequent binge drinking was correlated with more frequent concurrent cannabis use, and steeper increases in binge drinking were correlated with steeper increases in cannabis use during emerging adulthood. Within-person changes in binge drinking and cannabis use covaried. Within-person increases in cannabis use predicted subsequent increases in binge drinking between ages 18 and 21 years but decreases in binge drinking between ages 24 and 25 years. Within-person changes in binge drinking did not predict subsequent changes in cannabis use during emerging adulthood.
Changes in cannabis use coincided with changes in binge drinking, concurrently and subsequently, particularly between ages 18 and 21 years when changes in cannabis use predicted subsequent increases in binge drinking and ages 24 and 25 years when changes in cannabis use predicted decreases in subsequent binge drinking. Incorporating motivational approaches to reduce cannabis use in alcohol interventions may be efficacious in early emerging adulthood.
The alcohol cue-exposure paradigm has a long and rich history in alcohol use disorder (AUD) research, contributing to the identification of risk factors, the recognition of craving as a core symptom, the understanding of AUD neurobiology, and the development of both pharmacological and behavioral treatments. The goal of this review was to evaluate the utility of the alcohol cue-exposure paradigm as a screening tool for AUD medication development and to provide recommendations for refinement of the paradigm. First, we review evidence supporting the predictive validity and clinical applicability of the alcohol cue-exposure paradigm. Second, we examine current practices in implementing the paradigm in AUD pharmacotherapy studies. Third, we highlight several areas for refinement and offer recommendations for the implementation of this paradigm. Finally, we outline key conclusions and actionable future directions. In summary, while the alcohol cue-exposure paradigm has an established foundation in the study of AUD pharmacotherapies, its future success hinges on a concerted effort to refine and standardize protocols and validate outcome measures in large-scale studies. Addressing these priorities could accelerate the development and regulatory approval of novel treatments for AUD.
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