The Use of Functional Magnetic Resonance Imaging to Test Pharmacotherapies for Alcohol Use Disorder: A Systematic Review

Alcohol use disorder (AUD) is a chronic relapsing condition that represents a significant public health concern. Pharmacological treatment development for AUD is a top research priority, and many studies are being conducted to evaluate potential AUD treatments. Understanding the brain circuitry impacted by addiction is crucial for the development of efficacious pharmacological interventions. These neuroadaptations can be probed noninvasively using functional magnetic resonance neuroimaging (fMRI). fMRI may be an effective tool to identify biomarkers for AUD pharmacotherapies, evaluating changes associated with pharmacological treatment. Thus, the present qualitative review of the literature focuses on the role of fMRI as a tool for medication development for AUD. The aim of this review was to assemble research across a range of fMRI paradigms to study the effectiveness of pharmacological treatments of adult AUD. First, we present a qualitative review of fMRI AUD pharmacotherapy studies, differentiating studies based on their dosing regimen. Second, we provide recommendations for the field to improve the use of fMRI as a biomarker for AUD pharmacotherapy.     

Endocannabinoid Signaling in the Central Amygdala and Bed Nucleus of the Stria Terminalis: Implications for the Pathophysiology and Treatment of Alcohol Use Disorder

High rates of relapse are a chronic and debilitating obstacle to effective treatment of alcohol use disorder (AUD); however, no effective treatments are available to treat symptoms induced by protracted abstinence. In the first part of this 2‐part review series, we examine the literature supporting the effects of alcohol exposure within the extended amygdala (EA) neural circuitry. In Part 2, we focus on a potential way to combat negative affect associated with AUD, by exploring the therapeutic potential of the endogenous cannabinoid (eCB) system. The eCB system is a potent modulator of neural activity in the brain, and its ability to mitigate stress and negative affect has long been an area of interest for developing novel therapeutics. This review details the recent advances in our understanding of eCB signaling in 2 key regions of the EA, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), and their role in regulating negative affect. Despite an established role for EA eCB signaling in reducing negative affect, few studies have examined the potential for eCB‐based therapies to treat AUD‐associated negative affect. In this review, we present an overview of studies focusing on eCB signaling in EA and cannabinoid modulation on EA synaptic activity. We further discuss studies suggesting dysregulation of eCB signaling in models of AUD and propose that pharmacological augmentation of eCB could be a novel approach to treat aspects of AUD. Lastly, future directions are proposed to advance our understanding of the relationship between AUD‐associated negative affect and the EA eCB system that could yield new pharmacotherapies targeting negative affective symptoms associated with AUD.     

Overcoming the “Valley of Death” in Medications Development for Alcohol Use Disorder

As the development of novel pharmacotherapies for alcohol use disorder (AUD) has been slow, the discovery and testing of more efficacious pharmacotherapies for AUD represent a high priority research area. In fact, the transition from preclinical to clinical testing of novel compounds has been termed the “valley of death” in medications development. One key obstacle consists of the lack of an articulated set of goals for each stage of medications development. Specifically, the knowledge outputs required to make the transition from safety testing, to early efficacy detection, to confirming clinical efficacy remain unclear, and this is despite a great deal of interest and substantial financial investment in developing novel therapeutics for AUD. This qualitative critical review seeks to draw parallels and lessons from the well‐established stage model for behavioral therapies research with alcohol and other substance use disorders and to apply these insights into AUD pharmacotherapy development. We argue that human laboratory models and/or pilot randomized controlled trials should serve as intermediaries in the transition from preclinical studies to large, and costly, randomized controlled efficacy trials. The relative strengths and weaknesses of pilot clinical trials versus human laboratory studies for bridging the “valley of death” are discussed and explored via a Monte Carlo data simulation study. Multiple permutations of suitable research designs informed by the behavioral therapies development model are discussed with the overall goal of promoting consilience and maximizing efficiency across all phases of clinical testing of novel AUD pharmacotherapies.     

A Critical Review of Alcohol Administration Guidelines in Laboratory Medication Screening Research: Is It Time to Include Treatment Seekers?

Human laboratory studies play an important role in alcohol use disorder (AUD) medication development. Medications that are found to be safe and effective during human laboratory screening will then move to more expensive clinical trials in patient populations. Given the gatekeeping role of human laboratory studies in the medication development pipeline, it is critical that these studies accurately forecast how pharmacotherapies will perform under true-to-life clinical conditions. On the other hand, the design of these studies also must adhere to ethical guidelines: certain aspects of clinical reality cannot be incorporated into screening studies because doing so might place the participant at risk for harm or breach other ethical guidelines. Conventions exist that guide the resolution of these conflicting ideals. This article considers the practice of recruiting non–treatment-seeking heavy drinkers to participate in laboratory screening studies. By convention, volunteers are excluded from laboratory screening studies that involve alcohol administration if they are deemed “treatment seeking,” meaning that they recently stopped drinking or are motivated to do so. Although this common practice may reduce risk to participants, findings may not accurately predict medication effects on treatment seekers. Indeed, there is empirical evidence that treatment seekers differ from nontreatment seekers in their responses to medications (Neuropsychopharmacology 2017a; 42: 1776; Am J Drug Alcohol Abuse 2017b; 43: 703; J Psychiatr Res 2006; 40: 383). Here, we argue for the importance of recruiting treatment seekers for this research due to their qualitative difference from nontreatment seekers. We argue that these individuals should be the default population in human laboratory medication screening studies. We conclude by discussing 2 case examples of medication experiments led by our research groups that involved administering medications to treatment seekers.     

Handling of Drugs,Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liver-derived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.     

Posttraumatic Stress Disorder and Alcohol Use Disorder: A Critical Review of Pharmacologic Treatments

Treatment of alcohol use disorder (AUD) is complicated by the presence of psychiatric comorbidity including posttraumatic stress disorder (PTSD). This is a critical review of the literature to date on pharmacotherapy treatments of AUD and PTSD. A systematic literature search using PubMed MESH terms for alcohol and substance use disorders, PTSD, and treatment was undertaken to identify relevant randomized controlled trials (RCTs). The studies were independently evaluated (ILP and TLS) and those that evaluated the efficacy of a pharmacotherapy for individuals diagnosed with AUD and PTSD and were RCTs were selected. Studies were grouped in 3 categories: (i) those that evaluated first‐line treatments for PTSD, (ii) those that evaluated medications to target AUD, and (iii) those that evaluated medications hypothesized to be effective in targeting alcohol consumption as well as PTSD symptoms. Nine RCTs were identified; 3 focused on medications to treat PTSD, 4 focused on AUD, and 3 to target both. One study included both a medication to treat PTSD and 1 to treat AUD so was discussed twice. All but 1 of the studies found that PTSD symptoms and drinking outcomes improved significantly over time. There is not 1 agent with clear evidence of efficacy in this comorbid group. The results for medications to treat PTSD are inconclusive because of contradictory results. There was weak evidence to support the use of medications to treat AUD among those with comorbidity with PTSD. Findings for medications that were hypothesized to treat both disorders were also contradictory. Most studies provided a combination of interventions to treat both disorders. Despite the contradictory results, this review suggests that individuals with AUD and comorbid PTSD can safely be prescribed medications used in noncomorbid populations and patients improve with treatment.     

Carnitine in Alcohol Use Disorders: A Scoping Review

Recent studies in alcohol use disorders (AUDs) have demonstrated some connections between carnitine metabolism and the pathophysiology of the disease. In this scoping review, we aimed to collate and examine existing research available on carnitine metabolism and AUDs and develop hypotheses surrounding the role carnitine may play in AUD. A scoping review method was used to search electronic databases in September 2019. The database search terms used included “alcohol, alcoholism, alcohol abuse, alcohol consumption, alcohol drinking patterns, alcohol-induced disorders, alcoholic intoxication, alcohol-related disorders, binge drinking, Wernicke encephalopathy, acylcarnitine, acetyl-l-carnitine, acetylcarnitine, carnitine and palmitoylcarnitine.” The inclusion criteria included English language, human-based, AUD diagnosis and measured blood or tissue carnitine or used carnitine as a treatment. Of 586 studies that were identified and screened, 65 underwent abstract review, and 41 were fully reviewed. Eighteen studies were ultimately included for analysis. Data were summarized in an electronic data extraction form. We found that there is limited literature available. Alcohol use appears to impact carnitine metabolism, most clearly in the setting of alcoholic cirrhosis. Six studies found carnitine to be increased in AUD, of which 5 were conducted in patients with alcoholic cirrhosis. Only 3 placebo-controlled trials were identified and provide some support for the use of carnitine in AUD to decrease cravings, anhedonia, and withdrawal and improve cognition. The increase in plasma carnitine in alcoholic cirrhosis may be related to disordered fatty acid metabolism and oxidative stress that occurs in AUD. The multiple possible therapeutic effects carnitine could have on ethanol metabolism and the early evidence available for carnitine supplementation as a treatment for AUD provide a foundation for future randomized control trials of carnitine for treating AUD.     

Alcohol and Opioid Use,Co‐Use,and Chronic Pain in the Context of the Opioid Epidemic: A Critical Review

The dramatic increase in opioid misuse, opioid use disorder (OUD), and opioid‐related overdose deaths in the United States has led to public outcry, policy statements, and funding initiatives. Meanwhile, alcohol misuse and alcohol use disorder (AUD) are a highly prevalent public health problem associated with considerable individual and societal costs. This study provides a critical review of alcohol and opioid misuse, including issues of prevalence, morbidity, and societal costs. We also review research on interactions between alcohol and opioid use, the influence of opioids and alcohol on AUD and OUD treatment outcomes, respectively, the role of pain in the co‐use of alcohol and opioids, and treatment of comorbid OUD and AUD. Heavy drinking, opioid misuse, and chronic pain individually represent significant public health problems. Few studies have examined co‐use of alcohol and opioids, but available data suggest that co‐use is common and likely contributes to opioid overdose‐related morbidity and mortality. Co‐use of opioids and alcohol is related to worse outcomes in treatment for either substance. Finally, chronic pain frequently co‐occurs with use (and co‐use) of alcohol and opioids. Opioid use and alcohol use are also likely to complicate the treatment of chronic pain. Research on the interactions between alcohol and opioids, as well as treatment of the comorbid disorders is lacking. Currently, most alcohol research excludes patients with OUD and there is lack of measurement in both AUD and OUD research in relation to pain‐related functioning. Research in those with chronic pain often assesses opioid use, but rarely assesses alcohol use or AUD. New research to examine the nexus of alcohol, opioids, and pain, as well as their treatment, is critically needed.     

Comorbidity of Alcohol Use Disorder and Chronic Pain: Genetic Influences on Brain Reward and Stress Systems

Alcohol use disorder (AUD) is highly comorbid with chronic pain (CP). Evidence has suggested that neuroadaptive processes characterized by reward deficit and stress surfeit are involved in the development of AUD and pain chronification. Neurological data suggest that shared genetic architecture associated with the reward and stress systems may contribute to the comorbidity of AUD and CP. This monograph first delineates the prevailing theories of the development of AUD and pain chronification focusing on the reward and stress systems. It then provides a brief summary of relevant neurological findings followed by an evaluation of evidence documented by molecular genetic studies. Candidate gene association studies have provided some initial support for the genetic overlap between AUD and CP; however, these results must be interpreted with caution until studies with sufficient statistical power are conducted and replications obtained. Genomewide association studies have suggested a number of genes (e.g., TBX19, HTR7, and ADRA1A) that are either directly or indirectly related to the reward and stress systems in the AUD and CP literature. Evidence reviewed in this monograph suggests that shared genetic liability underlying the comorbidity between AUD and CP, if present, is likely to be complex. As the advancement in molecular genetic methods continues, future studies may show broader central nervous system involvement in AUD–CP comorbidity.     

Alcohol and depression

Aims To examine the literature on the associations between alcohol use disorders (AUD) and major depression (MD), and to evaluate the evidence for the existence of a causal relationship between the disorders. Methods PsycInfo; PubMed; Embase; Scopus; ISI Web of Science database searches for studies pertaining to AUD and MD from the 1980 to the present. Random‐effects models were used to derive estimates of the pooled adjusted odds ratios (AOR) for the links between AUD and MD among studies reporting an AOR. Results The analysis revealed that the presence of either disorder doubled the risks of the second disorder, with pooled AORs ranging from 2.00 to 2.09. Epidemiological data suggest that the linkages between the disorders cannot be accounted for fully by common factors that influence both AUD and MD, and that the disorders appear to be linked in a causal manner. Further evidence suggests that the most plausible causal association between AUD and MD is one in which AUD increases the risk of MD, rather than vice versa. Potential mechanisms underlying these causal linkages include neurophysiological and metabolic changes resulting from exposure to alcohol. The need for further research examining mechanisms of linkage, gender differences in associations between AUD and MD and classification issues was identified. Conclusions The current state of the literature suggests a causal linkage between alcohol use disorders and major depression, such that increasing involvement with alcohol increases risk of depression. Further research is needed in order to clarify the nature of this causal link, in order to develop effective intervention and treatment approaches.     

State-of-the-art behavioral and pharmacological treatments for alcohol use disorder

Background: Alcohol use disorder (AUD) and its associated consequences remain significant public health concerns. Given that AUD represents a spectrum of severity, treatment options represent a continuum of care, ranging from single-session brief interventions to more intensive, prolonged, and specialized treatment modalities. Objective: This qualitative literature review seeks to describe the best practices for AUD by placing a particular emphasis on identifying those practices which have received the most empirical support. Method: This review summarizes psychological and pharmacological intervention options for AUD treatment, with a focus on the relapse prevention phase of recovery. Psychological and pharmacological treatments are summarized in terms of the empirical evidence favoring each approach and the level of AUD severity for which they are most indicated. Scientific significance: One of the broad assertions from this review is that while AUD is highly prevalent, seeking treatment for AUD is not. There are a myriad of behavioral and pharmacological treatments that have shown compelling evidence of efficacy for the treatment of AUD. In the behavioral treatment literature, cognitive behavioral therapy has received the most consistent support. Opioid antagonism (via naltrexone) has been the most widely studied pharmacotherapy and has produced moderate effect sizes. While none of the treatments reviewed herein represents a so-called silver bullet for AUD, they each have the potential to significantly improve the odds of recovery. Precision medicine, or the identification of best treatment matches for individual patients, looms as an important overarching goal for the field, although specific matches are not yet sufficiently reliable in their empirical evidence to warrant clinical dissemination.     

Medications for treating alcohol use disorder: A narrative review

Chronic heavy alcohol use impacts all major neurotransmitter systems and is associated with multiple medical, psychiatric, and social problems. Available evidence-based medications to treat alcohol use disorder (AUD) are underutilized in clinical practice. These medications promote abstinence or reduce alcohol consumption, though there are questions regarding their optimal dosage, length of treatment, and utility in combination with one another. Pharmacogenetic approaches, which use a patient's genetic make-up to inform medication selection, have garnered great interest but have yet to yield results robust enough to incorporate them in routine clinical care. This narrative review summarizes the evidence both for medications approved by the Food and Drug Administration (disulfiram, oral naltrexone, acamprosate, and extended-release naltrexone) and those commonly used off-label (e.g., gabapentin, baclofen, and topiramate) for AUD treatment. We discuss these drugs' mechanisms of action, clinical use, pharmacogenetic findings, and treatment recommendations. We conclude that the most consistent evidence supporting the pharmacotherapy of AUD is for the opioid antagonists, naltrexone and nalmefene (which is not approved in the United States), and topiramate. These medications demonstrate consistent small or moderate effects in reducing the frequency of drinking and/or heavy drinking. Lastly, we make suggestions for research needed to refine and expand the current literature on effective pharmacotherapy for AUD.     

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline

While alcohol use disorder (AUD) is a highly heritable psychiatric disease, efforts to elucidate that heritability by examining genetic variation (e.g., single nucleotide polymorphisms) have been insufficient to fully account for familial AUD risk. Perhaps not coincidently, there has been a burgeoning interest in novel nongenomic mechanisms of inheritance (i.e., epigenetics) that are shaped in the male or female germ cells by significant lifetime experiences such as exposure to chronic stress, malnutrition, or drugs of abuse. While many epidemiological and preclinical studies have long pointed to a role for the parental preconception environment in offspring behavior, over the last decade many studies have implicated a causal relationship between the environmentally sensitive sperm epigenome and intergenerational phenotypes. This critical review will detail the heritable effects of alcohol and the potential role for epigenetics.     

Prefrontal cortex volumes in adolescents with alcohol use disorders: unique gender effects

Background:  Adolescents with alcohol use disorders (AUD) have shown smaller prefrontal cortex (PFC) volumes compared with healthy controls; however, differences may have been due to comorbid disorders. This study examined PFC volumes in male and female adolescents with AUD who did not meet criteria for comorbid mood or attention disorders.
Methods:  Participants were adolescents aged 15 to 17 who met criteria for AUD ( n  = 14), and demographically similar healthy controls ( n  = 17). Exclusions included any history of a psychiatric or neurologic disorder other than AUD or conduct disorder. Magnetic resonance imaging scans occurred after at least 5 days of abstinence from alcohol or drugs. Overall PFC volumes and white matter PFC volumes were compared between groups.
Results:  After controlling for conduct disorder, gender, and intracranial volume, AUD teens demonstrated marginally smaller anterior ventral PFC volumes ( p  = 0.09) than controls, and significant interactions between group and gender were observed ( p  < 0.001 to p  < 0.03). Compared with same-gender controls, females with AUD demonstrated smaller PFC volumes, while males with AUD had larger PFC volumes. The same pattern was observed for PFC white matter volumes.
Conclusions:  Consistent with adult literature, alcohol use during adolescence is associated with prefrontal volume abnormalities, including white matter differences. However, adolescents with AUD demonstrated gender-specific morphometric patterns. Thus, it is possible that gender may moderate the impact of adolescent alcohol use on prefrontal neurodevelopment, and the neurodevelopmental trajectories of heavy drinking boys and girls should be evaluated separately in longitudinal studies.     

The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?

Corticotropin releasing factor (CRF) is a neuropeptide that plays a key role in behavioral and physiological responses to stress. A large body of animal literature implicates CRF acting at type 1 CRF receptors (CRFR1) in consumption by alcohol‐dependent subjects, stress‐induced reinstatement of alcohol seeking, and possibly binge alcohol consumption. These studies have encouraged recent pilot studies of CRFR1 antagonists in humans with alcohol use disorder (AUD). It was a great disappointment to many in the field that these studies failed to show an effect of these compounds on stress‐induced alcohol craving. Here, we examine these studies to explore potential limitations and discuss preclinical and human literature to ask whether CRFR1 is still a valid drug target to pursue for the treatment of AUD.     

A Systematic Review of Naltrexone for Attenuating Alcohol Consumption in Women with Alcohol Use Disorders

Several clinical trials have evaluated naltrexone as a treatment for alcohol use disorders (AUDs), but few have focused on women. The aim of this review was to systematically review and summarize the evidence regarding the impact of naltrexone compared to placebo for attenuating alcohol consumption in women with an AUD. A systematic review was conducted using PubMed, Cochrane, Web of Science, CINAHL, and Alcohol Studies Database to identify relevant peer‐reviewed randomized controlled trials (RCTs) published between January 1990 and August 2016. Seven published trials have evaluated the impact of naltrexone on drinking outcomes in women distinct from men; 903 alcohol‐dependent or heavy drinking women were randomized to receive once daily oral or depot (injectable) naltrexone or placebo with/without behavioral intervention. Two studies examining the quantity of drinks per day observed trends toward reduction in drinking quantity among women who received naltrexone versus placebo. The 4 studies examining the frequency of drinking had mixed results, with 1 study showing a trend that favored naltrexone, 2 showing a trend that favored placebo, and 1 that showed no difference. Two of the 3 studies examining time to relapse observed trends that tended to favor naltrexone for time to any drinking and time to heavy drinking among women who received naltrexone versus placebo. While the growing body of evidence suggests a variety of approaches to treat AUD, the impact of naltrexone to combat AUD in women is understudied. Taken together, the results suggest that naltrexone may lead to modest reductions in quantity of drinking and time to relapse, but not on the frequency of drinking in women. Future research should incorporate sophisticated study designs that examine gender differences and treatment effectiveness among those diagnosed with an AUD and present data separately for men and women.     

Supervised disulfiram in the treatment of alcohol use disorder: a commentary

Background: This commentary discusses the systematic review “The efficacy of disulfiram for the treatment of alcohol use disorder (AUD)” by Jørgensen and colleagues (2011, Alcohol Clin Exp Res DOI: 10.1111/j.1530‐0277.2011.01523.x ). The main focus of the commentary is on long‐term effects, long‐term use, and psychotherapeutic application of supervised disulfiram. Methods: A brief qualitative overview is given of previous and recent clinical studies on disulfiram in alcoholism treatment. Results: The alcohol deterrent disulfiram is an effective pharmacological adjunct to the treatment of AUD when it is administered as supervised low‐dose disulfiram and is integrated in comprehensive biopsychosocial alcoholism therapy. However, the assumed underlying psychological effects of psychotherapeutic disulfiram application have never been properly investigated. Prospective long‐term follow‐up studies are rare and suggest that long‐term effects of disulfiram are associated with long‐term use and/or integration of the medication in cognitive behavior therapy. Conclusions: Evidence from decades of research suggests psychological effects as principal mode of action of supervised disulfiram. Future randomized controlled trials are needed that investigate psychological actions and long‐term outcomes of this alcohol deterrent.     

Alcohol use disorders among emergency department-treated older adolescents: a new brief screen (RUFT-Cut) using the AUDIT, CAGE, CRAFFT, and RAPS-QF

BACKGROUND: Early identification of alcohol use disorders (AUD) among emergency department (ED)-treated patients is important for facilitating intervention and further evaluation outside EDs. A number of brief screening instruments have been developed for identifying patients with AUD, but it is not clear whether they are practical and perform well with older adolescents in an ED setting. This study contrasted four brief screening instruments for detecting DSM-IV-defined AUD and tested a newly developed brief screen for use among ED-treated older adolescents. METHODS: The Alcohol Use Disorders Identification Test (AUDIT), the CAGE, the CRAFFT, and a modified RAPS-QF were given to 93 alcohol-using older adolescents (55% men; aged 18-20 years) in an ED. Receiver operator characteristic analyses were used to evaluate the performance of brief screens against the criterion of a lifetime DSM-IV alcohol abuse or dependence diagnosis. RESULTS: Of existing instruments, the AUDIT had the best overall performance in identifying AUD (sensitivity, 82%; specificity, 78%). A new, shorter screening instrument composed of two AUDIT items, two CRAFFT items, and one CAGE item (RUFT-Cut) performed as well as the AUDIT (sensitivity, 82%; specificity, 78%). CONCLUSIONS: Among existing alcohol screening instruments, the AUDIT performed best for identifying ED-treated older adolescents with alcohol use disorders. The RUFT-Cut is a brief screening instrument for AUD that shows promise for identifying ED-treated older adolescents who are in need of intervention or further evaluation. Future research should focus on use of the RUFT-Cut in other settings with larger, more diverse samples of adolescents.     

Diffusion tensor measures of the corpus callosum in adolescents with adolescent onset alcohol use disorders

Background: In adults, myelination injury is associated with alcoholism. Maturation of the corpus callosum is prominent during adolescence. We hypothesized that subjects with adolescent‐onset alcohol use disorders (AUD; defined as Diagnostic and Statistical Manual of Mental Disorders‐IV alcohol dependence or abuse) would have myelination mircostructural differences compared to controls. Methods: Adolescent subjects (25 males, 7 females) with an AUD (16.9 ± 1.2 years), who were recruited from substance abuse treatment programs and had co‐morbid mental disorders, and 28 sociodemographically similar healthy controls (17 males, 11 females; 15.9 ± 1.1 years) underwent a 3.0 T MRI diffusion tensor imaging scan. Results: Measures of rostral body fractional anisotropy (FA) were higher in the AUD group than in the control group. Compared to controls, mean diffusivity (MD) was lower, while FA was higher, in the AUD group in the isthmus region. Anterior corpus callosum mircostructural development differed in adolescents with AUD, as age was positively (not negatively) associated with rostrum MD and age was negatively (not positively) associated with rostrum FA. There were sex by group interactions in that control females had higher posterior midbody FA when compared to female adolescents with AUD. Conclusions: Lower MD and higher FA values in the AUD group suggest pre‐morbid vulnerability for accelerated prefrontal and temporo‐parietal myelin maturation that may enhance the risk for adolescent AUD. Significant (and opposite to developmentally expected) correlations were seen between anterior corpus callosum MD and FA measures and age in the AUD group, suggesting neurotoxic effects of alcohol on adolescent corpus callosum microstructure. As seen in adults, female adolescents with AUD may be especially vulnerable to corpus callosum mircostructural injury. Further diffusion tensor imaging studies of corpus callosum maturation in children at familial risk for alcoholism, and in those with AUD, need to be done to elucidate these mechanisms.