The efficacy of disulfiram for the treatment of alcohol use disorder

Background: Alcohol use disorders (AUD) involving hazardous, harmful, and addictive misuse of alcohol are widespread in most parts of the world. The aim of this study was to review the effect of disulfiram in the treatment of patients with AUD. The effect of disulfiram was evaluated according to the primary outcome of an intake of alcohol below 30 and 20 g/d for men and women, respectively, as well as secondary outcomes such as days until relapse, alcohol intake, and numbers of drinking days. Methods: A systematic review of the literature was conducted using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Results: Eleven randomized controlled trials were included with a total of 1,527 patients. They compared disulfiram treatment with placebo, none or other abstinence‐supportive treatments. Overall, 6 studies reported of a significant better effect on abstinence for patients treated with disulfiram. Six of 9 studies measuring secondary outcomes reported that patients treated with disulfiram had significantly more days until relapse and fewer drinking days, respectively. The quality of the included studies was moderate. Heterogeneity was significant in most of the meta‐analyses, but valid results were found regarding the effect of disulfiram versus placebo over 12 months and unsupervised disulfiram versus other or no treatment. The vast majority of significant studies were of shorter duration, while only 3 studies of 12 months were significant regarding more days until relapse and/or reduction in drinking days. Conclusions: Supervised treatment with disulfiram has some effect on short‐term abstinence and days until relapse as well as number of drinking days when compared with placebo, none, or other treatments for patients with alcohol dependency or abuse. Long‐term effect on abstinence has not been evaluated yet. However, there is a need for more homogeneous and high‐quality studies in the future regarding the efficacy of disulfiram.     

Disulfiram treatment for alcoholism in severe mental illness

Controlled research has shown that supervised disulfiram is an effective treatment for alcoholism. Despite this, little is known about the effects of disulfiram in persons with alcoholism and severe mental illness. We conducted comprehensive chart reviews on 33 patients with alcoholism and severe mental illness (70% schizophrenia or schizoaffective disorder) who had been prescribed disulfiram. Twenty-one percent reported side effects from disulfiram, whereas significant psychiatric complications were not reported. Although 76% of patients reported drinking while on disulfiram, only 28% experienced negative reactions to alcohol. Sixty-four percent of the patients saw a remission of alcoholism for at least one year during a three-year follow-up, and 30% experienced a two-year remission. Disulfiram treatment was associated with decreases in days hospitalized but not with changes in work status. The results suggest disulfiram may be a useful adjunctive treatment for alcoholism in patients with severe mental illness and that controlled research is needed to evaluate its effects in this population.     

Relationship between personality change and the onset and course of alcohol dependence in young adulthood

Aims To examine the reciprocal effects between the onset and course of alcohol use disorder (AUD) and normative changes in personality traits of behavioral disinhibition and negative emotionality during the transition between adolescence and young adulthood. Design Longitudinal–epidemiological study assessing AUD and personality at ages 17 and 24 years. Setting Participants were recruited from the community and took part in a day‐long, in‐person assessment. Participants Male (n = 1161) and female (n = 1022) twins participating in the Minnesota Twin Family Study. Measurements The effects of onset (adolescent versus young adult) and course (persistent versus desistent) of AUD on change in personality traits of behavioral disinhibition and negative emotionality from ages 17 to 24 years. Findings Onset and course of AUD moderated personality change from ages 17 to 24 years. Adolescent onset AUD was associated with greater decreases in behavioral disinhibition. Those with an adolescent onset and persistent course failed to exhibit normative declines in negative emotionality. Desistence was associated with a ‘recovery’ towards psychological maturity in young adulthood, while persistence was associated with continued personality dysfunction. Personality traits at age 11 predicted onset and course of AUD, indicating personality differences were not due to active substance abuse. Conclusions Personality differences present prior to initiation of alcohol use increase risk for alcohol use disorder, but the course of alcohol use disorder affects the rate of personality change during emerging adulthood. Examining the reciprocal effects of personality and alcohol use disorder within a developmental context is necessary to improve understanding for theory and intervention.     

Long-term influence of duration and intensity of treatment on previously untreated individuals with alcohol use disorders

Aims This study examined the influence of the duration and intensity of the first episode of treatment for previously untreated individuals with alcohol use disorders on short‐term and long‐term outcomes, and the effect of additional treatment and delayed treatment on outcomes. Design, setting, participants A sample of alcoholic individuals (n = 473) was recruited at alcoholism information and referral centers and detoxification units and was surveyed at baseline and 1 year, 3 years and 8 years later. Measurements At each contact point, participants completed an inventory that assessed their treatment utilization since the last assessment and their current alcohol‐related, psychological and social problems. Findings Compared with individuals who remained untreated, individuals who entered treatment relatively quickly and who obtained a longer duration of treatment had better short‐ and long‐term alcohol‐related outcomes and better short‐term social functioning. Individuals who obtained a longer duration of additional treatment had better alcohol‐related outcomes than individuals who obtained no additional treatment but, among individuals who delayed treatment entry, the duration of treatment was not associated with treatment outcomes. In general, the intensity of treatment was not related to better outcomes. Conclusions Rapid entry into treatment and the duration of treatment for alcohol use disorders may be more important than the intensity of treatment. Treatment providers should consider structuring their programs to emphasize continuity, rather than intensity of care.     

Should symptom frequency be factored into scalar measures of alcohol use disorder severity?

Aims To evaluate whether weighting counts of alcohol use disorder (AUD) criteria or symptoms by their frequency of occurrence improves their association with correlates of AUD. Design and participants Data were collected in personal interviews with a representative sample of US adults interviewed in 1991–92. Analyses were conducted among past‐year drinkers (12+ drinks, n = 18 352) and individuals with past‐year DSM‐IV AUD (n = 2770). Measurements Thirty‐one symptom item indicators, whose frequency of occurrence was measured in eight categories, were used to create unweighted and frequency‐weighted counts of DSM‐IV past‐year AUD symptoms and criteria. Correlates included density of familial alcoholism and past‐year volume of ethanol intake, frequency of intoxication and utilization of alcohol treatment. Findings Although the AUD correlates were associated strongly and positively with the frequency of AUD symptom occurrence, weighting for symptom frequency did not strengthen their association consistently with AUD severity scores. Improved performance of the weighted scores was observed primarily among AUD correlates linked closely with the frequency of heavy drinking and among individuals with AUD. Criterion counts were correlated nearly as strongly as symptom counts with the AUD correlates. Conclusions Frequency weighting may add somewhat to the validity of AUD severity measures, especially those that are intended for use among individuals with AUD, e.g. in clinical settings. For studying the etiology and course of AUD in the general population, an equally effective and less time‐consuming alternative to obtaining symptom frequency may be the use of unweighted criterion counts accompanied by independent measures of frequency of heavy drinking.     

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.     

Disentangling the Role of Astrocytes in Alcohol Use Disorder

Several laboratories recently identified that astrocytes are critical regulators of addiction machinery. It is now known that astrocyte pathology is a common feature of ethanol (EtOH) exposure in both humans and animal models, as even brief EtOH exposure is sufficient to elicit long‐lasting perturbations in astrocyte gene expression, activity, and proliferation. Astrocytes were also recently shown to modulate the motivational properties of EtOH and other strongly reinforcing stimuli. Given the role of astrocytes in regulating glutamate homeostasis, a crucial component of alcohol use disorder (AUD), astrocytes might be an important target for the development of next‐generation alcoholism treatments. This review will outline some of the more prominent features displayed by astrocytes, how these properties are influenced by acute and long‐term EtOH exposure, and future directions that may help to disentangle astrocytic from neuronal functions in the etiology of AUD.     

Coadministration of disulfiram and lorazepam in the treatment of alcohol dependence and co-occurring anxiety disorder: an open-label pilot study

ABSTRACT

Background: Anxiety is common among persons with alcohol use disorder during early abstinence from alcohol. Although benzodiazepines are effective for short-term treatment of anxiety, they are rarely used beyond acute detoxification due to concerns about misuse or interactions with alcohol. Objectives: We conducted an open-label trial to explore the effects of coadministering lorazepam and disulfiram to alcohol-dependent patients with anxiety disorder symptoms. The rationale for this model is to minimize the risks of the benzodiazepine, while also potentially enhancing adherence to disulfiram. Methods: Forty-one participants with DSM-IV alcohol dependence who also met syndromal criteria for anxiety disorder with or without co-occurring major depressive syndrome initiated treatment with lorazepam (starting dose 0.5 mg three times daily) and disulfiram (starting dose 500 mg three times weekly). Participants received 16 weeks of monitored pharmacotherapy with manualized medical management. Results: Adherence to treatment decreased steadily with time (85.4% at 4 weeks, 36.6% at 16 weeks). Participants showed significant increases in percent abstinent days during treatment and at 24 weeks follow-up. Large reductions in anxiety, depression, and craving were observed during treatment, and improvement remained significant at 24 weeks. Duration of adherence with disulfiram strongly predicted abstinence at 16 weeks. There was no evidence of misuse of lorazepam or dose escalation during the study. Conclusion: Lorazepam can be safely used for short-term treatment of anxiety in combination with disulfiram treatment of alcohol use disorder. However, it is not clear that making lorazepam dispensing contingent on adherence to disulfiram enhances retention in disulfiram treatment.     

Physicians' opinions about medications to treat alcoholism

Aims Medications play a limited role in the treatment of alcoholism. This paper examines physicians’ opinions about and use of two alcoholism medications currently approved in the US—disulfiram and naltrexone—and one alcoholism medication—acamprosate—that might be approved. Design A total of 1388 substance abuse specialist physicians who were members of the American Academy of Addiction Psychiatry or the American Society of Addiction Medicine completed a questionnaire in 2001 (65% response rate). Findings The average percentages of physicians’ patients with alcoholism who were prescribed the following medications were: 13% (naltrexone), 9% (disulfiram), 46% (antidepressants) and 11% (benzodiazepines). Almost all physicians had heard of naltrexone and disulfiram, but their self‐reported level of knowledge about these medications was lower than for antidepressants. Physicians estimated that naltrexone had a small‐to‐medium effect size, which was similar in magnitude to the effect size reported in recent meta‐analyses of randomized clinical trials. Physicians identified the following three courses of action as the most likely to result in greater use of medications to treat alcohol dependence: more research to develop new medications (33%), more education of physicians about existing medications (17%), and increased involvement of physicians in alcoholism treatment (17%). Conclusions Physicians’ low rate of use of naltrexone may reflect its small‐to‐medium effect size.     

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.     

Age and ethnic differences in the onset, persistence and recurrence of alcohol use disorder

Aims To estimate ethnic differences in three components of alcohol use disorder and alcohol dependence course (onset, persistence and recurrence) in a developmental framework. Design Longitudinal data from The National Epidemiologic Survey of Alcohol and Related Conditions (NESARC), collected using face‐to‐face interviews. Setting Civilian non‐institutionalized US population aged 18 years and older, with oversampling of Hispanics, blacks and those aged 18–24 years. Participants Individuals who completed both NESARC assessments, were not life‐long abstainers and were either white (n = 17 458), black (n = 4995), US‐born Hispanic (n = 2810) or Hispanic‐born outside the United States (n = 2389). Measurements Alcohol dependence (AD) and alcohol use disorder (AUD; abuse or dependence) onset, persistence and recurrence were examined using the Alcohol Use Disorders and Associated Disabilities Interview Schedule, DSM‐IV version. Findings Among men: relative to whites aged 18–29, AUD onset and persistence were elevated only in US‐born Hispanics aged 40 years and older; odds were reduced for all non‐US‐born Hispanics, older whites, most blacks and US‐born Hispanics aged 30–39. For AD, onset risk was elevated for all younger minority men and only reduced among non‐US‐born aged Hispanics 40 or older. For women: compared to young whites, non‐US‐born Hispanics were at decreased AUD and AD onset risk; AUD and AD onset and persistence were increased for older blacks and US‐born Hispanics. Conclusions In the United States, ethnic differences in alcohol disorder transitions (onset, persistence, and recurrence) vary across age, gender and whether a broad (alcohol use disorder) or narrow (alcohol dependence) alcohol definition is used. Evidence of increased risk for some transitions in minority groups suggests that attention should be paid to the course of alcohol use disorders, and that differences in prevalence should not be assumed to reflect differences in specific transitions.     

Genetic and Environmental Influences on Ethanol Consumption: Perspectives From Preclinical Research

Background: Alcohol use disorders (abuse and dependence, AUD) are multifactorial phenomena, depending on the interplay of environmental and genetic variables. Method: This review describes current developments in animal research that may help (a) develop gene therapies for the treatment of alcoholism, (b) understand the permissive role of stress on ethanol intake, and (c) elucidate why exposure to ethanol early in life is associated with a greater risk of AUD. Results: The polymorphisms found in liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) affect the elimination of ethanol and the susceptibility to ethanol intake. A highly active ADH protects against alcoholism, an effect related to a presteady state burst in arterial acetaldehyde. Social stressors, such as repeated early maternal separation or social defeat, exert a permissive effect on ethanol intake, perhaps by altering the normal development of the hypothalamic‐pituitary‐adrenal axis. Ethanol exposure during gestation, infancy, or adolescence increases the likelihood of AUD later in life. Early perception of ethanol’s positive and negative (anti‐anxiety) reinforcing effects may play a role in this phenomenon. Conclusions: The review underscores the advantages of using preclinical animal models of AUD and highlights points of intersection between the topics to help design a more integrated approach for the study of alcohol‐related problems.     

SLC Neurotransmitter Transporters as Therapeutic Targets for Alcohol Use Disorder: A Narrative Review

Alcohol use disorder (AUD) is 1 of the most prevalent of all substance use disorders and contributes significantly to global disease burden. Despite its prevalence, <10% of individuals with AUD receive treatment. A significant barrier to receiving treatment is a lack of effective pharmacotherapies. While 3 medications have been approved by the FDA for AUD (disulfiram, acamprosate, naltrexone), their efficacy remains low. Furthermore, a number of undesirable side effects associated with these drugs further reduce patient compliance. Thus, research into new effective pharmacotherapies for AUD is warranted. Due to their involvement in regulating synaptic neurotransmitter levels, solute carrier (SLC) transporters could be targeted for developing effective treatment strategies for AUD. Indeed, a number of studies have shown beneficial reductions in alcohol consumption through the use of drugs that target transporters of dopamine, serotonin, glutamate, glycine, and GABA. The purpose of this narrative review is to summarize preclinical and clinical studies from the last 2 decades targeting SLC neurotransmitter transporters for the treatment of AUD. Limitations, as well as future directions for expanding this field, are also discussed.     

Tolerance to disulfiram induced by chronic alcohol intake in the rat

Background: Disulfiram, an inhibitor of aldehyde dehydrogenase used in the treatment of alcoholism, is an effective medication when its intake is supervised by a third person. However, its therapeutic efficacy varies widely, in part due to the fact that disulfiram is a pro‐drug that requires its transformation into an active form and because it shows a wide range of secondary effects which often prevent the use of doses that ensure full therapeutic effectiveness. In this preclinical study in rats we report the development of tolerance to disulfiram induced by the chronic ingestion of ethanol, an additional source of variation for the actions of disulfiram with possible therapeutic significance, We also addresses the likely mechanism of this effect. Methods: Wistar‐derived rats bred for generations as high ethanol drinkers (UChB) were trained for either 3 days (Group A) or 30 days (Group B) to choose between ethanol (10% v/v) or water, which were freely available from 2 bottles on a 24‐hour basis. Subsequently, animals in both groups were administered disulfiram or cyanamide (another inhibitor of aldehyde dehydrogenase) and ethanol intake in this free choice paradigm was determined. Animals were also administered a standard dose of 1 g ethanol/kg (i.p) and arterial blood acetaldehyde was measured. Results: Disulfiram (12.5 and 25 mg/kg) and cyanamide (10 mg/kg) markedly inhibited ethanol intake (up to 60 to 70%) in animals that had ethanol access for only 3 days (Group A). However both drugs were inactive in inhibiting ethanol intake in animals that had consumed ethanol for 30 days (Group B). Following the injection of 1 g ethanol/kg, arterial blood acetaldehyde levels reached levels of 150 and 300 μM for disulfiram and cyanamide respectively, values which were virtually identical regardless of the length of prior ethanol intake of the animals. Conclusions: Chronic ethanol intake in high‐drinker rats leads to marked tolerance to the aversive effects of disulfiram and cyanamide on ethanol intake despite the presence of consistently high levels of blood acetaldehyde. These findings may have implications for the use of disulfiram for the treatment of alcoholism in humans.     

The contribution of parental alcohol use disorders and other psychiatric illness to the risk of alcohol use disorders in the offspring

Background: Few population‐based studies have investigated associations between parental history of alcoholism and the risk of alcoholism in offspring. The aim was to investigate in a large cohort the risk of alcohol use disorders (AUD) in the offspring of parents with or without AUD and with or without hospitalization for other psychiatric disorder (OPD). Methods: Longitudinal birth cohort study included 7,177 men and women born in Copenhagen between October 1959 and December 1961. Cases of AUD were identified in 3 Danish health registers and cases of OPD in the Danish Psychiatric Central Register. Offspring registration with AUD was analyzed in relation to parental registration with AUD and OPD. Covariates were offspring gender and parental social status. Results: Both maternal and paternal registration with AUD significantly predicted offspring risk of AUD (odds ratios 1.96; 95% CI 1.42 to 2.71 and 1.99; 95% CI 1.54 to 2.68, respectively). The association between maternal, but not paternal, OPD and offspring AUD was also significant (odds ratios 1.46; 95% CI 1.15 to 1.86 and 1.26; 95% CI 0.95 to 1.66, respectively). Other predictors were male gender and parental social status. A significant interaction was observed between paternal AUD and offspring gender on offspring AUD, and stratified analyses showed particularly strong associations of both paternal and maternal AUD with offspring AUD in female cohort members. Conclusions: Parental AUD was associated with an increased risk of offspring AUD independent of other significant predictors, such as gender, parental social status, and parental psychiatric hospitalization with other diagnoses. Furthermore, this association appeared to be stronger among female than male offspring. The results suggest that inherited factors related to alcoholism are at least as important in determining the risk of alcoholism among daughters as among sons.     

Differences between treatment-seeking and non-treatment-seeking participants in medication studies for alcoholism: do they matter?

Background: Medication development for alcoholism typically includes experimental pharmacology studies with non-treatment-seeking individuals with alcohol use disorder (AUD) paving the way for randomized controlled trials in treatment-seekers with AUD. Objectives: The goal of this study is to provide a direct comparison between AUD treatment-seeking research participants and non-treatment-seeking participants on demographic and clinical variables and to test whether variables that differentiate the two groups are associated with clinical outcomes. Method: Non-treatment-seeking AUD participants (n = 213; 76.3% male) who completed behavioral pharmacology studies were compared to treatment-seekers who completed the COMBINE Study (n = 1383; 69.1% male) on demographic and clinical variables. Analyses examined whether the variables that differentiated the two groups predicted treatment outcomes in the COMBINE Study. Results: Analyses revealed that treatment-seeking participants were older, had more years of education, higher Alcohol Dependence Scale scores, higher Drinker Inventory of Consequences scores, higher Obsessive Compulsive Drinking Scale scores, a greater number of DSM-IV symptoms of AUD, longer duration of AUD, and consumed more standard drinks and more drinks per drinking day (i.e., in the past 30 days) compared to non-treatment-seeking participants. Nearly all characteristics that differed between the groups predicted at least one of the primary clinical outcomes of the COMBINE Study. Conclusions: This study highlights a host of clinical and demographic factors that differ between non-treatment-seeking and treatment-seeking research participants and the clinical significance of these variables. Differences between samples should be considered and addressed in order to promote greater consilience across stages of medication development.     

Chemical Monitoring of Disulfiram Compliance: A Study of Alcoholic Outpatients

Poor compliance with disulfiram (Antabuse) therapy may reduce its efficacy in the treatment of alcoholism. This study was designed to examine two questions: (a) Could use of a chemical test for disulfiram ingestion be used clinically to improve disulfiram compliance and if so, (b) could improved disulfiram compliance contribute to improved compliance with other aspects of treatment? The results suggest that disulfiram compliance rates can be increased by clinical use of chemical monitoring data; however in this sample increased compliance with disulfiram did not correlate with improvements in other aspects of treatment compliance.     

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.