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Evidence-based models of care for the treatment of alcohol use disorder in primary health care settings: protocol for systematic review

• Susan A. Rombouts 1 ,
• James Conigrave 2 ,
• Eva Louie 1 ,
• Paul Haber 1 , 3 &
• Kirsten C. Morley   ORCID: orcid.org/0000-0002-0868-9928 1  

Systematic Reviews volume  8 , Article number:  275 ( 2019 ) Cite this article

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Alcohol use disorder (AUD) is highly prevalent and accounts globally for 1.6% of disability-adjusted life years (DALYs) among females and 6.0% of DALYs among males. Effective treatments for AUDs are available but are not commonly practiced in primary health care. Furthermore, referral to specialized care is often not successful and patients that do seek treatment are likely to have developed more severe dependence. A more cost-efficient health care model is to treat less severe AUD in a primary care setting before the onset of greater dependence severity. Few models of care for the management of AUD in primary health care have been developed and with limited implementation. This proposed systematic review will synthesize and evaluate differential models of care for the management of AUD in primary health care settings.

We will conduct a systematic review to synthesize studies that evaluate the effectiveness of models of care in the treatment of AUD in primary health care. A comprehensive search approach will be conducted using the following databases; MEDLINE (1946 to present), PsycINFO (1806 to present), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) (1991 to present), and Embase (1947 to present).

Reference searches of relevant reviews and articles will be conducted. Similarly, a gray literature search will be done with the help of Google and the gray matter tool which is a checklist of health-related sites organized by topic. Two researchers will independently review all titles and abstracts followed by full-text review for inclusion. The planned method of extracting data from articles and the critical appraisal will also be done in duplicate. For the critical appraisal, the Cochrane risk of bias tool 2.0 will be used.

This systematic review and meta-analysis aims to guide improvement of design and implementation of evidence-based models of care for the treatment of alcohol use disorder in primary health care settings. The evidence will define which models are most promising and will guide further research.

Protocol registration number

PROSPERO CRD42019120293.

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It is well recognized that alcohol use disorders (AUD) have a damaging impact on the health of the population. According to the World Health Organization (WHO), 5.3% of all global deaths were attributable to alcohol consumption in 2016 [ 1 ]. The 2016 Global Burden of Disease Study reported that alcohol use led to 1.6% (95% uncertainty interval [UI] 1.4–2.0) of total DALYs globally among females and 6.0% (5.4–6.7) among males, resulting in alcohol use being the seventh leading risk factor for both premature death and disability-adjusted life years (DALYs) [ 2 ]. Among people aged 15–49 years, alcohol use was the leading risk factor for mortality and disability with 8.9% (95% UI 7.8–9.9) of all attributable DALYs for men and 2.3% (2.0–2.6) for women [ 2 ]. AUD has been linked to many physical and mental health complications, such as coronary heart disease, liver cirrhosis, a variety of cancers, depression, anxiety, and dementia [ 2 , 3 ]. Despite the high morbidity and mortality rate associated with hazardous alcohol use, the global prevalence of alcohol use disorders among persons aged above 15 years in 2016 was stated to be 5.1% (2.5% considered as harmful use and 2.6% as severe AUD), with the highest prevalence in the European and American region (8.8% and 8.2%, respectively) [ 1 ].

Effective and safe treatment for AUD is available through psychosocial and/or pharmacological interventions yet is not often received and is not commonly practiced in primary health care. While a recent European study reported 8.7% prevalence of alcohol dependence in primary health care populations [ 4 ], the vast majority of patients do not receive the professional treatment needed, with only 1 in 5 patients with alcohol dependence receiving any formal treatment [ 4 ]. In Australia, it is estimated that only 3% of individuals with AUD receive approved pharmacotherapy for the disorder [ 5 , 6 ]. Recognition of AUD in general practice uncommonly leads to treatment before severe medical and social disintegration [ 7 ]. Referral to specialized care is often not successful, and those patients that do seek treatment are likely to have more severe dependence with higher levels of alcohol use and concurrent mental and physical comorbidity [ 4 ].

Identifying and treating early stage AUDs in primary care settings can prevent condition worsening. This may reduce the need for more complex and more expensive specialized care. The high prevalence of AUD in primary health care and the chronic relapsing character of AUD make primary care a suitable and important location for implementing evidence-based interventions. Successful implementation of treatment models requires overcoming multiple barriers. Qualitative studies have identified several of those barriers such as limited time, limited organizational capacity, fear of losing patients, and physicians feeling incompetent in treating AUD [ 8 , 9 , 10 ]. Additionally, a recent systematic review revealed that diagnostic sensitivity of primary care physicians in the identification of AUD was 41.7% and that only in 27.3% alcohol problems were recorded correctly in primary care records [ 11 ].

Several models for primary care have been created to increase identification and treatment of patients with AUD. Of those, the model, screening, brief interventions, and referral to specialized treatment for people with severe AUD (SBIRT [ 12 ]) is most well-known. Multiple systematic reviews exist, confirming its effectiveness [ 13 , 14 , 15 ], although implementation in primary care has been inadequate. Moreover, most studies have looked primarily at SBIRT for the treatment of less severe AUD [ 16 ]. In the treatment of severe AUD, efficacy of SBIRT is limited [ 16 ]. Additionally, many patient referred to specialized care often do not attend as they encounter numerous difficulties in health care systems including stigmatization, costs, lack of information about existing treatments, and lack of non-abstinence-treatment goals [ 7 ]. An effective model of care for improved management of AUD that can be efficiently implemented in primary care settings is required.

Review objective

This proposed systematic review will synthesize and evaluate differential models of care for the management of AUD in primary health care settings. We aim to evaluate the effectiveness of the models of care in increasing engagement and reducing alcohol consumption.

By providing this overview, we aim to guide improvement of design and implementation of evidence-based models of care for the treatment of alcohol use disorder in primary health care settings.

The systematic review is registered in PROSPERO international prospective register of systematic reviews (CRD42019120293) and the current protocol has been written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) recommended for systematic reviews [ 17 ]. A PRISMA-P checklist is included as Additional file  1 .

Eligibility criteria

Criteria for considering studies for this review are classified by the following:

Study design

Both individualized and cluster randomized trials will be included. Masking of patients and/or physicians is not an inclusion criterion as it is often hard to accomplish in these types of studies.

Patients in primary health care who are identified (using screening tools or by primary health care physician) as suffering from AUD (from mild to severe) or hazardous alcohol drinking habits (e.g., comorbidity, concurrent medication use). Eligible patients need to have had formal assessment of AUD with diagnostic tools such as Diagnostic and Statistical Manual of Mental Disorders (DSM-IV/V) or the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and/or formal assessment of hazardous alcohol use assessed by the Comorbidity Alcohol Risk Evaluation Tool (CARET) or the Alcohol Use Disorders Identification test (AUDIT) and/or alcohol use exceeding guideline recommendations to reduce health risks (e.g., US dietary guideline (2015–2020) specifies excessive drinking for women as ≥ 4 standard drinks (SD) on any day and/or ≥ 8 SD per week and for men ≥ 5 SD on any day and/or ≥ 15 SD per week).

Studies evaluating models of care for additional diseases (e.g., other dependencies/mental health) other than AUD are included when they have conducted data analysis on the alcohol use disorder patient data separately or when 80% or more of the included patients have AUD.

Intervention

The intervention should consist of a model of care; therefore, it should include multiple components and cover different stages of the care pathway (e.g., identification of patients, training of staff, modifying access to resources, and treatment). An example is the Chronic Care Model (CCM) which is a primary health care model designed for chronic (relapsing) conditions and involves six elements: linkage to community resources, redesign of health care organization, self-management support, delivery system redesign (e.g., use of non-physician personnel), decision support, and the use of clinical information systems [ 18 , 19 ].

As numerous articles have already assessed the treatment model SBIRT, this model of care will be excluded from our review unless the particular model adds a specific new aspect. Also, the article has to assess the effectiveness of the model rather than assessing the effectiveness of the particular treatment used. Because identification of patients is vital to including them in the trial, a care model that only evaluates either patient identification or treatment without including both will be excluded from this review.

Model effectiveness may be in comparison with the usual care or a different treatment model.

Included studies need to include at least one of the following outcome measures: alcohol consumption, treatment engagement, uptake of pharmacological agents, and/or quality of life.

Solely quantitative research will be included in this systematic review (e.g., randomized controlled trials (RCTs) and cluster RCTs). We will only include peer-reviewed articles.

Restrictions (language/time period)

Studies published in English after 1 January 1998 will be included in this systematic review.

Studies have to be conducted in primary health care settings as such treatment facilities need to be physically in or attached to the primary care clinic. Examples are co-located clinics, veteran health primary care clinic, hospital-based primary care clinic, and community primary health clinics. Specialized primary health care clinics such as human immunodeficiency virus (HIV) clinics are excluded from this systematic review. All studies were included, irrespective of country of origin.

Search strategy and information sources

A comprehensive search will be conducted. The following databases will be consulted: MEDLINE (1946 to present), PsycINFO (1806 to present), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) (1991 to present), and Embase (1947 to present). Initially, the search terms will be kept broad including alcohol use disorder (+synonyms), primary health care, and treatment to minimize the risk of missing any potentially relevant articles. Depending on the number of references attained by this preliminary search, we will add search terms referring to models such as models of care, integrated models, and stepped-care models, to limit the number of articles. Additionally, we will conduct reference searches of relevant reviews and articles. Similarly, a gray literature search will be done with the help of Google and the Gray Matters tool which is a checklist of health-related sites organized by topic. The tool is produced by the Canadian Agency for Drugs and Technologies in Health (CADTH) [ 20 ].

See Additional file  2 for a draft of our search strategy in MEDLINE.

Data collection

The selection of relevant articles is based on several consecutive steps. All references will be managed using EndNote (EndNote version X9 Clarivate Analytics). Initially, duplicates will be removed from the database after which all the titles will be screened with the purpose of discarding clearly irrelevant articles. The remaining records will be included in an abstract and full-text screen. All steps will be done independently by two researchers. Disagreement will lead to consultation of a third researcher.

Data extraction and synthesis

Two researchers will extract data from included records. At the conclusion of data extraction, these two researchers will meet with the lead author to resolve any discrepancies.

In order to follow a structured approach, an extraction form will be used. Key elements of the extraction form are information about design of the study (randomized, blinded, control), type of participants (alcohol use, screening tool used, socio-economic status, severity of alcohol use, age, sex, number of participants), study setting (primary health care setting, VA centers, co-located), type of intervention/model of care (separate elements of the models), type of health care worker (primary, secondary (co-located)), duration of follow-up, outcome measures used in the study, and funding sources. We do not anticipate having sufficient studies for a meta-analysis. As such, we plan to perform a narrative synthesis. We will synthesize the findings from the included articles by cohort characteristics, differential aspects of the intervention, controls, and type of outcome measures.

Sensitivity analyses will be conducted when issues suitable for sensitivity analysis are identified during the review process (e.g., major differences in quality of the included articles).

Potential meta-analysis

In the event that sufficient numbers of effect sizes can be extracted, a meta-analytic synthesis will be performed. We will extract effect sizes from each study accordingly. Two effect sizes will be extracted (and transformed where appropriate). Categorical outcomes will be given in log odds ratios and continuous measures will be converted into standardized mean differences. Variation in effect sizes attributable to real differences (heterogeneity) will be estimated using the inconsistency index ( I 2 ) [ 21 , 22 ]. We anticipate high degrees of variation among effect sizes, as a result moderation and subgroup-analyses will be employed as appropriate. In particular, moderation analysis will focus on the degree of heterogeneity attributable to differences in cohort population (pre-intervention drinking severity, age, etc.), type of model/intervention, and study quality. We anticipate that each model of care will require a sub-group analysis, in which case a separate meta-analysis will be performed for each type of model. Small study effect will be assessed with funnel plots and Egger’s symmetry tests [ 23 ]. When we cannot obtain enough effect sizes for synthesis or when the included studies are too diverse, we will aim to illustrate patterns in the data by graphical display (e.g., bubble plot) [ 24 ].

Critical appraisal of studies

All studies will be critically assessed by two researchers independently using the Revised Cochrane risk-of-bias tool (RoB 2) [ 25 ]. This tool facilitates systematic assessment of the quality of the article per outcome according to the five domains: bias due to (1) the randomization process, (2) deviations from intended interventions, (3) missing outcome data, (4) measurement of the outcome, and (5) selection of the reported results. An additional domain 1b must be used when assessing the randomization process for cluster-randomized studies.

Meta-biases such as outcome reporting bias will be evaluated by determining whether the protocol was published before recruitment of patients. Additionally, trial registries will be checked to determine whether the reported outcome measures and statistical methods are similar to the ones described in the registry. The gray literature search will be of assistance when checking for publication bias; however, completely eliminating the presence of publication bias is impossible.

Similar to article selection, any disagreement between the researchers will lead to discussion and consultation of a third researcher. The strength of the evidence will be graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [ 26 ].

The primary outcome measure of this proposed systematic review is the consumption of alcohol at follow-up. Consumption of alcohol is often quantified in drinking quantity (e.g., number of drinks per week), drinking frequency (e.g., percentage of days abstinent), binge frequency (e.g., number of heavy drinking days), and drinking intensity (e.g., number of drinks per drinking day). Additionally, outcomes such as percentage/proportion included patients that are abstinent or considered heavy/risky drinkers at follow-up. We aim to report all these outcomes. The consumption of alcohol is often self-reported by patients. When studies report outcomes at multiple time points, we will consider the longest follow-up of individual studies as a primary outcome measure.

Depending on the included studies, we will also consider secondary outcome measures such as treatment engagement (e.g., number of visits or pharmacotherapy uptake), economic outcome measures, health care utilization, quality of life assessment (physical/mental), alcohol-related problems/harm, and mental health score for depression or anxiety.

This proposed systematic review will synthesize and evaluate differential models of care for the management of AUD in primary health care settings.

Given the complexities of researching models of care in primary care and the paucity of a focus on AUD treatment, there are likely to be only a few studies that sufficiently address the research question. Therefore, we will do a preliminary search without the search terms for model of care. Additionally, the search for online non-academic studies presents a challenge. However, the Gray Matters tool will be of guidance and will limit the possibility of missing useful studies. Further, due to diversity of treatment models, outcome measures, and limitations in research design, it is possible that a meta-analysis for comparative effectiveness may not be appropriate. Moreover, in the absence of large, cluster randomized controlled trials, it will be difficult to distinguish between the effectiveness of the treatment given and that of the model of care and/or implementation procedure. Nonetheless, we will synthesize the literature and provide a critical evaluation of the quality of the evidence.

This review will assist the design and implementation of models of care for the management of AUD in primary care settings. This review will thus improve the management of AUD in primary health care and potentially increase the uptake of evidence-based interventions for AUD.

Availability of data and materials

Not applicable.

Abbreviations

Alcohol use disorder

Alcohol Use Disorders Identification test

Canadian Agency for Drugs and Technologies in Health

The Comorbidity Alcohol Risk Evaluation

Cochrane Central Register of Controlled Trials

Diagnostic and Statistical Manual of Mental Disorders

Human immunodeficiency virus

10 - International Statistical Classification of Diseases and Related Health Problems

Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols

Screening, brief intervention, referral to specialized treatment

Standard drinks

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Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

Susan A. Rombouts, Eva Louie, Paul Haber & Kirsten C. Morley

NHMRC Centre of Research Excellence in Indigenous Health and Alcohol, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

James Conigrave

Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

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Contributions

KM and PH conceived the presented idea of a systematic review and meta-analysis and helped with the scope of the literature. KM is the senior researcher providing overall guidance and the guarantor of this review. SR developed the background, search strategy, and data extraction form. SR and EL will both be working on the data extraction and risk of bias assessment. SR and JC will conduct the data analysis and synthesize the results. All authors read and approved the final manuscript.

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Correspondence to Kirsten C. Morley .

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Supplementary information

Additional file 1..

PRISMA-P 2015 Checklist.

Additional file 2.

Draft search strategy MEDLINE. Search strategy.

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Rombouts, S.A., Conigrave, J., Louie, E. et al. Evidence-based models of care for the treatment of alcohol use disorder in primary health care settings: protocol for systematic review. Syst Rev 8 , 275 (2019). https://doi.org/10.1186/s13643-019-1157-7

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Binge drinking is a growing public health crisis − a neurobiologist explains how research on alcohol use disorder has shifted

Assistant Professor of Biology, Biomedical Engineering and Pharmacology, Penn State

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Nikki Crowley receives funding from The National Institutes of Health, The Brain and Behavior Research Foundation, and the Penn State Huck Institutes of the Life Sciences endowment funds.

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With the new Amy Winehouse biopic “Back to Black ” in U.S. theaters as of May 17, 2024, the late singer’s relationship with alcohol and drugs is under scrutiny again. In July 2011, Winehouse was found dead in her flat in north London from “death by misadventure” at the age of 27. That’s the official British term used for accidental death caused by a voluntary risk.

Her blood alcohol concentration was 0.416%, more than five times the legal intoxication limit in the U.S. – leading her cause of death to be later adjusted to include “alcohol toxicity” following a second coroner’s inquest.

Nearly 13 years later, alcohol consumption and binge drinking remain a major public health crisis , not just in the U.K. but also in the U.S.

Roughly 1 in 5 U.S. adults report binge drinking at least once a week, with an average of seven drinks per binge episode . This is well over the amount of alcohol thought to produce legal intoxication, commonly defined as a blood alcohol concentration over 0.08% – on average, four drinks in two hours for women, five drinks in two hours for men.

Among women, days of “heavy drinking” increased 41% during the COVID-19 pandemic compared with pre-pandemic levels , and adult women in their 30s and 40s are rapidly increasing their rates of binge drinking , with no evidence of these trends slowing down. Despite efforts to comprehend the overall biology of substance use disorders, scientists’ and physicians’ understanding of the relationship between women’s health and binge drinking has lagged behind.

I am a neurobiologist focused on understanding the chemicals and brain regions that underlie addiction to alcohol . I study how neuropeptides – unique signaling molecules in the prefrontal cortex , one of the key brain regions in decision-making, risk-taking and reward – are altered by repeated exposure to binge alcohol consumption in animal models.

My lab focuses on understanding how things like alcohol alter these brain systems before diagnosable addiction, so that we can better inform efforts toward both prevention and treatment.

The biology of addiction

While problematic alcohol consumption has likely occurred as long as alcohol has existed, it wasn’t until 2011 that the American Society of Addiction Medicine recognized substance addiction as a brain disorder – the same year as Winehouse’s death. A diagnosis of an alcohol use disorder is now used over outdated terms such as labeling an individual as an alcoholic or having alcoholism.

Researchers and clinicians have made great strides in understanding how and why drugs – including alcohol, a drug – alter the brain. Often, people consume a drug like alcohol because of the rewarding and positive feelings it creates, such as enjoying drinks with friends or celebrating a milestone with a loved one. But what starts off as manageable consumption of alcohol can quickly devolve into cycles of excessive alcohol consumption followed by drug withdrawal.

While all forms of alcohol consumption come with health risks, binge drinking appears to be particularly dangerous due to how repeated cycling between a high state and a withdrawal state affect the brain. For example, for some people, alcohol use can lead to “ hangxiety ,” the feeling of anxiety that can accompany a hangover.

Repeated episodes of drinking and drunkenness, coupled with withdrawal, can spiral, leading to relapse and reuse of alcohol. In other words, alcohol use shifts from being rewarding to just trying to prevent feeling bad.

It makes sense. With repeated alcohol use over time, the areas of the brain engaged by alcohol can shift away from those traditionally associated with drug use and reward or pleasure to brain regions more typically engaged during stress and anxiety .

All of these stages of drinking, from the enjoyment of alcohol to withdrawal to the cycles of craving, continuously alter the brain and its communication pathways . Alcohol can affect several dozen neurotransmitters and receptors , making understanding its mechanism of action in the brain complicated.

Work in my lab focuses on understanding how alcohol consumption changes the way neurons within the prefrontal cortex communicate with each other. Neurons are the brain’s key communicator, sending both electrical and chemical signals within the brain and to the rest of your body.

What we’ve found in animal models of binge drinking is that certain subtypes of neurons lose the ability to talk to each other appropriately. In some cases, binge drinking can permanently remodel the brain. Even after a prolonged period of abstinence, conversations between the neurons don’t return to normal .

These changes in the brain can appear even before there are noticeable changes in behavior . This could mean that the neurobiological underpinnings of addiction may take root well before an individual or their loved ones suspect a problem with alcohol.

Researchers like us don’t yet fully understand why some people may be more susceptible to this shift, but it likely has to do with genetic and biological factors, as well as the patterns and circumstances under which alcohol is consumed.

Women are forgotten

While researchers are increasingly understanding the medley of biological factors that underlie addiction, there’s one population that’s been largely overlooked until now: women.

Women may be more likely than men to have some of the most catastrophic health effects caused by alcohol use, such as liver issues, cardiovascular disease and cancer . Middle-aged women are now at the highest risk for binge drinking compared with other populations.

When women consume even moderate levels of alcohol, their risk for various cancers goes up, including digestive, breast and pancreatic cancer , among other health problems – and even death. So the worsening rates of alcohol use disorder in women prompt the need for a greater focus on women in the research and the search for treatments.

Yet, women have long been underrepresented in biomedical research.

It wasn’t until 1993 that clinical research funded by the National Institutes of Health was required to include women as research subjects. In fact, the NIH did not even require sex as a biological variable to be considered by federally funded researchers until 2016. When women are excluded from biomedical research, it leaves doctors and researchers with an incomplete understanding of health and disease, including alcohol addiction.

There is also increasing evidence that addictive substances can interact with cycling sex hormones such as estrogen and progesterone . For instance, research has shown that when estrogen levels are high, like before ovulation, alcohol might feel more rewarding , which could drive higher levels of binge drinking. Currently, researchers don’t know the full extent of the interaction between these natural biological rhythms or other unique biological factors involved in women’s health and propensity for alcohol addiction.

Looking ahead

Researchers and lawmakers are recognizing the vital need for increased research on women’s health. Major federal investments into women’s health research are a vital step toward developing better prevention and treatment options for women.

While women like Amy Winehouse may have been forced to struggle both privately and publicly with substance use disorders and alcohol, the increasing focus of research on addiction to alcohol and other substances as a brain disorder will open new treatment avenues for those suffering from the consequences.

For more information on alcohol use disorder, causes, prevention and treatments, visit the National Institute on Alcohol Abuse and Alcoholism .

• Amy Winehouse
• Binge drinking
• Neurobiology
• Intoxication
• Alcohol consumption
• Alcohol use
• Alcohol use disorder
• COVID-19 pandemic

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Alcohol use disorder with comorbid anxiety disorder: a case report and focused literature review

• Victor Mocanu 1 , 2 &
• Evan Wood   ORCID: orcid.org/0000-0001-9412-6699 1 , 2  

Addiction Science & Clinical Practice volume  17 , Article number:  62 ( 2022 ) Cite this article

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Alcohol use disorder (AUD) and anxiety disorders (AnxD) are prevalent health concerns in clinical practice which frequently co-occur (AUD-AnxD) and compound one another. Concurrent AUD-AnxD poses a challenge for clinical management as approaches to treatment of one disorder may be ineffective or potentially counterproductive for the other disorder.

Case Presentation

We present the case of a middle-aged man with anxiety disorder, AUD, chronic pain, and gamma-hydroxybutyrate use in context of tapering prescribed benzodiazepines who experienced severe alcohol withdrawal episodes during a complicated course of repeated inpatient withdrawal management. After medical stabilization, the patient found significant improvement in symptoms and no return to alcohol use with a regimen of naltrexone targeting his AUD, gabapentin targeting both his AUD and AnxD, and engagement with integrated psychotherapy, Alcoholics Anonymous, and addictions medicine follow-up.

Proper recognition and interventions for AUD and AnxD, ideally with overlapping efficacy, can benefit individuals with comorbid AUD-AnxD. Gabapentin, tobacco cessation, and integrated psychotherapy have preliminary evidence of synergistic effects in AUD-AnxD. Meta-analysis evidence does not support serotoninergic medications (e.g. selective serotonin reuptake inhibitors) which are commonly prescribed in AnxD and mood disorders as their use has not been associated with improved outcomes for AUD-AnxD. Additionally, several double-blind placebo-controlled randomized trials have suggested that serotonergic medications may worsen alcohol-related outcomes in some individuals with AUD. Areas for future investigation are highlighted.

Introduction

Alcohol use disorder (AUD) is a prevalent health concern with a recent epidemiologic survey of the United States indicating a lifetime AUD prevalence of 29.1% and previous 12 month prevalence of 13.9% [ 1 ]. AUD portends an increased risk for diagnosis of a primary anxiety disorder (AnxD) [ 1 ], the definition of which, for the purposes of this case report, aligns with the most recent Canadian clinical practice guidelines for treatment of AnxD to include the DSM-IV umbrella of generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, specific phobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD) [ 2 ]. A quarter or more of individuals with AUD qualify for dual diagnosis with a concurrent primary AnxD in cross-sectional studies [ 3 ]. Furthermore, individuals with comorbid AUD-AnxD fare worse in terms of severity, treatment response, and rate of relapse for both conditions [ 3 ]. Alcohol intoxication, withdrawal, and biopsychosocial consequences of AUD may all contribute to AnxD symptomatology and vice versa, some individuals with a primary AnxD may use alcohol as self-medication. Alternatively, these conditions may share a common neuropathophysiology influenced by environmental factors at the level of brain structures such as the amygdala and neurotransmitters including gamma aminobutyric acid (GABA), endogenous opioids, dopamine, and serotonin, with implications for clinical management [ 3 ].

We present a case report of an individual with comorbid AUD-AnxD and review literature for treatment options to aid clinicians in applying best current evidence for such individuals. Literature review consisted of relevant published studies extracted from author collections and PubMed search with no language or date restrictions for combinations of the following terms: alcohol, alcohol use disorder, anxiety, anxiety disorder, comorbidity, dual diagnosis. In addition, reference lists of selected articles were reviewed for eligible and relevant studies. We find that commonly used treatment options for either AUD or AnxD can have a range of positive and potentially negative impacts for AUD-AnxD which requires accurate understanding of evidence-based care in this area.

A middle-aged man with a longstanding but reportedly well managed history of anxiety disorder dating back to childhood presented for medicalized alcohol withdrawal management services. The individual had a workplace injury approximately 10 years prior that resulted in several spine fractures after which his anxiety deteriorated and he developed AUD. Around this time, an SSRI was trialed for AnxD over several months without benefit and ultimately discontinued. He did not endorse a history for a mood disorder, nor had he received a diagnosis as such. He went on to live with chronic pain and AUD-AnxD for half a decade at which point he had an accidental caustic ingestion resulting in an esophagectomy and jejunostomy tube feeding for one year. His AUD-AnxD subsequently deteriorated further resulting in a prescription of benzodiazepines which were taken for approximately one month until the patient experienced rebound anxiety, worsening of his AUD, and the emergence of gamma-hydroxybutyrate (GHB) use in the context of attempting to discontinue benzodiazepines. The individual sought care through an inpatient withdrawal management program where he had a number of repeated admissions complicated by alcohol withdrawal seizures. He was fortunately stabilized and benzodiazepines were tapered off at which point he was taking no other prescribed medications regularly. Prior to discharge, he was informed of AUD and AnxD treatment options. He was keen to engage with psychosocial supports while starting naltrexone 50 mg once daily and gabapentin 600 mg three times daily.

Eighteen months since discharge, he has found success engaging regularly with substance counselling, Alcoholics Anonymous, and outpatient addictions medicine as well as continuing with naltrexone and gabapentin, the majority of which were intended as synergistic treatments for AUD-AnxD (Fig.  1 ). He reports good health and no alcohol use, and although experiencing cravings, he describes feeling a shift from the sensation of “premeditated” or inevitable relapse as he had in previous attempts at reducing alcohol use.

Venn diagram of current evidence-based interventions reviewed for alcohol use and anxiety disorders

AUD-AnxD indicates comorbid alcohol use disorder and anxiety disorder

* Caution to be exercised with serotoninergic agents given evidence for potential worsening of alcohol outcomes in comorbid AUD-AnxD

Patient perspective

Hi, I’m here to share with you a little bit of the trial and tribulations endured over the many years of addiction. I was an individual who had a seemingly normal life, but under this was a person with undiagnosed mental problems. I was always a drinker who could take or leave drugs, and kept steady employment and had a very loving partner, it wasn’t until an injury in 2009 when my pace with alcohol quickened and I noticed that my consumption was now an everyday affair. Slowly I developed shakes and my day would start with vomiting until I had alcohol of some variety introduced, this continued on for many years and I was now a product of full-blown alcoholism. There now was no job, no partner and very few things that resembled a person who was still an active part of society. I was in and out of hospitals for experiencing multiple seizures and would go weeks with no food or water and begun isolating. I would become so weak physically that I could not move, and would some days awake in with bruises and cuts from either sizing or pass out, I was never sure which. Then I would begin my process of detox recovery house or treatment only to get home and start the vicious cycle again, some time I could stay sober longer if I was using GHB. Nothing would stop my craving and I no longer felt human. I wanted to die… I am proud to inform you that of Dec 12 2020 I have been living a life of sobriety but continue to struggle with cravings, but I use Alcoholics Anonymous as a support and by surrounding like minded people I find myself sober today.

Alcohol use disorder and anxiety

AUD and AnxD are common clinical concerns with evidence-based treatment options. Clinicians should recognize that when two conditions such as AUD and AnxD co-occur, clinical management may require nuance and differ from an approach taken in the context of an individual disorder. As we discuss below, research specifically concerning concurrent AUD-AnxD is still rare despite its high prevalence so data must often be extrapolated. The best available evidence indicates that approaches for treating one disorder may be efficacious, ineffective, or in fact counterproductive for comorbid AUD-AnxD.

AUD treatments

It is critical to recognize and offer proper treatment for AUD even when the primary presenting concern of a client may be an AnxD and vice versa. Whether sequential treatment of AUD and then AnxD, or vice versa, could reduce polypharmacy and iatrogenic harms versus their concurrent treatment remains largely unexplored. Unhealthy alcohol use and AUD are associated with more severe AnxD and conversely abstinence from alcohol is associated with improvement of AnxD [ 3 , 4 ]. To that effect, longitudinal strategies to address AUD may improve AnxD by extension. As conveyed by the reflections of the individual described in the present report, motivational enhancement, formal psychotherapy, mutual self-help interventions such as Alcoholics Anonymous, and supportive settings such as residential treatment facilities, all highlighting the health benefits of reduction or cessation of alcohol use, can serve an important psychosocial role alongside appropriate evidence-based AUD pharmacotherapy [ 5 ]. Nevertheless, the question remains whether certain interventions have additional efficacy in AnxD beyond their efficacy for AUD.

Naltrexone and Acamprosate

Naltrexone is a first-line evidence-based pharmacotherapy which functions as a non-selective opioid antagonist, reducing the rewarding effects of alcohol use mediated by endogenous opioids and downstream neurotransmitters. Studies have demonstrated efficacy for reducing binge drinking (number needed to treat [NNT] = 12) as well as relapse to any alcohol use (NNT = 20) [ 5 ], which motivated our use of naltrexone in the case strongly featuring AUD. To our knowledge, no clinical trial has yet effectively addressed whether naltrexone treatment for AUD can improve a comorbid AnxD, nor an AnxD disorder in isolation.

Acamprosate, which modulates glutamate and GABA signaling disrupted by chronic alcohol use, is another first-line AUD medication effective in preventing relapse to any alcohol use (NNT = 12) [ 5 ]. In terms of comorbid AnxD, some preliminary data suggests benefit of acamprosate for augmentation in various AnxD at doses equivalent or lower than those used in AUD [ 6 ]. However, as with naltrexone, there is a paucity of data to confidently gauge the effect of these first-line AUD medications on a comorbid AnxD and further research would be valuable in this area.

Gabapentinoids

Gabapentinoids such as gabapentin and pregabalin also modulate glutamate and GABA signaling implicated in AnxD and AUD specifically by antagonism of voltage-gated calcium channels. For AUD, gabapentin can be used in the short-term to treat alcohol withdrawal symptoms and in the longer-term to reduce heavy drinking days although efficacy for other endpoints such as reduction in cravings is debated [ 7 ]. Importantly, the data suggest that a key element of clinical efficacy of gabapentin is appropriate patient selection, specifically those with more severe AUD and alcohol withdrawal symptoms. For example, a recent positive randomized clinical trial (RCT) of gabapentin in AUD, which excluded any major psychiatric condition besides PTSD, found that patients with less severe withdrawal tended to fare worse numerically on all indices of alcohol use compared to placebo, although not statistically significant [ 8 ]. To date, some literature exists to support using pregabalin during alcohol withdrawal but data for longer-term treatment of AUD is very limited [ 5 ]. Interestingly, a RCT comparing pregabalin versus naltrexone in subjects with AUD (approximately 15% with comorbid AnxD in each arm) suggested pregabalin was about as effective as naltrexone in terms of AUD outcomes and more effective in reducing phobic anxiety, a subscale of the particular psychiatric questionnaire used in the study [ 9 ]. Further research is needed in this area to better characterize the efficacy of gabapentinoids for treating AnxD specifically in individuals with AUD-AnxD.

The available evidence more strongly supports efficacy of gabapentinoids in treatment of isolated primary AnxD. Gabapentin may be effective for several types of AnxD, [ 2 ] although to our knowledge there is no high-quality data yet available to support gabapentin for treatment of GAD which is frequently encountered in clinical practice. On the other hand, pregabalin has extensive data demonstrating efficacy for GAD as well as SAD, so much so that national practice guidelines currently view pregabalin as a first-line agent for these two conditions [ 2 ].

In sum, the current evidence indicates gabapentinoids have a role in the treatment of both AUD and AnxD and this class of medications may hold promise for treatment of comorbid AUD-AnxD. This emerging evidence supported the prescription of gabapentin in the above case which we believe ultimately contributed to the substantial benefit the individual found with the regimen described. In the interim while further evidence accumulates, a pertinent consideration in the application of gabapentinoids remains the risk of misuse. Gabapentin misuse occurs in the general population, particularly those with substance use disorders, for a variety of reasons including self-medication (e.g. anxiety, pain, and drug withdrawal symptoms) as well as documented recreational use or self-harm [ 10 ]. Even in context of supportive evidence, clinicians should nevertheless be aware of these reports and potential for gabapentinoids to be misused or diverted in treatment of AUD, AnxD, or overlap AUD-AnxD.

Other studied AUD medications

Other medications which have received research attention for AUD include baclofen, topiramate, antipsychotics, and benzodiazepines [ 5 ]. The evidence base for these agents is even more limited and inconclusive in the realm of AUD and comorbid AUD-AnxD. For example, baclofen is a GABA-B agonist medication with a Cochrane systematic review finding conflicting evidence for AUD, comorbid anxiety, and lack of high-quality evidence for use in alcohol withdrawal [ 11 ].

AnxD pharmacotherapies

Psychotropics.

Regarding selective serotonin reuptake inhibitors (SSRIs), the prevalent pharmacologic treatment for AnxD [ 2 ], a Cochrane systematic review of RCTs for comorbid AUD-AnxD found modest improvements in anxiety measures but unreliable or even unhelpful effects on comorbid AUD [ 12 ]. At this juncture, we acknowledge SSRIs are also frequently prescribed according to clinical practice guidelines for treatment of mood disorders that can be challenging to distinguish clinically from AUD and AnxD, which are commonly comorbid [ 13 ]. Nevertheless, meta-analyses demonstrate a lack of benefit of SSRIs in the context of AUD with mood disorder with similar concerns of worsening outcomes [ 14 , 15 , 16 ]. Given the common co-presentation of anxiety and depression among individuals with AUD, the following discussion instead explores the literature from the perspective of AUD outcomes for individuals with any exposure to SSRI or other serotoninergic medications, such as the individual in our case report, regardless of the primary indication for their use. Notably, comorbid mood and anxiety disorders are frequently reported in the available studies and often served as the primary indication for SSRI use.

We note with interest the underappreciated phenomenon of enhanced serotoninergic neurotransmission exacerbating AUD for certain individuals. For example, a secondary analysis of a RCT studying naltrexone for individuals with AUD and comorbid mood and anxiety disorders found prescriptions for SSRI outside of study protocol during follow-up to be associated with worse drinking outcomes for participants randomized to placebo, an effect which was attenuated if participants received naltrexone [ 17 ]. More convincing evidence supporting the potential for harm also exists in several RCTs. In an RCT of the SSRI citalopram for AUD in which mood, AnxD, and both disorders were highly comorbid, participants consumed more alcohol on more days compared to placebo regardless of mood or anxiety measures [ 16 ]. Several trials have also evaluated sertraline in AUD and found that younger participants with more severe AUD in particular tend to fare worse when prescribed an SSRI [ 18 ], moderated in part by the presence of an allele of the serotonin transporter gene favoring greater serotonergic tone [ 18 ]. However, these data are complicated to apply in clinical practice since the predisposing allele may also be found in older participants who happen to develop AUD later in life. Based on allele prevalence in the general US population, Kranzler et al. extrapolated that approximately double the number of individuals with AUD on a population level would be adversely affected by unselected SSRI treatment rather than find benefit [ 18 ]. One small trial comparing combinations of venlafaxine and cognitive behavioral therapy (CBT) for AUD found the only effective treatment for reducing heavy drinking days to be CBT alone with placebo medication, suggesting that selective serotonin and norepinephrine reuptake inhibitors such as venlafaxine may likewise be unhelpful for AUD outcomes [ 19 ].

Trazodone, another psychotropic medication which modulates serotonin transmission, although used for mood disorders and insomnia rather than AnxD, should be addressed in context of AUD. Trazodone is occasionally prescribed with intent as an antidepressant and sleep aid for individuals with AUD but one RCT found a minimal short-term improvement in sleep quality, while also reporting reduced abstinent days, and increased severity of alcohol consumption following withdrawl of trazodone [ 20 ].

In sum, despite the evidence for first-line treatment of isolated AnxD or mood disorders with serotoninergic agents such as SSRIs, clinicians should reconsider and exercise caution in prescribing these medications for patients with comorbid AUD given current observational, RCT, and meta-analysis evidence demonstrating lack of benefit and potential of harm to alcohol use outcomes. In the interim, further investigation is needed to clarify which selected subpopulations in clinical practice would benefit from step-wise approach later involving serotoninergic agents or conversely serotonin antagonists [ 21 ]. Careful use of pharmacologic agents targeting AnxD, such as pregabalin or gabapentin, in tandem with other biopsychosocial strategies may have more of an evidence-based role to play since AnxD are frequently comorbid, have been reported to more frequently precede rather than follow AUD [ 3 ], and are associated with worsening of AUD [ 22 ], suggesting that effective treatment of AnxD may prevent AUD deterioration.

Tobacco cessation

Although not directly relevant to the individual described in our case report, tobacco use may impact clinical outcomes for individuals with AUD-AnxD. Research indicates that weekly smoking in youth is a risk factor for worsening of AUD [ 22 ], and tobacco cessation has been shown to improve anxiety symptoms for both individuals with and without psychiatric disorders [ 23 ]. For instance, a recent meta-analysis demonstrated that the nicotinic receptor partial agonist varenicline was safe and conferred a 25% lower risk of anxiety compared to placebo - likely a result of reduction and cessation in tobacco use [ 24 ]. However, data specific to AUD-AnxD clinical outcomes after tobacco cessation interventions is still limited and inconclusive to date [ 25 ]. In addition to other known broad health benefits such as reduced incidence of cardiovascular disease and cancer, the cessation of tobacco use may also play a synergistic role in treatment of AUD-AnxD.

Psychotherapies

Formal psychotherapy holds promise for addressing the propagating psychosocial factors of AUD and AnxD alone or in addition to pharmacotherapy. In the realm of AnxD, CBT can be equally or more effective than medication alone [ 2 ]. For comorbid AUD-AnxD, motivational interviewing and CBT are effective for both conditions, especially as longer-term modalities with more durable efficacy [ 26 ]. Such targeted and integrated psychotherapy might be particularly effective for individuals with AnxD attempting to self-medicate anxiety symptoms by using alcohol.

Teaching points

AnxD and AUD are prevalent health concerns which frequently co-occur and can compound one another as demonstrated in our report. Their co-occurrence requires a thoughtful approach to treatment given the evidence that treatments of one disorder have been shown to be ineffective or counterproductive for the other disorder (Fig.  1 ). Although evidence is scarce for synergistic treatments of comorbid AUD-AnxD, the literature supports overlapping efficacy of tobacco cessation, use of gabapentinoids, and integrated psychotherapy, the latter two of which were applied with success for the individual in this case report. While the first-line AUD pharmacotherapies naltrexone and acamprosate do not yet have evidence of concurrent benefit for AnxD, effectively treating AUD may yield downstream benefit for AnxD as suggested by treatment response in this report. Lastly, caution should be exercised with serotoninergic medications such as SSRIs as there appears to be underappreciated evidence suggesting that SSRIs are not of benefit in the context of AUD [ 12 ], and may actually worsen alcohol related outcomes for certain individuals [ 16 ]. Further investigation is needed to understand synergistic versus step-wise approaches to treatment of comorbid AUD-AnxD and identification of specific population subgroups which may derive benefit with serotoninergic agonists versus antagonists.

Data availability

Not applicable to case report.

Abbreviations

anxiety disorder

alcohol use disorder

comorbid alcohol use disorder and anxiety disorder

cognitive Behavioral Therapy

gamma aminobutyric acid

generalized anxiety disorder

gamma-hydroxybutyrate

post-traumatic stress disorder

randomized clinical trial

social anxiety disorder

selective serotonin reuptake inhibitors

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Mocanu, V., Wood, E. Alcohol use disorder with comorbid anxiety disorder: a case report and focused literature review. Addict Sci Clin Pract 17 , 62 (2022). https://doi.org/10.1186/s13722-022-00344-z

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Alcohol and Your Brain: The Latest Scientific Insights

Want to protect your brain here's what you need to know about alcohol consumption..

Posted March 18, 2024 | Reviewed by Devon Frye

• What Is Alcoholism?
• Find a therapist to overcome addiction
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• Heavy or excessive alcohol consumption is dangerous to the brain for a number of reasons.
• The impact of mild to moderate alcohol consumption (1-3 drinks a day) on brain function is less clear.

Depending on who you ask, you might be told to drink a few glasses of red wine a day or to avoid alcohol altogether. The reasons for such recommendations are many, but, by and large, they tend to stem from a study someone read about or saw reported in the news.

So why is it so hard to know whether alcohol is good or bad for us—especially for our brains? In this post, we’ll explore the current science and some practical ideas on how to approach the topic.

What Is Alcohol Anyway?

When people talk about drinking “alcohol,” they’re almost always referring to the consumption of ethanol. Ethanol is a natural product that is formed from the fermentation of grains, fruits, and other sources of sugar. It’s found in a wide range of alcoholic beverages including beer, wine, and spirits like vodka, whiskey, rum, and gin.

Evidence for human consumption of alcohol dates back over 10,000 years. Consumption of alcohol has and continues to serve major roles in religious and cultural ceremonies around the world. But unlike most food products, in the last century, alcohol has been wrapped up in nearly perpetual controversy over its moral effects and health implications.

How Does Alcohol Impact the Brain?

As anyone who’s consumed alcohol knows, ethanol can directly influence brain function. Ethanol is classified as a “depressant” because it has a generally slowing effect on brain activity through activation of γ-aminobutyric acid (GABA) pathways.

In an acute sense, consumption of alcohol can lead to uninhibited behavior, sedation, lapses in judgment, and impairments in motor function. At higher levels, the effects can progress to coma and even death.

The Known Brain-Damaging Effects of Excess Alcohol

There is no debate here: Excessively high levels of alcohol consumption over short periods of time are toxic and potentially deadly, specifically because of its effects on the brain.

One critical fact to understand about the overall and brain-specific effects of alcohol is that the entirety of the debate around the risk/benefit ratio concerns mild to moderate alcohol consumption. As it relates to the effects of high amounts of alcohol on the body and brain, the research is consistent: It’s a very bad choice.

High amounts of alcohol use are causal risk factors in the development of disease in the heart, liver, pancreas, and brain (including the brains of children in utero). In fact, 1 in 8 deaths in Americans aged 20-64 is attributable to alcohol use. When it comes to adults, excessive alcohol use can cause multiple well-defined brain issues ranging from short-term confusion to dementia .

What Is “Excessive” or “High” Alcohol Use?

Key to the nuance in the conversation about alcohol use are definitions. Across the board, “excessive” or “high” alcohol use is linked to worse overall and brain health outcomes. So what does that mean?

While definitions can be variable, one way to look at this is the consumption of 4 or more drinks on an occasion (for women) and 5 or more for men. Additionally, excess alcohol is defined as drinking more than 8 drinks a week (women) and 15 a week (men), or consuming alcohol if you are pregnant or younger than age 21.

Beyond this, by definition, consuming enough alcohol to cause a “brownout,” “blackout,” hangover, or other overt brain symptomatology is evidence that the alcohol you’ve consumed is creating problems in your brain. Alcohol use disorder (or alcoholism ) is also a clear issue for the brain. It has been linked to a higher risk for dementia, especially early-onset dementia in a study of 262,000 adults, as well as to smaller brain size .

Is There a “Safe” Amount of Alcohol for the Brain?

In a highly publicized article from Nature Communications , researchers looked at brain imaging data from nearly 37,000 middle-aged to older adults and cross-referenced their brain scans with their reported alcohol consumption. The findings were profound: People who drank more alcohol had smaller brains, even in people drinking only one or two alcoholic beverages a day.

Conversely, other recent data suggest a lower risk for dementia in people consuming a few alcoholic beverages a day. This includes a 2022 study showing that in around 27,000 people, consuming up to 40 grams of alcohol (around 2.5 drinks) a day was linked to a lower risk for dementia versus abstinence in adults over age 60. A much larger study of almost 4 million people in Korea noted that mild to moderate alcohol consumption was linked to a lower risk for dementia compared to non-drinking.

How Do We Make Sense of This Data?

When it comes to the bottom line as it relates to alcohol consumption and brain health, the data are rather solid on some fronts, and a bit less so on others. There’s also the potential for confounding variables, including the fact that many people like to drink alcohol to enjoy and enhance social bonds (which we know are beneficial for the brain). Here’s a summary of what the most recent research is telling us.

• Experiencing transient memory loss, “blackouts,” or hangovers related to alcohol consumption is overt evidence of threats to brain health.
• The impact of mild to moderate alcohol consumption (1-3 drinks a day) on brain function is less clear, but it seems unreasonable to start alcohol use for brain health.

Austin Perlmutter, M.D. , is a board-certified internal medicine physician and the co-author of Brain Wash .

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• Published: 14 May 2024

A burden of proof study on alcohol consumption and ischemic heart disease

• Sinclair Carr   ORCID: orcid.org/0000-0003-0421-3145 1 ,
• Dana Bryazka 1 ,
• Susan A. McLaughlin 1 ,
• Peng Zheng 1 , 2 ,
• Sarasvati Bahadursingh 3 ,
• Aleksandr Y. Aravkin 1 , 2 , 4 ,
• Simon I. Hay   ORCID: orcid.org/0000-0002-0611-7272 1 , 2 ,
• Hilary R. Lawlor 1 ,
• Erin C. Mullany 1 ,
• Christopher J. L. Murray   ORCID: orcid.org/0000-0002-4930-9450 1 , 2 ,
• Sneha I. Nicholson 1 ,
• Jürgen Rehm 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ,
• Gregory A. Roth 1 , 2 , 13 ,
• Reed J. D. Sorensen 1 ,
• Sarah Lewington 3 &
• Emmanuela Gakidou   ORCID: orcid.org/0000-0002-8992-591X 1 , 2  

Nature Communications volume  15 , Article number:  4082 ( 2024 ) Cite this article

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• Cardiovascular diseases
• Epidemiology
• Risk factors

Cohort and case-control data have suggested an association between low to moderate alcohol consumption and decreased risk of ischemic heart disease (IHD), yet results from Mendelian randomization (MR) studies designed to reduce bias have shown either no or a harmful association. Here we conducted an updated systematic review and re-evaluated existing cohort, case-control, and MR data using the burden of proof meta-analytical framework. Cohort and case-control data show low to moderate alcohol consumption is associated with decreased IHD risk – specifically, intake is inversely related to IHD and myocardial infarction morbidity in both sexes and IHD mortality in males – while pooled MR data show no association, confirming that self-reported versus genetically predicted alcohol use data yield conflicting findings about the alcohol-IHD relationship. Our results highlight the need to advance MR methodologies and emulate randomized trials using large observational databases to obtain more definitive answers to this critical public health question.

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Introduction.

It is well known that alcohol consumption increases the risk of morbidity and mortality due to many health conditions 1 , 2 , with even low levels of consumption increasing the risk for some cancers 3 , 4 . In contrast, a large body of research has suggested that low to moderate alcohol intake – compared to no consumption – is associated with a decreased risk of ischemic heart disease (IHD). This has led to substantial epidemiologic and public health interest in the alcohol-IHD relationship 5 , particularly given the high prevalence of alcohol consumption 6 and the global burden of IHD 7 .

Extensive evidence from experimental studies that vary short-term alcohol exposure suggests that average levels of alcohol intake positively affect biomarkers such as apolipoprotein A1, adiponectin, and fibrinogen levels that lower the risk of IHD 8 . In contrast, heavy episodic drinking (HED) may have an adverse effect on IHD by affecting blood lipids, promoting coagulation and thus thrombosis risk, and increasing blood pressure 9 . With effects likely to vary materially by patterns of drinking, alcohol consumption must be considered a multidimensional factor impacting IHD outcomes.

A recent meta-analysis of the alcohol-IHD relationship using individual participant data from 83 observational studies 4 found, among current drinkers, that – relative to drinking less than 50 g/week – any consumption above this level was associated with a lower risk of myocardial infarction (MI) incidence and consumption between >50 and <100 g/week was associated with lower risk of MI mortality. When evaluating other subtypes of IHD excluding MI, the researchers found that consumption between >100 and <250 g/week was associated with a decreased risk of IHD incidence, whereas consumption greater than 350 g/week was associated with an increased risk of IHD mortality. Roerecke and Rehm further observed that low to moderate drinking was not associated with reduced IHD risk when accompanied by occasional HED 10 .

The cohort studies and case-control studies (hereafter referred to as ‘conventional observational studies’) used in these meta-analyses are known to be subject to various types of bias when used to estimate causal relationships 11 . First, neglecting to separate lifetime abstainers from former drinkers, some of whom may have quit due to developing preclinical symptoms (sometimes labeled ‘sick quitters’ 12 , 13 ), and to account for drinkers who reduce their intake as a result of such symptoms may introduce reverse causation bias 13 . That is, the risk of IHD in, for example, individuals with low to moderate alcohol consumption may be lower when compared to IHD risk in sick quitters, not necessarily because intake at this level causes a reduction in risk but because sick quitters are at higher risk of IHD. Second, estimates can be biased because of measurement error in alcohol exposure resulting from inaccurate reporting, random fluctuation in consumption over time (random error), or intentional misreporting of consumption due, for example, to social desirability effects 14 (systematic error). Third, residual confounding may bias estimates if confounders of the alcohol-IHD relationship, such as diet or physical activity, have not been measured accurately (e.g., only via a self-report questionnaire) or accounted for. Fourth, because alcohol intake is a time-varying exposure, time-varying confounding affected by prior exposure must be accounted for 15 . To date, only one study that used a marginal structural model to appropriately adjust for time-varying confounding found no association between alcohol consumption and MI risk 16 . Lastly, if exposure to a risk factor, such as alcohol consumption, did not happen at random – even if all known confounders of the relationship between alcohol and IHD were perfectly measured and accounted for – the potential for unmeasured confounders persists and may bias estimates 11 .

In recent years, the analytic method of Mendelian randomization (MR) has been widely adopted to quantify the causal effects of risk factors on health outcomes 17 , 18 , 19 . MR uses single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for the exposure of interest. A valid IV should fulfill the following three assumptions: it must be associated with the risk factor (relevance assumption); there must be no common causes of the IV and the outcome (independence assumption); and the IV must affect the outcome only through the exposure (exclusion restriction or ‘no horizontal pleiotropy’ assumption) 20 , 21 . If all three assumptions are fulfilled, estimates derived from MR are presumed to represent causal effects 22 . Several MR studies have quantified the association between alcohol consumption and cardiovascular disease 23 , including IHD, using genes known to impact alcohol metabolism (e.g., ADH1B/C and ALDH2 24 ) or SNP combinations from genome-wide association studies 25 . In contrast to the inverse associations found in conventional observational studies, MR studies have found either no association or a harmful relationship between alcohol consumption and IHD 26 , 27 , 28 , 29 , 30 , 31 .

To advance the knowledge base underlying our understanding of this major health issue – critical given the worldwide ubiquity of alcohol use and of IHD – there is a need to systematically review and critically re-evaluate all available evidence on the relationship between alcohol consumption and IHD risk from both conventional observational and MR studies.

The burden of proof approach, developed by Zheng et al. 32 , is a six-step meta-analysis framework that provides conservative estimates and interpretations of risk-outcome relationships. The approach systematically tests and adjusts for common sources of bias defined according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria: representativeness of the study population, exposure assessment, outcome ascertainment, reverse causation, control for confounding, and selection bias. The key statistical tool to implement the approach is MR-BRT (meta-regression—Bayesian, regularized, trimmed 33 ), a flexible meta-regression tool that does not impose a log-linear relationship between the risk and outcome, but instead uses a spline ensemble to model non-linear relationships. MR-BRT also algorithmically detects and trims outliers in the input data, takes into account different reference and alternative exposure intervals in the data, and incorporates unexplained between-study heterogeneity in the uncertainty surrounding the mean relative risk (RR) curve (henceforth ‘risk curve’). For those risk-outcome relationships that meet the condition of statistical significance using conventionally estimated uncertainty intervals (i.e., without incorporating unexplained between-study heterogeneity), the burden of proof risk function (BPRF) is derived by calculating the 5th (if harmful) or 95th (if protective) quantile risk curve – inclusive of between-study heterogeneity – closest to the log RR of 0. The resulting BPRF is a conservative interpretation of the risk-outcome relationship based on all available evidence. The BPRF represents the smallest level of excess risk for a harmful risk factor or reduced risk for a protective risk factor that is consistent with the data, accounting for between-study heterogeneity. To quantify the strength of the evidence for the alcohol-IHD relationship, the BPRF can be summarized in a single metric, the risk-outcome score (ROS). The ROS is defined as the signed value of the average log RR of the BPRF across the 15th to 85th percentiles of alcohol consumption levels observed across available studies. The larger a positive ROS value, the stronger the alcohol-IHD association. For ease of interpretation, the ROS is converted into a star rating from one to five. A one-star rating (ROS < 0) indicates a weak alcohol-IHD relationship, and a five-star rating (ROS > 0.62) indicates a large effect size and strong evidence. Publication and reporting bias are evaluated with Egger’s regression and by visual inspection with funnel plots 34 . Further conceptual and technical details of the burden of proof approach are described in detail elsewhere 32 .

Using the burden of proof approach, we systematically re-evaluate all available eligible evidence from cohort, case-control, and MR studies published between 1970 and 2021 to conservatively quantify the dose-response relationship between alcohol consumption and IHD risk, calculated relative to risk at zero alcohol intake (i.e., current non-drinking, including lifetime abstinence or former use). We pool the evidence from all conventional observational studies combined, as well as individually for all three study designs, to estimate mean IHD risk curves. Based on patterns of results established by previous meta-analyses 4 , 35 , we also use data from conventional observational studies to estimate risk curves by IHD endpoint (morbidity or mortality) and further by sex, in addition to estimating risk curves for MI overall and by endpoint. We follow PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines 36 through all stages of this study (Supplementary Information section  1 , Fig.  S1 and Tables  S1 and S2 ) and comply with GATHER (Guidelines on Accurate and Transparent Health Estimates Reporting) recommendations 37 (Supplementary Information section  2 , Table  S3 ). The main findings and research implications of this work are summarized in Table  1 .

We updated the systematic review on the dose-response relationship between alcohol consumption and IHD previously conducted for the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 1 . Of 4826 records identified in our updated systematic review (4769 from databases/registers and 57 by citation search and known literature), 11 were eligible based on our inclusion criteria and were included. In total, combined with the results of the previous systematic reviews 1 , 38 , information from 95 cohort studies 26 , 27 , 29 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 27 case-control studies 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , and five MR studies 26 , 27 , 28 , 29 , 31 was included in our meta-analysis (see Supplementary Information section  1 , Fig.  S1 , for the PRISMA diagram). Details on the extracted effect sizes, the design of each included study, underlying data sources, number of participants, duration of follow-up, number of cases and controls, and bias covariates that were evaluated and potentially adjusted for can be found in the Supplementary Information Sections  4 , 5 , and 6 .

Table  2 summarizes key metrics of each risk curve modeled, including estimates of mean RR and 95% UI (inclusive of between-study heterogeneity) at select alcohol exposure levels, the exposure level and RR and 95% UI at the nadir (i.e., lowest RR), the 85th percentile of exposure observed in the data and its corresponding RR and 95% UI, the BPRF averaged at the 15th and 85th percentile of exposure, the average excess risk or risk reduction according to the exposure-averaged BPRF, the ROS, the associated star rating, the potential presence of publication or reporting bias, and the number of studies included.

We found large variation in the association between alcohol consumption and IHD by study design. When we pooled the results of cohort and case-control studies, we observed an inverse association between alcohol at average consumption levels and IHD risk; that is, drinking average levels of alcohol was associated with a reduced IHD risk relative to drinking no alcohol. In contrast, we did not find a statistically significant association between alcohol consumption and IHD risk when pooling results from MR studies. When we subset the conventional observational studies to those reporting on IHD by endpoint, we found no association between alcohol consumption and IHD morbidity or mortality due to large unexplained heterogeneity between studies. When we further subset those studies that reported effect size estimates by sex, we found that average alcohol consumption levels were inversely associated with IHD morbidity in males and in females, and with IHD mortality in males but not in females. When we analyzed only the studies that reported on MI, we found significant inverse associations between average consumption levels and MI overall and with MI morbidity. Visualizations of the risk curves for morbidity and mortality of IHD and MI are provided in Supplementary Information Section  9 (Figs.  S2a –c, S3a –c, and S4a–c ). Among all modeled risk curves for which a BPRF was calculated, the ROS ranged from −0.40 for MI mortality to 0.20 for MI morbidity. In the Supplementary Information, we also provide details on the RR and 95% UIs with and without between-study heterogeneity associated with each 10 g/day increase in consumption for each risk curve (Table  S10 ), the parameter specifications of the model (Tables  S11 and S12 ), and each risk curve from the main analysis estimated without trimming 10% of the data (Fig.  S5a–l and Table  S13 ).

Risk curve derived from conventional observational study data

The mean risk curve and 95% UI were first estimated by combining all evidence from eligible cohort and case-control studies that quantified the association between alcohol consumption and IHD risk. In total, information from 95 cohort studies and 27 case-control studies combining data from 7,059,652 participants were included. In total, 243,357 IHD events were recorded. Thirty-seven studies quantified the association between alcohol consumption and IHD morbidity only, and 44 studies evaluated only IHD mortality. The estimated alcohol-IHD association was adjusted for sex and age in all but one study. Seventy-five studies adjusted the effect sizes for sex, age, smoking, and at least four other covariates. We adjusted our risk curve for whether the study sample was under or over 50 years of age, whether the study outcome was consistent with the definition of IHD (according to the International Classification of Diseases [ICD]−9: 410-414; and ICD-10: I20-I25) or related to specified subtypes of IHD, whether the outcome was ascertained by self-report only or by at least one other measurement method, whether the study accounted for risk for reverse causation, whether the reference group was non-drinkers (including lifetime abstainers and former drinkers), and whether effect sizes were adjusted (1) for sex, age, smoking, and at least four other variables, (2) for apolipoprotein A1, and (3) for cholesterol, as these bias covariates were identified as significant by our algorithm.

Pooling all data from cohort and case-control studies, we found that alcohol consumption was inversely associated with IHD risk (Fig.  1 ). The risk curve was J-shaped – without crossing the null RR of 1 at high exposure levels – with a nadir of 0.69 (95% UI: 0.48–1.01) at 23 g/day. This means that compared to individuals who do not drink alcohol, the risk of IHD significantly decreases with increasing consumption up to 23 g/day, followed by a risk reduction that becomes less pronounced. The average BPRF calculated between 0 and 45 g/day of alcohol intake (the 15th and 85th percentiles of the exposure range observed in the data) was 0.96. Thus, when between-study heterogeneity is accounted for, a conservative interpretation of the evidence suggests drinking alcohol across the average intake range is associated with an average decrease in the risk of IHD of at least 4% compared to drinking no alcohol. This corresponds to a ROS of 0.04 and a star rating of two, which suggests that the association – on the basis of the available evidence – is weak. Although we algorithmically identified and trimmed 10% of the data to remove outliers, Egger’s regression and visual inspection of the funnel plot still indicated potential publication or reporting bias.

The panels show the log(relative risk) function, the relative risk function, and a modified funnel plot showing the residuals (relative to 0) on the x-axis and the estimated standard error that includes the reported standard error and between-study heterogeneity on the y-axis. RR relative risk, UI uncertainty interval. Source data are provided as a Source Data file.

Risk curve derived from case-control study data

Next, we estimated the mean risk curve and 95% UI for the relationship between alcohol consumption and IHD by subsetting the data to case-control studies only. We included a total of 27 case-control studies (including one nested case-control study) with data from 60,914 participants involving 16,892 IHD cases from Europe ( n  = 15), North America ( n  = 6), Asia ( n  = 4), and Oceania ( n  = 2). Effect sizes were adjusted for sex and age in most studies ( n  = 25). Seventeen of these studies further adjusted for smoking and at least four other covariates. The majority of case-control studies accounted for the risk of reverse causation ( n  = 25). We did not adjust our risk curve for bias covariates, as our algorithm did not identify any as significant.

Evaluating only data from case-control studies, we observed a J-shaped relationship between alcohol consumption and IHD risk, with a nadir of 0.65 (0.50–0.85) at 23 g/day (Fig.  2 ). The inverse association between alcohol consumption and IHD risk reversed at an intake level of 61 g/day. In other words, alcohol consumption between >0 and 60 g/day was associated with a lower risk compared to no consumption, while consumption at higher levels was associated with increased IHD risk. However, the curve above this level is flat, implying that the association between alcohol and increased IHD risk is the same between 61 and 100 g/day, relative to not drinking any alcohol. The BPRF averaged across the exposure range between the 15th and 85th percentiles, or 0–45 g/day, was 0.87, which translates to a 13% average reduction in IHD risk across the average range of consumption. This corresponds to a ROS of 0.14 and a three-star rating. After trimming 10% of the data, no potential publication or reporting bias was found.

The panels show the log(relative risk) function, the relative risk function, and a modified funnel plot showing the residuals (relative to 0) on the x-axis and the estimated standard deviation that includes the reported standard deviation and between-study heterogeneity on the y-axis. RR relative risk, UI uncertainty interval. Source data are provided as a Source Data file.

Risk curve derived from cohort study data

We also estimated the mean risk curve and 95% UI for the relationship between alcohol consumption and IHD using only data from cohort studies. In total, 95 cohort studies – of which one was a retrospective cohort study – with data from 6,998,738 participants were included. Overall, 226,465 IHD events were recorded. Most data were from Europe ( n  = 43) and North America ( n  = 33), while a small number of studies were conducted in Asia ( n  = 14), Oceania ( n  = 3), and South America ( n  = 2). The majority of studies adjusted effect sizes for sex and age ( n  = 76). Fifty-seven of these studies also adjusted for smoking and at least four other covariates. Out of all cohort studies included, 88 accounted for the risk of reverse causation. We adjusted our risk curve for whether the study outcome was consistent with the definition of IHD or related to specified subtypes of IHD, and whether effect sizes were adjusted for apolipoprotein A1, as these bias covariates were identified as significant by our algorithm.

When only data from cohort studies were evaluated, we found a J-shaped relationship between alcohol consumption and IHD risk that did not cross the null RR of 1 at high exposure levels, with a nadir of 0.69 (0.47–1.01) at 23 g/day (Fig.  3 ). The shape of the risk curve was almost identical to the curve estimated with all conventional observational studies (i.e., cohort and case-control studies combined). When we calculated the average BPRF of 0.95 between the 15th and 85th percentiles of observed alcohol exposure (0–50 g/day), we found that alcohol consumption across the average intake range was associated with an average reduction in IHD risk of at least 5%. This corresponds to a ROS of 0.05 and a two-star rating. We identified potential publication or reporting bias after 10% of the data were trimmed.

Risk curve derived from Mendelian randomization study data

Lastly, we pooled evidence on the relationship between genetically predicted alcohol consumption and IHD risk from MR studies. Four MR studies were considered eligible for inclusion in our main analysis, with data from 559,708 participants from China ( n  = 2), the Republic of Korea ( n  = 1), and the United Kingdom ( n  = 1). Overall, 22,134 IHD events were recorded. Three studies used the rs671 ALDH2 genotype found in Asian populations, one study additionally used the rs1229984 ADH1B variant, and one study used the rs1229984 ADH1B Arg47His variant and a combination of 25 SNPs as IVs. All studies used the two-stage least squares (2SLS) method to estimate the association, and one study additionally applied the inverse-variance-weighted (IVW) method and multivariable MR (MVMR). For the study that used multiple methods to estimate effect sizes, we used the 2SLS estimates for our main analysis. Further details on the included studies are provided in Supplementary Information section  4 (Table  S6 ). Due to limited input data, we elected not to trim 10% of the observations. We adjusted our risk curve for whether the endpoint of the study outcome was mortality and whether the associations were adjusted for sex and/or age, as these bias covariates were identified as significant by our algorithm.

We did not find any significant association between genetically predicted alcohol consumption and IHD risk using data from MR studies (Fig.  4 ). No potential publication or reporting bias was detected.

As sensitivity analyses, we modeled risk curves with effect sizes estimated from data generated by Lankester et al. 28 using IVW and MVMR methods. We also used effect sizes from Biddinger et al. 31 , obtained using non-linear MR with the residual method, instead of those from Lankester et al. 28 in our main model (both were estimated with UK Biobank data) to estimate a risk curve. Again, we did not find a significant association between genetically predicted alcohol consumption and IHD risk (see Supplementary Information Section  10 , Fig.  S6a–c and Table  S14 ). To test for consistency with the risk curve we estimated using all included cohort studies, we also pooled the conventionally estimated effect sizes provided in the four MR studies. We did not observe an association between alcohol consumption and IHD risk due to large unexplained heterogeneity between studies (see Supplementary Information Section  10 , Fig.  S7, and Table  S14 ). Lastly, we pooled cohort studies that included data from China, the Republic of Korea, and the United Kingdom to account for potential geographic influences. Again, we did not find a significant association between alcohol consumption and IHD risk (see Supplementary Information Section  10 , Fig.  S8, and Table  S14 ).

Conventional observational and MR studies published to date provide conflicting estimates of the relationship between alcohol consumption and IHD. We conducted an updated systematic review and conservatively re-evaluated existing evidence on the alcohol-IHD relationship using the burden of proof approach. We synthesized evidence from cohort and case-control studies combined and separately and from MR studies to assess the dose-response relationship between alcohol consumption and IHD risk and to compare results across different study designs. It is anticipated that the present synthesis of evidence will be incorporated into upcoming iterations of GBD.

Our estimate of the association between genetically predicted alcohol consumption and IHD runs counter to our estimates from the self-report data and those of other previous meta-analyses 4 , 35 , 158 that pooled conventional observational studies. Based on the conservative burden of proof interpretation of the data, our results suggested an inverse association between alcohol and IHD when all conventional observational studies were pooled (alcohol intake was associated with a reduction in IHD risk by an average of at least 4% across average consumption levels; two-star rating). In evaluating only cohort studies, we again found an inverse association between alcohol consumption and IHD (alcohol intake was associated with a reduction in IHD risk by an average of at least 5% at average consumption levels; two-star rating). In contrast, when we pooled only case-control studies, we estimated that average levels of alcohol consumption were associated with at least a 13% average decrease in IHD risk (three-star rating), but the inverse association reversed when consumption exceeded 60 g/day, suggesting that alcohol above this level is associated with a slight increase in IHD risk. Our analysis of the available evidence from MR studies showed no association between genetically predicted alcohol consumption and IHD.

Various potential biases and differences in study designs may have contributed to the conflicting findings. In our introduction, we summarized important sources of bias in conventional observational studies of the association between alcohol consumption and IHD. Of greatest concern are residual and unmeasured confounding and reverse causation, the effects of which are difficult to eliminate in conventional observational studies. By using SNPs within an IV approach to predict exposure, MR – in theory – eliminates these sources of bias and allows for more robust estimates of causal effects. Bias may still occur, however, when using MR to estimate the association between alcohol and IHD 159 , 160 . There is always the risk of horizontal pleiotropy in MR – that is, the genetic variant may affect the outcome via pathways other than exposure 161 . The IV assumption of exclusion restriction is, for example, violated if only a single measurement of alcohol consumption is used in MR 162 ; because alcohol consumption varies over the life course, the gene directly impacts IHD through intake at time points other than that used in the MR analysis. To date, MR studies have not succeeded in separately capturing the multidimensional effects of alcohol intake on IHD risk (i.e., effects of average alcohol consumption measured through frequency-quantity, in addition to the effects of HED) 159 because the genes used to date only target average alcohol consumption that encompasses intake both at average consumption levels and HED. In other words, the instruments used are not able to separate out the individual effects of these two different dimensions of alcohol consumption on IHD risk using MR. Moreover, reverse causation may occur through cross-generational effects 160 , 163 , as the same genetic variants predispose both the individual and at least one of his or her parents to (increased) alcohol consumption. In this situation, IHD risk could be associated with the parents’ genetically predicted alcohol consumption and not with the individual’s own consumption. None of the MR studies included accounted for cross-generational effects, which possibly introduced bias in the effect estimates. It is important to note that bias by ancestry might also occur in conventional observational studies 164 . In summary, estimates of the alcohol-IHD association are prone to bias in all three study designs, limiting inferences of causation.

The large difference in the number of available MR versus conventional observational studies, the substantially divergent results derived from the different study types, and the rapidly developing field of MR clearly argue for further investigation of MR as a means to quantify the association between alcohol consumption and IHD risk. Future studies should investigate non-linearity in the relationship using non-linear MR methods. The residual method, commonly applied in non-linear MR studies such as Biddinger et al. 31 , assumes a constant, linear relationship between the genetic IV and the exposure in the study population; a strong assumption that may result in biased estimates and inflated type I error rates if the relationship varies by population strata 165 . However, by log-transforming the exposure, the relationships between the genetic IV and the exposure as expressed on a logarithmic scale may be more homogeneous across strata, possibly reducing the bias effect of violating the assumption of a constant, linear relationship. Alternatively, or in conjunction, the recently developed doubly ranked method, which obviates the need for this assumption, could be used 166 . Since methodology for non-linear MR is an active field of study 167 , potential limitations of currently available methods should be acknowledged and latest guidelines be followed 168 . Future MR studies should further (i) employ sensitivity analyses such as the MR weighted median method 169 to relax the exclusion restriction assumption that may be violated, as well as applying other methods such as the MR-Egger intercept test; (ii) use methods such as g-estimation of structural mean models 162 to adequately account for temporal variation in alcohol consumption in MR, and (iii) attempt to disaggregate the effects of alcohol on IHD by dimension in MR, potentially through the use of MVMR 164 . General recommendations to overcome common MR limitations are described in greater detail elsewhere 159 , 163 , 170 , 171 and should be carefully considered. With respect to prospective cohort studies used to assess the alcohol-IHD relationship, they should, at a minimum: (i) adjust the association between alcohol consumption and IHD for all potential confounders identified, for example, using a causal directed acyclic graph, and (ii) account for reverse causation introduced by sick quitters and by drinkers who changed their consumption. If possible, they should also (iii) use alcohol biomarkers as objective measures of alcohol consumption instead of or in addition to self-reported consumption to reduce bias through measurement error, (iv) investigate the association between IHD and HED, in addition to average alcohol consumption, and (v) when multiple measures of alcohol consumption and potential confounders are available over time, use g-methods to reduce bias through confounding as fully as possible within the limitations of the study design. However, some bias – due, for instance, to unmeasured confounding in conventional observational and to horizontal pleiotropy in MR studies – is likely inevitable, and the interpretation of estimates should be appropriately cautious, in accordance with the methods used in the study.

With the introduction of the Moderate Alcohol and Cardiovascular Health Trial (MACH15) 172 , randomized controlled trials (RCTs) have been revisited as a way to study the long-term effects of low to moderate alcohol consumption on cardiovascular disease, including IHD. In 2018, soon after the initiation of MACH15, the National Institutes of Health terminated funding 173 , reportedly due to concerns about study design and irregularities in the development of funding opportunities 174 . Although MACH15 was terminated, its initiation represented a previously rarely considered step toward investigating the alcohol-IHD relationship using an RCT 175 . However, while the insights from an RCT are likely to be invaluable, the implementation is fraught with potential issues. Due to the growing number of studies suggesting increased disease risk, including cancer 3 , 4 , associated with alcohol use even at very low levels 176 , the use of RCTs to study alcohol consumption is ethically questionable 177 . A less charged approach could include the emulation of target trials 178 using existing observational data (e.g., from large-scale prospective cohort studies such as the UK Biobank 179 , Atherosclerosis Risk in Communities Study 180 , or the Framingham Heart Study 181 ) in lieu of real trials to gather evidence on the potential cardiovascular effects of alcohol. Trials like MACH15 can be emulated, following the proposed trial protocols as closely as the observational dataset used for the analysis allows. Safety and ethical concerns, such as those related to eligibility criteria, initiation/increase in consumption, and limited follow-up duration, will be eliminated because the data will have already been collected. This framework allows for hypothetical trials investigating ethically challenging or even untenable questions, such as the long-term effects of heavy (episodic) drinking on IHD risk, to be emulated and inferences to broader populations drawn.

There are several limitations that must be considered when interpreting our findings. First, record screening for our systematic review was not conducted in a double-blinded fashion. Second, we did not have sufficient evidence to estimate and examine potential differential associations of alcohol consumption with IHD risk by beverage type or with MI endpoints by sex. Third, despite using a flexible meta-regression tool that overcame several limitations common to meta-analyses, the results of our meta-analysis were only as good as the quality of the studies included. We were able, however, to address the issue of varying quality of input data by adjusting for bias covariates that corresponded to core study characteristics in our analyses. Fourth, because we were only able to include one-sample MR studies that captured genetically predicted alcohol consumption, statistical power may be lower than would have been possible with the inclusion of two-sample MR studies, and studies that directly estimated gene-IHD associations were not considered 23 . Finally, we were not able to account for participants’ HED status when pooling effect size estimates from conventional observational studies. Given established differences in IHD risk for drinkers with and without HED 35 and the fact that more than one in three drinkers reports HED 6 , we would expect that the decreased average risk we found at moderate levels of alcohol consumption would be attenuated (i.e., approach the IHD risk of non-drinkers) if the presence of HED was taken into account.

Using the burden of proof approach 32 , we conservatively re-evaluated the dose-response relationship between alcohol consumption and IHD risk based on existing cohort, case-control, and MR data. Consistent with previous meta-analyses, we found that alcohol at average consumption levels was inversely associated with IHD when we pooled conventional observational studies. This finding was supported when aggregating: (i) all studies, (ii) only cohort studies, (iii) only case-control studies, (iv) studies examining IHD morbidity in females and males, (v) studies examining IHD mortality in males, and (vi) studies examining MI morbidity. In contrast, we found no association between genetically predicted alcohol consumption and IHD risk based on data from MR studies. Our confirmation of the conflicting results derived from self-reported versus genetically predicted alcohol use data highlights the need to advance methodologies that will provide more definitive answers to this critical public health question. Given the limitations of randomized trials, we advocate using advanced MR techniques and emulating target trials using observational data to generate more conclusive evidence on the long-term effects of alcohol consumption on IHD risk.

This study was approved by the University of Washington IRB Committee (study #9060).

The burden of proof approach is a six-step framework for conducting meta-analysis 32 : (1) data from published studies that quantified the dose-response relationship between alcohol consumption and ischemic heart disease (IHD) risk were systematically identified and obtained; (2) the shape of the mean relative risk (RR) curve (henceforth ‘risk curve’) and associated uncertainty was estimated using a quadratic spline and algorithmic trimming of outliers; (3) the risk curve was tested and adjusted for biases due to study attributes; (4) unexplained between-study heterogeneity was quantified, adjusting for within-study correlation and number of studies included; (5) the evidence for small-study effects was evaluated to identify potential risks of publication or reporting bias; and (6) the burden of proof risk function (BPRF) – a conservative interpretation of the average risk across the exposure range found in the data – was estimated relative to IHD risk at zero alcohol intake. The BPRF was converted to a risk-outcome score (ROS) that was mapped to a star rating from one to five to provide an intuitive interpretation of the magnitude and direction of the dose-response relationship between alcohol consumption and IHD risk.

We calculated the mean RR and 95% uncertainty intervals (UIs) for IHD associated with levels of alcohol consumption separately with all evidence available from conventional observational studies and from Mendelian randomization (MR) studies. For the risk curves that met the condition of statistical significance when the conventional 95% UI that does not include unexplained between-study heterogeneity was evaluated, we calculated the BPRF, ROS, and star rating. Based on input data from conventional observational studies, we also estimated these metrics by study design (cohort studies, case-control studies), and by IHD endpoint (morbidity, mortality) for both sexes (females, males) and sex-specific. For sex-stratified analyses, we only considered studies that reported effect sizes for both females and males to allow direct comparison of IHD risk across different exposure levels; however, we did not collect information about the method each study used to determine sex. We also estimated risk curves for myocardial infarction (MI), overall and by endpoint, using data from conventional observational studies. As a comparison, we also estimated each risk curve without trimming 10% of the input data. We did not consider MI as an outcome or disaggregate findings by sex or endpoint for MR studies due to insufficient data.

With respect to MR studies, several statistical methods are typically used to estimate the associations between genetically predicted exposure and health outcomes (e.g., two-stage least squares [2SLS], inverse-variance-weighted [IVW], multivariable Mendelian randomization [MVMR]). For our main analysis synthesizing evidence from MR studies, we included the reported effect sizes estimated using 2SLS if a study applied multiple methods because this method was common to all included studies. In sensitivity analyses, we used the effect sizes obtained by other MR methods (i.e., IVW, MVMR, and non-linear MR) and estimated the mean risk curve and uncertainty. We also pooled conventionally estimated effect sizes from MR studies to allow comparison with the risk curve estimated with cohort studies. Due to limited input data from MR studies, we elected not to trim 10% of the observations. Furthermore, we estimated the risk curve from cohort studies with data from countries that corresponded to those included in MR studies (China, the Republic of Korea, and the United Kingdom). Due to a lack of data, we were unable to estimate a risk curve from case-control studies in these geographic regions.

Conducting the systematic review

In step one of the burden of proof approach, data for the dose-response relationship between alcohol consumption and IHD risk were systematically identified, reviewed, and extracted. We updated a previously published systematic review 1 in PubMed that identified all studies evaluating the dose-response relationship between alcohol consumption and risk of IHD morbidity or mortality from January 1, 1970, to December 31, 2019. In our update, we additionally considered all studies up to and including December 31, 2021, for eligibility. We searched articles in PubMed on March 21, 2022, with the following search string: (alcoholic beverage[MeSH Terms] OR drinking behavior[MeSH Terms] OR “alcohol”[Title/Abstract]) AND (Coronary Artery Disease[Mesh] OR Myocardial Ischemia[Mesh] OR atherosclerosis[Mesh] OR Coronary Artery Disease[TiAb] OR Myocardial Ischemia[TiAb] OR cardiac ischemia[TiAb] OR silent ischemia[TiAb] OR atherosclerosis Outdent [TiAb] OR Ischemic heart disease[TiAb] OR Ischemic heart disease[TiAb] OR coronary heart disease[TiAb] OR myocardial infarction[TiAb] OR heart attack[TiAb] OR heart infarction[TiAb]) AND (Risk[MeSH Terms] OR Odds Ratio[MeSH Terms] OR “risk”[Title/Abstract] OR “odds ratio”[Title/Abstract] OR “cross-product ratio”[Title/Abstract] OR “hazards ratio”[Title/Abstract] OR “hazard ratio”[Title/Abstract]) AND (“1970/01/01”[PDat]: “2021/12/31”[PDat]) AND (English[LA]) NOT (animals[MeSH Terms] NOT Humans[MeSH Terms]). Studies were eligible for inclusion if they met all of the following criteria: were published between January 1, 1970, and December 31, 2021; were a cohort study, case-control study, or MR study; described an association between alcohol consumption and IHD and reported an effect size estimate (relative risk, hazard ratio, odds ratio); and used a continuous dose as exposure of alcohol consumption. Studies were excluded if they met any of the following criteria: were an aggregate study (meta-analysis or pooled cohort); utilized a study design not designated for inclusion in this analysis: not a cohort study, case-control study, or MR study; were a duplicate study: the underlying sample of the study had also been analyzed elsewhere (we always considered the analysis with the longest follow-up for cohort studies or the most recently published analysis for MR studies); did not report on the exposure of interest: reported on combined exposure of alcohol and drug use or reported alcohol consumption in a non-continuous way; reported an outcome that was not IHD or a composite outcome that included but was not limited to IHD, or outcomes lacked specificity, such as cardiovascular disease or all-cause mortality; were not in English; and were animal studies. All screenings of titles and abstracts of identified records, as well as full texts of potentially eligible studies, and extraction of included studies, were done by a single reviewer (SC or HL) independently. If eligible, studies were extracted for study characteristics, exposure, outcome, adjusted confounders, and effect sizes and their uncertainty. While the previous systematic review only considered cohort and case-control studies, our update also included MR studies. We chose to consider only ‘one-sample’ MR studies, i.e., those in which genes, risk factors, and outcomes were measured in the same participants, and not ‘two-sample’ MR studies in which two different samples were used for the MR analysis so that we could fully capture study-specific information. We re-screened previously identified records for MR studies to consider all published MR studies in the defined time period. We also identified and included in our sensitivity analysis an MR study published in 2022 31 which used a non-linear MR method to estimate the association between genetically predicted alcohol consumption and IHD. When eligible studies reported both MR and conventionally estimated effect sizes (i.e., for the association between self-reported alcohol consumption and IHD risk), we extracted both. If studies used the same underlying sample and investigated the same outcome in the same strata, we included the study that had the longest follow-up. This did not apply when the same samples were used in conventional observational and MR studies, because they were treated separately when estimating the risk curve of alcohol consumption and IHD. Continuous exposure of alcohol consumption was defined as a frequency-quantity measure 182 and converted to g/day. IHD was defined according to the International Classification of Diseases (ICD)−9, 410-414, and ICD-10, I20-I25.

The raw data were extracted with a standardized extraction sheet (see Supplementary Information Section  3 , Table  S4 ). For conventional observational studies, when multiple effect sizes were estimated from differently adjusted regression models, we used those estimated with the model reported to be fully adjusted or the one with the most covariates. In the majority of studies, alcohol consumption was categorized based on the exposure range available in the data. If the lower end of a categorical exposure range (e.g., <10 g/day) of an effect size was not specified in the input data, we assumed that this was 0 g/day. If the upper end was not specified (e.g., >20 g/day), it was calculated by multiplying the lower end of the categorical exposure range by 1.5. When the association between alcohol and IHD risk was reported as a linear slope, the average consumption level in the sample was multiplied by the logarithm of the effect size to effectively render it categorical. From the MR study which employed non-linear MR 31 , five effect sizes and their uncertainty were extracted at equal intervals across the reported range of alcohol exposure using WebPlotDigitizer. To account for the fact that these effect sizes were derived from the same non-linear risk curve, we adjusted the extracted standard errors by multiplying them by the square root of five (i.e., the number of extracted effect sizes). Details on data sources are provided in Supplementary Information Section  4 .

Estimating the shape of the risk-outcome relationship

In step two, the shape of the dose-response relationship (i.e., ‘signal’) between alcohol consumption and IHD risk was estimated relative to risk at zero alcohol intake. The meta-regression tool MR-BRT (meta-regression—Bayesian, regularized, trimmed), developed by Zheng et al. 33 , was used for modeling. To allow for non-linearity, thus relaxing the common assumption of a log-linear relationship, a quadratic spline with two interior knots was used for estimating the risk curve 33 . We used the following three risk measures from included studies: RRs, odds ratios (ORs), and hazard ratios (HRs). ORs were treated as equivalent to RRs and HRs based on the rare outcome assumption. To counteract the potential influence of knot placement on the shape of the risk curve when using splines, an ensemble model approach was applied. Fifty component models with random knot placements across the exposure domain were computed. These were combined into an ensemble by weighting each model based on model fit and variation (i.e., smoothness of fit to the data). To prevent bias from outliers, a robust likelihood-based approach was applied to trim 10% of the observations. Technical details on estimating the risk curve, use of splines, the trimming procedure, the ensemble model approach, and uncertainty estimation are described elsewhere 32 , 33 . Details on the model specifications for each risk curve are provided in Supplementary Information section  8 . We first estimated each risk curve without trimming input data to visualize the shape of the curve, which informed knot placement and whether to set a left and/or right linear tail when data were sparse at low or high exposure levels (see Supplementary Information Section  10 , Fig.  S5a–l ).

Testing and adjusting for biases across study designs and characteristics

In step three, the risk curve was tested and adjusted for systematic biases due to study attributes. According to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria 183 , the following six bias sources were quantified: representativeness of the study population, exposure assessment, outcome ascertainment, reverse causation, control for confounding, and selection bias. Representativeness was quantified by whether the study sample came from a location that was representative of the underlying geography. Exposure assessment was quantified by whether alcohol consumption was recorded once or more than once in conventional observational studies, or with only one or multiple SNPs in MR studies. Outcome ascertainment was quantified by whether IHD was ascertained by self-report only or by at least one other measurement method. Reverse causation was quantified by whether increased IHD risk among participants who reduced or stopped drinking was accounted for (e.g., by separating former drinkers from lifetime abstainers). Control for confounding factors was quantified by which and how many covariates the effect sizes were adjusted for (i.e., through stratification, matching, weighting, or standardization). Because the most adjusted effect sizes in each study were extracted in the systematic review process and thus may have been adjusted for mediators, we additionally quantified a bias covariate for each of the following potential mediators of the alcohol-IHD relationship: body mass index, blood pressure, cholesterol (excluding high-density lipoprotein cholesterol), fibrinogen, apolipoprotein A1, and adiponectin. Selection bias was quantified by whether study participants were selected and included based on pre-existing disease states. We also quantified and considered as possible bias covariates whether the reference group was non-drinkers, including lifetime abstainers and former drinkers; whether the sample was under or over 50 years of age; whether IHD morbidity, mortality, or both endpoints were used; whether the outcome mapped to IHD or referred only to subtypes of IHD; whether the outcome mapped to MI; and what study design (cohort or case-control) was used when conventional observational studies were pooled. Details on quantified bias covariates for all included studies are provided in Supplementary Information section  5 (Tables  S7 and S8 ). Using a Lasso approach 184 , the bias covariates were first ranked. They were then included sequentially, based on their ranking, as effect modifiers of the ‘signal’ obtained in step two in a linear meta-regression. Significant bias covariates were included in modeling the final risk curve. Technical details of the Lasso procedure are described elsewhere 32 .

Quantifying between-study heterogeneity, accounting for heterogeneity, uncertainty, and small number of studies

In step four, the between-study heterogeneity was quantified, accounting for heterogeneity, uncertainty, and small number of studies. In a final linear mixed-effects model, the log RRs were regressed against the ‘signal’ and selected bias covariates, with a random intercept to account for within-study correlation and a study-specific random slope with respect to the ‘signal’ to account for between-study heterogeneity. A Fisher information matrix was used to estimate the uncertainty associated with between-study heterogeneity 185 because heterogeneity is easily underestimated or may be zero when only a small number of studies are available. We estimated the mean risk curve with a 95% UI that incorporated between-study heterogeneity, and we additionally estimated a 95% UI without between-study heterogeneity as done in conventional meta-regressions (see Supplementary Information Section  7 , Table  S10 ). The 95% UI incorporating between-study heterogeneity was calculated from the posterior uncertainty of the fixed effects (i.e., the ‘signal’ and selected bias covariates) and the 95% quantile of the between-study heterogeneity. The estimate of between-study heterogeneity and the estimate of the uncertainty of the between-study heterogeneity were used to determine the 95% quantile of the between-study heterogeneity. Technical details of quantifying uncertainty of between-study heterogeneity are described elsewhere 32 .

Evaluating potential for publication or reporting bias

In step five, the potential for publication or reporting bias was evaluated. The trimming algorithm used in step two helps protect against these biases, so risk curves found to have publication or reporting bias using the following methods were derived from data that still had bias even after trimming. Publication or reporting bias was evaluated using Egger’s regression 34 and visual inspection using funnel plots. Egger’s regression tested for a significant correlation between residuals of the RR estimates and their standard errors. Funnel plots showed the residuals of the risk curve against their standard errors. We reported publication or reporting bias when identified.

Estimating the burden of proof risk function

In step six, the BPRF was calculated for risk-outcome relationships that were statistically significant when evaluating the conventional 95% UI without between-study heterogeneity. The BPRF is either the 5th (if harmful) or the 95th (if protective) quantile curve inclusive of between-study heterogeneity that is closest to the RR line at 1 (i.e., null); it indicates a conservative estimate of a harmful or protective association at each exposure level, based on the available evidence. The mean risk curve, 95% UIs (with and without between-study heterogeneity), and BPRF (where applicable) are visualized along with included effect sizes using the midpoint of each alternative exposure range (trimmed data points are marked with a red x), with alcohol consumption in g/day on the x-axis and (log)RR on the y-axis.

We calculated the ROS as the average log RR of the BPRF between the 15th and 85th percentiles of alcohol exposure observed in the study data. The ROS summarizes the association of the exposure with the health outcome in a single measure. A higher, positive ROS indicates a larger association, while a negative ROS indicates a weak association. The ROS is identical for protective and harmful risks since it is based on the magnitude of the log RR. For example, a mean log BPRF between the 15th and 85th percentiles of exposure of −0.6 (protective association) and a mean log BPRF of 0.6 (harmful association) would both correspond to a ROS of 0.6. The ROS was then translated into a star rating, representing a conservative interpretation of all available evidence. A star rating of 1 (ROS: <0) indicates weak evidence of an association, a star rating of 2 (ROS: 0–0.14) indicates a >0–15% increased or >0–13% decreased risk, a star rating of 3 (ROS: >0.14–0.41) indicates a >15–50% increased or >13–34% decreased risk, a star rating of 4 (ROS: >0.41–0.62) indicates a >50–85% increased or >34–46% decreased risk, and a star rating of 5 (ROS: >0.62) indicates a >85% increased or >46% decreased risk.

Statistics & reproducibility

The statistical analyses conducted in this study are described above in detail. No statistical method was used to predetermine the sample size. When analyzing data from cohort and case-control studies, we excluded 10% of observations using a trimming algorithm; when analyzing data from MR studies, we did not exclude any observations. As all data used in this meta-analysis were from observational studies, no experiments were conducted, and no randomization or blinding took place.

Reporting summary

Further information on research design is available in the  Nature Portfolio Reporting Summary linked to this article.

Data availability

The findings from this study were produced using data extracted from published literature. The relevant studies were identified through a systematic literature review and can all be accessed online as referenced in the current paper 26 , 27 , 28 , 29 , 31 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 . Further details on the relevant studies can be found on the GHDx website ( https://ghdx.healthdata.org/record/ihme-data/gbd-alcohol-ihd-bop-risk-outcome-scores ). Study characteristics of all relevant studies included in the analyses are also provided in Supplementary Information Section  4 (Tables  S5 and S6 ). The template of the data collection form is provided in Supplementary Information section  3 (Table  S4 ). The source data includes processed data from these studies that underlie our estimates. Source data are provided with this paper.

Code availability

Analyses were carried out using R version 4.0.5 and Python version 3.10.9. All code used for these analyses is publicly available online ( https://github.com/ihmeuw-msca/burden-of-proof ).

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Acknowledgements

Research reported in this publication was supported by the Bill & Melinda Gates Foundation [OPP1152504]. S.L. has received grants or contracts from the UK Medical Research Council [MR/T017708/1], CDC Foundation [project number 996], World Health Organization [APW No 2021/1194512], and is affiliated with the NIHR Oxford Biomedical Research Centre. The University of Oxford’s Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) is supported by core grants from the Medical Research Council [Clinical Trial Service Unit A310] and the British Heart Foundation [CH/1996001/9454]. The CTSU receives research grants from industry that are governed by University of Oxford contracts that protect its independence and has a staff policy of not taking personal payments from industry. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders. The funders of the study had no role in study design, data collection, data analysis, data interpretation, writing of the final report, or the decision to publish.

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S.C., S.A.M., S.I.H., and E.C.M. managed the estimation or publications process. S.C. wrote the first draft of the manuscript. S.C. had primary responsibility for applying analytical methods to produce estimates. S.C. and H.R.L. had primary responsibility for seeking, cataloging, extracting, or cleaning data; designing or coding figures and tables. S.C., D.B., S.B., E.C.M., S.I.N., J.R., and R.J.D.S. provided data or critical feedback on data sources. S.C., D.B., P.Z., A.Y.A., S.I.N., and R.J.D.S. developed methods or computational machinery. S.C., D.B., P.Z., S.B., S.I.H., E.C.M., C.J.L.M., S.I.N., J.R., R.J.D.S., S.L., and E.G. provided critical feedback on methods or results. S.C., D.B., S.A.M., S.B., S.I.H., C.J.L.M., J.R., G.A.R., S.L., and E.G. drafted the work or revised it critically for important intellectual content. S.C., S.I.H., E.C.M., and E.G. managed the overall research enterprise.

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G.A.R. has received support for this manuscript from the Bill and Melinda Gates Foundation [OPP1152504]. S.L. has received grants or contracts from the UK Medical Research Council [MR/T017708/1], CDC Foundation [project number 996], World Health Organization [APW No 2021/1194512], and is affiliated with the NIHR Oxford Biomedical Research Centre. The University of Oxford’s Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) is supported by core grants from the Medical Research Council [Clinical Trial Service Unit A310] and the British Heart Foundation [CH/1996001/9454]. The CTSU receives research grants from industry that are governed by University of Oxford contracts that protect its independence and has a staff policy of not taking personal payments from industry. All other authors declare no competing interests.

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Carr, S., Bryazka, D., McLaughlin, S.A. et al. A burden of proof study on alcohol consumption and ischemic heart disease. Nat Commun 15 , 4082 (2024). https://doi.org/10.1038/s41467-024-47632-7

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Alcohol is dangerous. so is ‘alcoholic.’.

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Researcher explains the human toll of language that makes addiction feel worse 

When Mass General transplant hepatologist Wei Zhang says he wants his colleagues to think before they speak, he has the tragedy of a recent patient in mind.

Admitted to intensive care for advanced alcohol-associated liver disease, the 36-year-old woman hid the truth when asked about her drinking. “She was like, ‘No, I quit over a year ago, I didn’t drink at all,’” said Zhang, also director of the hospital’s Alcohol-Associated Liver Disease Clinic. “But we have tools that can detect the use of alcohol in the past three, four weeks.”

The patient, who had been traumatized by years of physical abuse, was denied a liver transplant, in part because she withheld information about her alcohol use. Her death days later was “a consequence of stigma,” Zhang said. Patients too often “feel they’re being judged and may fear that their condition is seen as a result of personal failing rather than a medical issue that needs treatment.” 

Amid increases in high-risk drinking and alcohol-associated liver disease across the country , he hopes  that new research can help complete the years-long work of erasing that stigma, saving lives in the process. 

For decades, medical terminology has labeled liver disease and other alcohol-related conditions as “alcoholic”: alcoholic liver disease, alcoholic hepatitis, alcoholic cirrhosis, alcoholic pancreatitis. Meanwhile, clinicians and administrators have described patients as addicts and alcoholics. 

More recently, specialists and advocates have sought with some success to revise how we talk about substance use and those struggling to overcome it, not just to reduce stigma but also to combat bias among medical professionals. According to the  National Institute on Alcohol Abuse and Alcoholism , the term “alcohol use disorder” is now preferable to “alcohol abuse,” “alcohol dependence,” and “alcoholism.”

“Emphasizing non-stigmatizing language is crucial not only for fostering honesty but also for supporting the overall treatment process and patient outcomes,” Zhang said. 

The new study is a step toward that goal. Inspired by his patients, Zhang set out to observe whether the terminology used by institutions that treat alcohol-associated liver disease reflects or rejects stigma. He and his team reviewed messages on more than 100 accredited liver transplant center websites, along with language used by addiction psychiatry sites. They found that almost nine of 10 transplant center websites use stigmatizing language such as “alcoholic.” Less than half of addiction psychiatry websites do the same.

“The gap between professional society recommendations and actual practice is concerning, since patients frequently use these online resources for information which can significantly influence their behavior and perceptions about alcohol-associated liver disease,” Zhang said.

Zhang’s anti-stigma efforts are grounded in strong evidence, according to Harvard Medical School psychiatrist  John F. Kelly , who published “Does It Matter How We Refer to Individuals with Substance-Related Conditions?” in 2009.

“Emphasizing non-stigmatizing language is crucial not only for fostering honesty but also for supporting the overall treatment process and patient outcomes.”

“Drug use disorder and alcohol use disorder are among the most stigmatized conditions universally across different societies because people feel that it’s self-induced — that people are to blame because they put it in their body,” said Kelly, also the founder of Mass General’s  Recovery Research Institute . “Just because they made that decision initially, doesn’t mean they plan on becoming addicted.”

In the 2009 study, Kelly and his colleagues described patients to more than 600 clinicians, alternating between “substance abuser” and “having a substance use disorder.” Those in the latter category were viewed more sympathetically and as more worthy of treatment. 

“I was quite surprised just how susceptible they were,” Kelly said. “These were passionate, dedicated clinicians. They were still susceptible to the negative punitive bias.”

They still are today, Zhang’s findings suggest. 

“We are very good at seeing patients with liver disease but if we add this behavioral mental disorder, it is somewhat out of our scope,” he said. “I think education could at least have them be more familiar with this topic and be willing to at least listen to the adoption and use of non-stigmatizing language.” 

“I think education could at least have them be more familiar with this topic and be willing to at least listen to the adoption and use of non-stigmatizing language.”

Building on the new study, Zhang has recommended to healthcare institutions and professional societies that they implement website feedback mechanisms and carry out regular content audits to guard against potentially harmful language. 

“The steps we are recommending should not only help to align clinical practice with sound language guidelines, but also foster a more empathetic and supportive healthcare environment for patients,” he said. 

Zhang also said healthcare institutions should look to leverage technology to support adoption of appropriate standards.

His team is collaborating with Mass General’s Research Patient Data Registry to obtain de-identified patient records, which they plan to review for instances of stigmatizing language. He hopes the process will help researchers quantify the prevalence of such language in clinical notes and identify patterns that can inform interventions. The team will also analyze the association of stigmatizing language with patient outcomes.  

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How Binge Drinking Shifted Research On Alcohol Use Disorders

"roughly 1 in 5 u.s. adults report binge drinking at least once a week.".

With the new Amy Winehouse biopic “Back to Black ” in U.S. theaters as of May 17, 2024, the late singer’s relationship with alcohol and drugs is under scrutiny again. In July 2011, Winehouse was found dead in her flat in north London from “death by misadventure” at the age of 27. That’s the official British term used for accidental death caused by a voluntary risk.

Her blood alcohol concentration was 0.416%, more than five times the legal intoxication limit in the U.S. – leading her cause of death to be later adjusted to include “alcohol toxicity” following a second coroner’s inquest.

Nearly 13 years later, alcohol consumption and binge drinking remain a major public health crisis , not just in the U.K. but also in the U.S.

Roughly 1 in 5 U.S. adults report binge drinking at least once a week, with an average of seven drinks per binge episode . This is well over the amount of alcohol thought to produce legal intoxication, commonly defined as a blood alcohol concentration over 0.08% – on average, four drinks in two hours for women, five drinks in two hours for men.

Among women, days of “heavy drinking” increased 41% during the COVID-19 pandemic compared with pre-pandemic levels , and adult women in their 30s and 40s are rapidly increasing their rates of binge drinking , with no evidence of these trends slowing down. Despite efforts to comprehend the overall biology of substance use disorders, scientists’ and physicians’ understanding of the relationship between women’s health and binge drinking has lagged behind.

I am a neurobiologist focused on understanding the chemicals and brain regions that underlie addiction to alcohol . I study how neuropeptides – unique signaling molecules in the prefrontal cortex , one of the key brain regions in decision-making, risk-taking and reward – are altered by repeated exposure to binge alcohol consumption in animal models.

My lab focuses on understanding how things like alcohol alter these brain systems before diagnosable addiction, so that we can better inform efforts toward both prevention and treatment.

The Biology Of Addiction

While problematic alcohol consumption has likely occurred as long as alcohol has existed, it wasn’t until 2011 that the American Society of Addiction Medicine recognized substance addiction as a brain disorder – the same year as Winehouse’s death. A diagnosis of an alcohol use disorder is now used over outdated terms such as labeling an individual as an alcoholic or having alcoholism.

Researchers and clinicians have made great strides in understanding how and why drugs – including alcohol, a drug – alter the brain. Often, people consume a drug like alcohol because of the rewarding and positive feelings it creates, such as enjoying drinks with friends or celebrating a milestone with a loved one. But what starts off as manageable consumption of alcohol can quickly devolve into cycles of excessive alcohol consumption followed by drug withdrawal.

While all forms of alcohol consumption come with health risks, binge drinking appears to be particularly dangerous due to how repeated cycling between a high state and a withdrawal state affect the brain. For example, for some people, alcohol use can lead to “ hangxiety ,” the feeling of anxiety that can accompany a hangover.

Repeated episodes of drinking and drunkenness, coupled with withdrawal, can spiral, leading to relapse and reuse of alcohol. In other words, alcohol use shifts from being rewarding to just trying to prevent feeling bad.

It makes sense. With repeated alcohol use over time, the areas of the brain engaged by alcohol can shift away from those traditionally associated with drug use and reward or pleasure to brain regions more typically engaged during stress and anxiety .

All of these stages of drinking, from the enjoyment of alcohol to withdrawal to the cycles of craving, continuously alter the brain and its communication pathways . Alcohol can affect several dozen neurotransmitters and receptors , making understanding its mechanism of action in the brain complicated.

Work in my lab focuses on understanding how alcohol consumption changes the way neurons within the prefrontal cortex communicate with each other. Neurons are the brain’s key communicator, sending both electrical and chemical signals within the brain and to the rest of your body.

What we’ve found in animal models of binge drinking is that certain subtypes of neurons lose the ability to talk to each other appropriately. In some cases, binge drinking can permanently remodel the brain. Even after a prolonged period of abstinence, conversations between the neurons don’t return to normal .

These changes in the brain can appear even before there are noticeable changes in behavior . This could mean that the neurobiological underpinnings of addiction may take root well before an individual or their loved ones suspect a problem with alcohol.

Researchers like us don’t yet fully understand why some people may be more susceptible to this shift, but it likely has to do with genetic and biological factors, as well as the patterns and circumstances under which alcohol is consumed.

Women are Forgotten

While researchers are increasingly understanding the medley of biological factors that underlie addiction, there’s one population that’s been largely overlooked until now: women.

Women may be more likely than men to have some of the most catastrophic health effects caused by alcohol use, such as liver issues, cardiovascular disease and cancer . Middle-aged women are now at the highest risk for binge drinking compared with other populations.

When women consume even moderate levels of alcohol, their risk for various cancers goes up, including digestive, breast and pancreatic cancer , among other health problems – and even death. So the worsening rates of alcohol use disorder in women prompt the need for a greater focus on women in the research and the search for treatments.

Yet, women have long been underrepresented in biomedical research.

It wasn’t until 1993 that clinical research funded by the National Institutes of Health was required to include women as research subjects. In fact, the NIH did not even require sex as a biological variable to be considered by federally funded researchers until 2016. When women are excluded from biomedical research, it leaves doctors and researchers with an incomplete understanding of health and disease, including alcohol addiction.

There is also increasing evidence that addictive substances can interact with cycling sex hormones such as estrogen and progesterone . For instance, research has shown that when estrogen levels are high, like before ovulation, alcohol might feel more rewarding , which could drive higher levels of binge drinking. Currently, researchers don’t know the full extent of the interaction between these natural biological rhythms or other unique biological factors involved in women’s health and propensity for alcohol addiction.

Looking Ahead

Researchers and lawmakers are recognizing the vital need for increased research on women’s health. Major federal investments into women’s health research are a vital step toward developing better prevention and treatment options for women.

While women like Amy Winehouse may have been forced to struggle both privately and publicly with substance use disorders and alcohol, the increasing focus of research on addiction to alcohol and other substances as a brain disorder will open new treatment avenues for those suffering from the consequences.

For more information on alcohol use disorder, causes, prevention and treatments, visit the National Institute on Alcohol Abuse and Alcoholism .

Nikki Crowley is an Assistant Professor of Biology, Biomedical Engineering and Pharmacology at Penn State. This article is republished from The Conversation under a Creative Commons license . Read the original article .

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Module 9: Substance-Related and Addictive Disorders

Case studies: substance-abuse disorders, learning objectives.

• Identify substance abuse disorders in case studies

Case Study: Benny

The following story comes from Benny, a 28-year-old living in the Metro Detroit area, USA. Read through the interview as he recounts his experiences dealing with addiction and recovery.

Q : How long have you been in recovery?

Benny : I have been in recovery for nine years. My sobriety date is April 21, 2010.

Q: What can you tell us about the last months/years of your drinking before you gave up?

Benny : To sum it up, it was a living hell. Every day I would wake up and promise myself I would not drink that day and by the evening I was intoxicated once again. I was a hardcore drug user and excessively taking ADHD medication such as Adderall, Vyvance, and Ritalin. I would abuse pills throughout the day and take sedatives at night, whether it was alcohol or a benzodiazepine. During the last month of my drinking, I was detached from reality, friends, and family, but also myself. I was isolated in my dark, cold, dorm room and suffered from extreme paranoia for weeks. I gave up going to school and the only person I was in contact with was my drug dealer.

Q : What was the final straw that led you to get sober?

Benny : I had been to drug rehab before and always relapsed afterwards. There were many situations that I can consider the final straw that led me to sobriety. However, the most notable was on an overcast, chilly October day. I was on an Adderall bender. I didn’t rest or sleep for five days. One morning I took a handful of Adderall in an effort to take the pain of addiction away. I knew it wouldn’t, but I was seeking any sort of relief. The damage this dosage caused to my brain led to a drug-induced psychosis. I was having small hallucinations here and there from the chemicals and a lack of sleep, but this time was different. I was in my own reality and my heart was racing. I had an awful reaction. The hallucinations got so real and my heart rate was beyond thumping. That day I ended up in the psych ward with very little recollection of how I ended up there. I had never been so afraid in my life. I could have died and that was enough for me to want to change.

Q : How was it for you in the early days? What was most difficult?

Benny : I had a different experience than most do in early sobriety. I was stuck in a drug-induced psychosis for the first four months of sobriety. My life was consumed by Alcoholics Anonymous meetings every day and sometimes two a day. I found guidance, friendship, and strength through these meetings. To say early sobriety was fun and easy would be a lie. However, I did learn it was possible to live a life without the use of drugs and alcohol. I also learned how to have fun once again. The most difficult part about early sobriety was dealing with my emotions. Since I started using drugs and alcohol that is what I used to deal with my emotions. If I was happy I used, if I was sad I used, if I was anxious I used, and if I couldn’t handle a situation I used. Now that the drinking and drugs were out of my life, I had to find new ways to cope with my emotions. It was also very hard leaving my old friends in the past.

Q : What reaction did you get from family and friends when you started getting sober?

Benny : My family and close friends were very supportive of me while getting sober. Everyone close to me knew I had a problem and were more than grateful when I started recovery. At first they were very skeptical because of my history of relapsing after treatment. But once they realized I was serious this time around, I received nothing but loving support from everyone close to me. My mother was especially helpful as she stopped enabling my behavior and sought help through Alcoholics Anonymous. I have amazing relationships with everyone close to me in my life today.

Q : Have you ever experienced a relapse?

Benny : I experienced many relapses before actually surrendering. I was constantly in trouble as a teenager and tried quitting many times on my own. This always resulted in me going back to the drugs or alcohol. My first experience with trying to become sober, I was 15 years old. I failed and did not get sober until I was 19. Each time I relapsed my addiction got worse and worse. Each time I gave away my sobriety, the alcohol refunded my misery.

Q : How long did it take for things to start to calm down for you emotionally and physically?

Benny : Getting over the physical pain was less of a challenge. It only lasted a few weeks. The emotional pain took a long time to heal from. It wasn’t until at least six months into my sobriety that my emotions calmed down. I was so used to being numb all the time that when I was confronted by my emotions, I often freaked out and didn’t know how to handle it. However, after working through the 12 steps of AA, I quickly learned how to deal with my emotions without the aid of drugs or alcohol.

Q : How hard was it getting used to socializing sober?

Benny : It was very hard in the beginning. I had very low self-esteem and had an extremely hard time looking anyone in the eyes. But after practice, building up my self-esteem and going to AA meetings, I quickly learned how to socialize. I have always been a social person, so after building some confidence I had no issue at all. I went back to school right after I left drug rehab and got a degree in communications. Upon taking many communication classes, I became very comfortable socializing in any situation.

Q : Was there anything surprising that you learned about yourself when you stopped drinking?

Benny : There are surprises all the time. At first it was simple things, such as the ability to make people smile. Simple gifts in life such as cracking a joke to make someone laugh when they are having a bad day. I was surprised at the fact that people actually liked me when I wasn’t intoxicated. I used to think people only liked being around me because I was the life of the party or someone they could go to and score drugs from. But after gaining experience in sobriety, I learned that people actually enjoyed my company and I wasn’t the “prick” I thought I was. The most surprising thing I learned about myself is that I can do anything as long as I am sober and I have sufficient reason to do it.

Q : How did your life change?

Benny : I could write a book to fully answer this question. My life is 100 times different than it was nine years ago. I went from being a lonely drug addict with virtually no goals, no aspirations, no friends, and no family to a productive member of society. When I was using drugs, I honestly didn’t think I would make it past the age of 21. Now, I am 28, working a dream job sharing my experience to inspire others, and constantly growing. Nine years ago I was a hopeless, miserable human being. Now, I consider myself an inspiration to others who are struggling with addiction.

Q : What are the main benefits that emerged for you from getting sober?

Benny : There are so many benefits of being sober. The most important one is the fact that no matter what happens, I am experiencing everything with a clear mind. I live every day to the fullest and understand that every day I am sober is a miracle. The benefits of sobriety are endless. People respect me today and can count on me today. I grew up in sobriety and learned a level of maturity that I would have never experienced while using. I don’t have to rely on anyone or anything to make me happy. One of the greatest benefits from sobriety is that I no longer live in fear.

Case Study: Lorrie

Figure 1. Lorrie.

Lorrie Wiley grew up in a neighborhood on the west side of Baltimore, surrounded by family and friends struggling with drug issues. She started using marijuana and “popping pills” at the age of 13, and within the following decade, someone introduced her to cocaine and heroin. She lived with family and occasional boyfriends, and as she puts it, “I had no real home or belongings of my own.”

Before the age of 30, she was trying to survive as a heroin addict. She roamed from job to job, using whatever money she made to buy drugs. She occasionally tried support groups, but they did not work for her. By the time she was in her mid-forties, she was severely depressed and felt trapped and hopeless. “I was really tired.” About that time, she fell in love with a man who also struggled with drugs.

They both knew they needed help, but weren’t sure what to do. Her boyfriend was a military veteran so he courageously sought help with the VA. It was a stroke of luck that then connected Lorrie to friends who showed her an ad in the city paper, highlighting a research study at the National Institute of Drug Abuse (NIDA), part of the National Institutes of Health (NIH.) Lorrie made the call, visited the treatment intake center adjacent to the Johns Hopkins Bayview Medical Center, and qualified for the study.

“On the first day, they gave me some medication. I went home and did what addicts do—I tried to find a bag of heroin. I took it, but felt no effect.” The medication had stopped her from feeling it. “I thought—well that was a waste of money.” Lorrie says she has never taken another drug since. Drug treatment, of course is not quite that simple, but for Lorrie, the medication helped her resist drugs during a nine-month treatment cycle that included weekly counseling as well as small cash incentives for clean urine samples.

To help with heroin cravings, every day Lorrie was given the medication buprenorphine in addition to a new drug. The experimental part of the study was to test if a medication called clonidine, sometimes prescribed to help withdrawal symptoms, would also help prevent stress-induced relapse. Half of the patients received daily buprenorphine plus daily clonidine, and half received daily buprenorphine plus a daily placebo. To this day, Lorrie does not know which one she received, but she is deeply grateful that her involvement in the study worked for her.

The study results? Clonidine worked as the NIDA investigators had hoped.

“Before I was clean, I was so uncertain of myself and I was always depressed about things. Now I am confident in life, I speak my opinion, and I am productive. I cry tears of joy, not tears of sadness,” she says. Lorrie is now eight years drug free. And her boyfriend? His treatment at the VA was also effective, and they are now married. “I now feel joy at little things, like spending time with my husband or my niece, or I look around and see that I have my own apartment, my own car, even my own pots and pans. Sounds silly, but I never thought that would be possible. I feel so happy and so blessed, thanks to the wonderful research team at NIDA.”

• Liquor store. Authored by : Fletcher6. Located at : https://commons.wikimedia.org/wiki/File:The_Bunghole_Liquor_Store.jpg . License : CC BY-SA: Attribution-ShareAlike
• Benny Story. Provided by : Living Sober. Located at : https://livingsober.org.nz/sober-story-benny/ . License : CC BY: Attribution
• One patientu2019s story: NIDA clinical trials bring a new life to a woman struggling with opioid addiction. Provided by : NIH. Located at : https://www.drugabuse.gov/drug-topics/treatment/one-patients-story-nida-clinical-trials-bring-new-life-to-woman-struggling-opioid-addiction . License : Public Domain: No Known Copyright

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Advances in the science and treatment of alcohol use disorder

K. witkiewitz.

1 Department of Psychology and Center on Alcoholism, Substance Abuse, and Addictions, University of New Mexico, 2650 Yale Blvd. SE, Albuquerque, NM 87106, USA.

R. Z. Litten

2 Division of Medications Development and Division of Treatment and Recovery Research, National Institute on Alcohol Abuse and Alcoholism, 6700B Rockledge Drive, Bethesda, MD 20892-6902, USA.

3 Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 10 Center Drive (10CRC/15330), Bethesda, MD 21224, USA.

4 Medication Development Program, National Institute on Drug Abuse Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224, USA.

5 Center for Alcohol and Addiction Studies, Brown University, Providence, RI 02912, USA.

Pharmacological and behavioral treatments exist for alcohol use disorder, but more are needed, and several are under development.

Alcohol is a major contributor to global disease and a leading cause of preventable death, causing approximately 88,000 deaths annually in the United States alone. Alcohol use disorder is one of the most common psychiatric disorders, with nearly one-third of U.S. adults experiencing alcohol use disorder at some point during their lives. Alcohol use disorder also has economic consequences, costing the United States at least $249 billion annually. Current pharmaceutical and behavioral treatments may assist patients in reducing alcohol use or facilitating alcohol abstinence. Although recent research has expanded understanding of alcohol use disorder, more research is needed to identify the neurobiological, genetic and epigenetic, psychological, social, and environmental factors most critical in the etiology and treatment of this disease. Implementation of this knowledge in clinical practice and training of health care providers is also needed to ensure appropriate diagnosis and treatment of individuals suffering from alcohol use disorder.

INTRODUCTION

In most regions of the world, most adults consume alcohol at least occasionally ( 1 ). Alcohol is among the leading causes of preventable death worldwide, with 3 million deaths per year attributable to alcohol. In the United States, more than 55% of those aged 26 and older consumed alcohol in a given month, and one in four adults in this age group engaged in binge drinking (defined as more than four drinks for women and five drinks for men on a single drinking occasion) ( 2 ). Excessive alcohol use costs U.S. society more than $249 billion annually and is the fifth leading risk factor for premature death and disability ( 3 ).

The morbidity and mortality associated with alcohol are largely due to the high rates of alcohol use disorder in the population. Alcohol use disorder is defined in the Diagnostic and Statistical Manual for Mental Disorders , 5th edition (DSM-5) ( 4 ) as a pattern of alcohol consumption, leading to problems associated with 2 or more of 11 potential symptoms of alcohol use disorder (see Table 1 for criteria). In the United States, approximately one-third of all adults will meet criteria for alcohol use disorder at some point during their lives ( 5 ), and approximately 15.1 million of U.S. adults meet criteria for alcohol use disorder in the previous 12 months ( 6 ). The public health impacts of alcohol use extend far beyond those individuals who drink alcohol, engage in heavy alcohol use, and/or meet criteria for an alcohol use disorder. Alcohol use is associated with increased risk of accidents, workplace productivity losses, increased medical and mental health costs, and greater rates of crime and violence ( 1 ). Analyses that take into account the overall harm due to drugs (harm to both users and others) show that alcohol is the most harmful drug ( 7 ).

Only a small percent of individuals with alcohol use disorder contribute to the greatest societal and economic costs ( 8 ). For example, in the 2015 National Survey on Drug Use and Health survey (total n = 43,561), a household survey conducted across the United States, 11.8% met criteria for an alcohol use disorder ( n = 5124) ( 6 ). Of these 5124 individuals, 67.4% ( n = 3455) met criteria for a mild disorder (two or three symptoms, based on DSM-5), 18.8% ( n = 964) met criteria for a moderate disorder (four or five symptoms, based on DSM-5), and only 13.8% ( n = 705) met criteria for a severe disorder (six or more symptoms) ( 6 ). There is a large treatment gap for alcohol use disorder, arising from the fact that many individuals with alcohol use disorder do not seek treatment. Those with a mild or moderate alcohol use disorder may be able to reduce their drinking in the absence of treatment ( 9 ) and have a favorable course; but it is those with more severe alcohol use disorder who most often seek treatment and who may experience a chronic relapsing course ( 10 ).

HISTORY OF TREATMENT FOR ALCOHOL USE DISORDER

Near the end of the 18th century, the Pennsylvania physician Benjamin Rush described the loss of control of alcohol and its potential treatments ( 11 ). 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. Over the past 80 years, empirical studies have provided support for both mutual support [A.A. 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. In addition, there are several public health policy initiatives (e.g., taxation, restrictions on advertising, and outlet density) and brief intervention programs (e.g., social norms interventions) that can be effective in reducing prevalence of alcohol use disorder and alcohol-related harms ( 1 ).

NEUROBIOLOGY OF ALCOHOL USE DISORDER

Alcohol use disorder is characterized by loss of control over alcohol drinking that is accompanied by changes in brain regions related to the execution of motivated behaviors and to the control of stress and emotionality (e.g., the midbrain, the limbic system, the prefrontal cortex, and the amygdala). Mechanisms of positive and negative reinforcement both play important roles with individual drinking behavior being maintained by positive reinforcement (rewarding and desirable effects of alcohol) and/or negative reinforcement mechanisms (negative affective and physiological states that are relieved by alcohol consumption) ( 15 , 16 ). At the neurotransmitter level, the positive reinforcing effects of alcohol are primarily mediated by dopamine, opioid peptides, serotonin, γ-aminobutyric acid (GABA), and endocannabinoids, while negative reinforcement involves increased recruitment of corticotropin-releasing factor and glutamatergic systems and down-regulation of GABA transmission ( 16 ). Long-term exposure to alcohol causes adaptive changes in several neurotransmitters, including GABA, glutamate, and norepinephrine, among many others. Discontinuation of alcohol ingestion results in the nervous system hyperactivity and dysfunction that characterizes alcohol withdrawal ( 15 , 16 ). Acting on several types of brain receptors, glutamate represents one of the most common excitatory neurotransmitters. As one of the major inhibitory neurotransmitters, GABA plays a key role in the neurochemical mechanisms involved in intoxication, tolerance, and withdrawal. This brief review can offer only a very simplified overview of the complex neurobiological basis of alcohol use disorder. For deeper, more detailed analysis of this specific topic, the reader is encouraged to consult other reviews ( 15 , 16 ).

CLINICAL MANAGEMENT OF ALCOHOL WITHDRAWAL SYNDROME

Alcohol withdrawal symptoms may include anxiety, tremors, nausea, insomnia, and, in severe cases, seizures and delirium tremens. Although up to 50% of individuals with alcohol use disorder present with some withdrawal symptoms after stopping drinking, only a small percentage requires medical treatment for detoxification, and some individuals may be able to reduce their drinking spontaneously. Medical treatment may take place either in an outpatient or, when clinically indicated, inpatient setting. In some cases, clinical monitoring may suffice, typically accompanied by supportive care for hydration and electrolytes and thiamine supplementation. For those patients in need of pharmacological treatment, benzodiazepines (e.g., diazepam, chlordiazepoxide, lorazepam, oxazepam, and midazolam) are the most commonly used medications to treat alcohol withdrawal syndrome. Benzodiazepines work by enhancing the effect of the GABA neurotransmitter at the GABA A receptor. Notably, benzodiazepines represent the gold standard treatment, as they are the only class of medications that not only reduces the severity of the alcohol withdrawal syndrome but also reduces the risk of withdrawal seizures and/or delirium tremens. Because of the potential for benzodiazepine abuse and the risk of overdose, if benzodiazepine treatment for alcohol withdrawal syndrome is managed in an outpatient setting, careful monitoring is required, particularly when combined with alcohol and/or opioid medications ( 17 ).

a-2 agonists (e.g., clonidine) and β-blockers (atenolol) are sometimes used as an adjunct treatment to benzodiazepines to control neuro-autonomic manifestations of alcohol withdrawal not fully controlled by benzodiazepine administration ( 18 ). 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.

Of critical importance to a successful outcome is the fact that alcohol withdrawal treatment provides an opportunity for the patient and the health care provider to engage the patient in a treatment program aimed at achieving and maintaining long-term abstinence from alcohol or reductions in drinking. Such a treatment may include pharmacological and/or psychosocial tools, as summarized in the next sections.

PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF ALCOHOL USE DISORDER

U.s. food and drug administration–approved pharmacological treatments.

Development of novel pharmaceutical reagents is a lengthy, costly, and expensive process. Once a new compound is ready to be tested for human research use, it is typically tested for safety first via phase 0 and phase 1 clinical studies in a very limited number of individuals. Efficacy and side effects may then be further tested in larger phase 2 clinical studies, which may be followed by larger phase 3 clinical studies, typically conducted in several centers and are focused on efficacy, effectiveness, and safety. If approved for use in clinical practice, this medication is still monitored from a safety standpoint, via phase 4 postmarketing surveillance.

Only three drugs are currently approved by the U.S. Food and Drug Administration (FDA) for use in alcohol use disorder. The acetaldehyde dehydrogenase inhibitor disulfiram was the first medication approved for the treatment of alcohol use disorder by the FDA, in 1951. The most common pathway in alcohol metabolism is the oxidation of alcohol via alcohol dehydrogenase, which metabolizes alcohol to acetaldehyde, and aldehyde dehydrogenase, which converts acetaldehyde into acetate. Disulfiram leads to an irreversible inhibition of aldehyde dehydrogenase and accumulation of acetaldehyde, a highly toxic substance. Although additional mechanisms (e.g., inhibition of dopamine β-hydroxylase) may also play a role in disulfiram’s actions, the blockade of aldehyde dehydrogenase activity represents its main mechanism of action. Therefore, alcohol ingestion in the presence of disulfiram leads to the accumulation of acetaldehyde, resulting in numerous related unpleasant symptoms, including tachycardia, headache, nausea, and vomiting. In this way, disulfiram administration paired with alcohol causes the aversive reaction, initially proposed as a remedy for alcohol use disorder by Rush ( 11 ) in 1784. One challenge in conducting a double-blind, placebo-controlled alcohol trial of disulfiram is that it is easy to break the blind unless the “placebo” medication also creates an aversive reaction when consumed with alcohol, which would then provide the same mechanism of action as the medication (e.g., the placebo and disulfiram would both have the threat of an aversive reaction). Open-label studies of disulfiram do provide support for its efficacy, as compared to controls, with a medium effect size ( 19 ), as defined by Cohen’s d effect size ranges of small d = 0.2, medium d = 0.5, and large d = 0.8 ( 20 ). The efficacy of disulfiram largely depends on patient motivation to take the medication and/or supervised administration, given that the medication is primarily effective by the potential threat of an aversive reaction when paired with alcohol ( 21 ).

The next drug approved for treatment of alcohol use disorder was acamprosate; first approved as a treatment for alcohol dependence in Europe in 1989, acamprosate has subsequently been approved for use in the United States, Canada, and Japan. Although the exact mechanisms of acamprosate action are still not fully understood, there is evidence that it targets the glutamate system by modulating hyperactive glutamatergic states, possibly acting as an N -methyl- d -aspartate receptor agonist ( 22 ). The efficacy of acamprosate has been evaluated in numerous double-blind, randomized controlled trials and meta-analyses, with somewhat mixed conclusions ( 23 – 26 ). Although a meta-analysis conducted in 2013 ( 25 ) indicated small to medium effect sizes in favor of acamprosate over placebo in supporting abstinence, recent large-scale trials conducted in the United States ( 27 ) and Germany ( 28 ) failed to find effects of acamprosate distinguishable from those of a placebo. Overall, there is evidence that acamprosate may be more effective in promoting abstinence and preventing relapse in already detoxified patients than in helping individuals reduce drinking ( 25 ), therefore suggesting its use as an important pharmacological aid in treatment of abstinent patients with alcohol use disorder. The most common side effect with acamprosate is diarrhea. Other less common side effects may include nausea, vomiting, stomachache, headache, and dizziness, although the causal role of acamprosate in giving these side effects is unclear.

A third drug, the opioid receptor antagonist naltrexone, was approved for the treatment of alcohol dependence by the FDA in 1994. Later, a monthly extended-release injectable formulation of naltrexone, developed with the goal of improving patient adherence, was also approved by the FDA in 2006. 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 ). Common side effects of naltrexone may include nausea, headache, dizziness, and sleep problems. 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). Nonetheless, transient, asymptomatic hepatic transaminase elevations have also been observed in some clinical trials and in the postmarketing period; therefore, naltrexone should be used with caution in patients with active liver disease and should not be used in patients with acute hepatitis or liver failure.

Additional pharmacological treatments approved for alcohol use disorder in Europe

Disulfiram, acamprosate, and naltrexone have been approved for use in Europe and in the United States. Pharmacologically similar to naltrexone, nalmefene was also approved for the treatment of alcohol dependence in Europe in 2013. Nalmefene is a m- and d-opioid receptor antagonist and a partial agonist of the k-opioid receptor ( 32 ). Side effects of nalmefene are similar to naltrexone; compared to naltrexone, nalmefene has a longer half-life. Meta-analyses have indicated that nalmefene is effective in reducing heavy drinking days ( 32 ). An indirect meta-analysis of these two drugs concluded that nalmefene may be more effective than naltrexone ( 33 ), although whether a clinically relevant difference between the two medications really exists is still an open question ( 34 ). Network meta-analysis and microsimulation studies suggest that nalmefene may have some benefits over placebo for reducing total alcohol consumption ( 35 , 36 ). The approval of nalmefene in Europe was accompanied by some controversy ( 37 ); a prospective head-to-head trial of nalmefene and naltrexone could help clarify whether nalmefene has added benefits to the existing medications available for alcohol use disorder. Last, nalmefene was approved in Europe as a medication that can be taken “as needed” (i.e., on days when drinking was going to occur). Prior work has also demonstrated the efficacy of taking naltrexone only on days that drinking was potentially going to occur ( 38 ).

In addition to these drugs, a GABA B receptor agonist used to treat muscle spasms, baclofen, was approved for treatment of alcohol use disorder in France in 2018 and has been used off label for alcohol use disorder for over a decade in other countries, especially in other European countries and in Australia ( 39 , 40 ). Recent human laboratory work suggests that baclofen may disrupt the effects of an initial priming dose of alcohol on subsequent craving and heavy drinking ( 41 ). Meta-analyses and systematic reviews examining the efficacy of baclofen have yielded mixed results ( 35 , 39 , 42 ); however, there is some evidence that baclofen might be useful in treatment of alcohol use disorder among individuals with liver disease ( 43 , 44 ). Evidence of substantial heterogeneity in baclofen pharmacokinetics among different individuals with alcohol use disorder ( 41 ) could explain the variability in the efficacy of baclofen across studies. The appropriate dose of baclofen for use in treatment of alcohol use disorder remains a controversial topic, and a recent international consensus statement highlighted the importance of tailoring doses based on safety, tolerability, and efficacy ( 40 ).

Promising pharmacological treatments

Numerous other medications have been used off label in the treatment of alcohol use disorder, and many of these have been shown to be modestly effective in meta-analyses and systematic reviews ( 23 , 24 , 26 , 35 ). Systematic studies of these medications suggest promising findings for topiramate, ondansetron, gabapentin, and varenicline. The anticonvulsant drug topiramate represents one of the most promising medications in terms of efficacy, based on its medium effect size from several clinical trials [for a review, see ( 45 )], including a multisite clinical study ( 46 ). One strength of topiramate is the possibility of starting treatment while people are still drinking alcohol, therefore serving as a potentially effective treatment to initiate abstinence (or to reduce harm) rather than to prevent relapse in already detoxified patients ( 45 ). Although not approved by the FDA, it is worth noticing that topiramate is a recommended treatment for alcohol use disorder in the U.S. Department of Veterans Affairs ( 47 ). A concern with topiramate is the potential for significant side effects, especially those affecting cognition and memory, warranting a slow titration of its dose and monitoring for side effects. Furthermore, recent attention has been paid on zonisamide, another anticonvulsant medication, whose pharmacological mechanisms of actions are similar to topiramate but with a better tolerability and safety profile ( 48 ). Recently published and ongoing research focuses on a potential pharmacogenetic approach to treatment in the use of topiramate to treat alcohol use disorder, based on the possibility that both efficacy and tolerability and safety of topiramate may be moderated by a functional single-nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit ( 49 ). Human laboratory studies ( 50 ) and treatment clinical trials ( 51 ) have also used a primarily pharmacogenetic approach to testing the efficacy of the antinausea drug ondansetron, a 5HT 3 antagonist, in alcohol use disorder. Overall, these studies suggest a potential role for ondansetron in alcohol use disorder, but only in those individuals with certain variants of the genes encoding the serotonin transporter 5-HTT and the 5-HT 3 receptor. The anticonvulsant gabapentin has shown promising results in human laboratory studies and clinical trials ( 52 – 54 ), although a more recent multisite trial with an extended-release formulation of the medication did not have an effect of gabapentin superior to that of a placebo ( 55 ). Although the latter findings might be related to potential pharmacokinetic issues secondary to the specific formulation used, it is nonetheless possible that gabapentin may be more effective in patients with more clinically relevant alcohol withdrawal symptoms ( 52 ). Several human laboratory studies support a role for varenicline, a nicotinic acetylcholine receptor partial agonist approved for smoking cessation, in alcohol use disorder [for a review, see ( 56 )], and two of three clinical trials also support its efficacy on alcohol outcomes ( 57 – 59 ), especially in heavy drinkers who are males ( 59 ) and in male and female alcohol-dependent individuals who are also smokers ( 60 ). Additional details on the FDA-approved medications and other medications tested in clinical research settings for the treatment of alcohol use disorder are summarized in Table 2 .

FDA, U.S. Food and Drug Administration; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N -methyl- d -aspartate; PO, per os (oral); IM, intramuscular; HT, serotonin.

The medications and targets described above have shown promising results in phase 2 or phase 3 medication trials. However, owing to the development of novel neuroscience techniques, a growing and exciting body of data is expanding the armamentarium of targets currently under investigation in animal models and/or in early-phase clinical studies. Pharmacological approaches with particular promise for future drug development include, but are not limited to the following [for recent reviews, see, e.g., ( 56 , 61 – 68 )]: the antipsychotic drug aripiprazole, which has multiple pharmacological actions (mainly on dopamine and serotonin receptors), the antihypertensive alpha-1 blocker drugs prazosin and doxazosin, neurokinin-1 antagonism, the glucocorticoid receptor blocker mifepristone, vasopressin receptor 1b antagonism, oxytocin, ghrelin receptor antagonism, glucagon-like peptide-1 agonism, and pharmacological manipulations of the nociception receptor (We are intentionally using a general pharmacological terminology for the nociceptin receptor, given that it is unclear whether agonism, antagonism, or both may represent the best approach.). New medications development is particularly important for the treatment of comorbid disorders that commonly co-occur among individuals with alcohol use disorder, particularly affective disorders, anxiety disorders, suicidality, and other substance use disorders. This aspect of alcohol use disorder is relevant to the fact that addictive disorders often present with significantly more severe symptoms when they coexist with other mental health disorders ( 69 ). Likewise, there is evidence that pharmacotherapy is most effective when implemented in conjunction with behavioral interventions ( 70 ), and all phase 2 and phase 3 medication trials, mentioned above, have included a brief psychosocial behavioral treatment in combination with medication.

BEHAVIORAL/PSYCHOLOGICAL TREATMENTS FOR ALCOHOL USE DISORDER

Evidence-based treatments.

A wide range of behavioral and psychological treatments are available for alcohol use disorder, and many treatments are equally effective in supporting abstinence or drinking reduction goals ( 71 – 74 ). Treatments with the greatest evidence of efficacy range from brief interventions, including motivational interviewing approaches, to operant conditioning approaches, including contingency management and the community reinforcement approach, to cognitive behavioral treatments, including coping skills training and relapse prevention, and to acceptance- and mindfulness-based approaches. Twelve-step facilitation, which was designed specifically to connect individuals with mutual support groups, has also been shown to be effective ( 75 ). In addition, harm reduction treatments, including guided self-control training and controlled drinking interventions, have been successful in supporting drinking reduction goals ( 70 ).

Meta-analyses and systematic reviews have found that brief interventions, especially those based on the principles of motivational interviewing, are effective in the treatment of alcohol use disorder. These interventions can include self-monitoring of alcohol use, increasing awareness of high-risk situations, and training in cognitive and behavioral techniques to help clients cope with potential drinking situations, as well as life skills training, communication training, and coping skills training. Cognitive behavioral treatments can be delivered in individual or group settings and can also be extended to the treatment of families and couples ( 72 , 73 ).

Acceptance- and mindfulness-based interventions are increasingly being used to target alcohol use disorder and show evidence of efficacy in a variety of settings and formats, including brief intervention formats ( 76 ). Active ingredients include raising present moment awareness, developing a nonjudgmental approach to self and others, and increasing acceptance of present moment experiences. Acceptance- and mindfulness-based interventions are commonly delivered in group settings and can also be delivered in individual therapy contexts.

Computerized, web-based, and mobile interventions have also been developed, incorporating the principles of brief interventions, behavioral and cognitive behavioral approaches, as well as mindfulness and mutual support group engagement; many of these approaches have demonstrated efficacy in initial trials ( 77 – 79 ). For example, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has developed the Take Control computerized intervention that includes aspects of motivational interviewing and coping skills training and was designed to provide psychosocial support (particularly among those assigned to the placebo medication) and also to increase adherence and retention among individuals enrolled in pharmacotherapy trials ( 80 ).

Mutual support group (e.g., A.A. and SMART) attendance and engagement have been shown to be associated with recovery from alcohol use disorder, even in the absence of formal treatment ( 81 ). However, selection biases (e.g., people selecting to attend these groups) raise difficulties in assessing whether other factors that are associated with treatment effectiveness may be the active ingredients for improving outcomes among those who attend mutual support groups. For example, individuals who are highly motivated to change might be more likely to attend mutual support groups. Likewise, mutual support groups often provide individuals with increased social network support for abstinence ( 82 ). Motivation to change and having a social network that supports abstinence (or reductions in drinking) are both factors that are associated with greater treatment effectiveness ( 83 ).

As noted above, most behavioral and psychological treatments are equally effective with small effect size differences [Cohen’s d = 2.0 to 0.3 ( 20 )] between active treatments ( 84 – 88 ). Behavioral interventions have also been shown to be as effective as pharmacotherapy options, with a 16-week cognitive behavioral intervention shown to be statistically equivalent to naltrexone in reducing heavy drinking days in a large randomized trial ( 27 ). One of the challenges of examining behavioral interventions in randomized trials is that intervention blinding and placebo controls cannot be implemented in most contexts, other than in computerized interventions. Furthermore, the general therapeutic factors common to most behavioral interventions (e.g., therapist empathy and supportive therapeutic relationship) in treatment of alcohol use disorder are as powerful as the specific therapeutic targets of specific behavioral interventions (e.g., teaching skills in a cognitive behavioral treatment) in facilitating behavioral change ( 89 ).

Promising future behavioral treatments and neuromodulation treatments

With respect to behavioral treatments, there are numerous opportunities for the development of novel mobile interventions that could provide treatment and recovery support in near real time. This mobile technology may also extend the reach of treatments to individuals with alcohol use disorder, particularly in rural areas. On the basis of a contextual self-regulation model of alcohol use ( 90 ), it is critical to address the immediate situational context alongside the broader social, environmental, and familial context in which an individual experiences the world and engages in momentary decision-making. Ambulatory assessment, particularly tools that require only passive monitoring (e.g., GPS, heart rate, and skin conductance) and real-time support via mobile health, could provide immediate environmental supports and could extend the reach of medications and behavioral treatments for alcohol use disorder. For example, a mobile device could potentially signal a high-risk situation by indicating the geographic location (near a favorite drinking establishment) and the heart rate (increased heart rate when approaching the establishment). The device could provide a warning either to the individual under treatment and/or to a person supporting that individual’s recovery. In addition, developments in alcohol sensing technology (e.g., transdermal alcohol sensors) could greatly increase rigor of research on alcohol use disorder and also provide real-time feedback on alcohol consumption levels to individuals who are attempting to moderate and/or reduce their alcohol use.

Recent advances in neuromodulation techniques may also hold promise for the development of novel treatments for alcohol use disorder. Deep brain stimulation, transcranial magnetic stimulation, transcranial electrical stimulation (including transcranial direct current stimulation and transcranial alternating current stimulation), and real-time neurofeedback have recently been tested as potential treatments for addiction, although evidence in favor of these treatments is currently uncertain and focused mostly on intermediate targets (e.g., alcohol craving) ( 91 ). These techniques attempt to directly target specific brain regions and addiction-related cognitive processes via surgically implanted electrodes (deep brain stimulation), electrical currents or magnetic fields applied to the scalp (transcranial electrical and magnetic stimulation, respectively), or individual self-generated modulation via feedback (neurofeedback). Although robust large scale trials with double-blind, sham controls, and long-term follow-ups of alcohol behavior change and relapse have not been conducted ( 91 ), the heterogeneity of alcohol use disorder suggests that targeting one specific neural region may be insufficient to treat such a complex disorder, with its multiple etiologies and diverse clinical courses ( 92 ).

Factors contributing to the effectiveness of treatments

Numerous models have examined factors that predict treatment readiness, treatment engagement, and treatment outcomes for alcohol use disorder. The transtheoretical model of change proposes that an individual’s own readiness to change his or her drinking behavior may have an impact on treatment engagement and effectiveness ( 93 ). The dynamic model of relapse proposes the involvement of multiple interacting biological, psychological, cognitive, emotional, social, and situational risk factors that are static and dynamic in their association with treatment outcomes ( 83 ). Neurobiological models of addiction focus on the brain reward and stress system dysfunction that contributes to the development and maintenance of alcohol use disorder, that is, the “addiction cycle” ( 15 , 16 ). The alcohol and addiction research domain criteria (AARDoC) ( 92 ), which have been operationalized in the addictions neuroclinical assessment ( 94 ), focus on the following three domains that correspond to particular phases in the addiction cycle: incentive salience in the binge/intoxication phase, negative emotionality in the withdrawal/negative affect phase, and executive function in the preoccupation/anticipation phase. Within each domain of the AARDoC, the addictions neuroclinical assessment proposes constructs that can be measured at multiple levels of analysis, such as craving in the incentive salience domain, negative affect and emotion dysregulation in the negative emotionality domain, and cognitive impairment and impulsivity in the executive function domain. The AARDoC acknowledge that environmental and contextual factors play a role in alcohol use disorder and treatment outcomes. Moreover, because of the heterogeneity of alcohol use disorder, the significance of these domains in causing alcohol use disorder and alcohol-related problems will vary among individuals.

Each of the abovementioned theoretical models proposes factors that may affect treatment effectiveness; however, many of the constructs proposed in each of these models are overlapping and likely contribute to the effectiveness of alcohol use disorder treatment across a range of populations and settings. A heuristic model combining components from each of these models is shown in Fig. 1 . Specifically, this model highlights the precipitants of alcohol use that are influenced by the neurobiological adaptations proposed in the addiction cycle (indicated by bold font) and additional contextual factors (regular font) that decrease or increase the likelihood of drinking in context, depending on whether an individual uses effective coping regulation in the moment. The domains supporting alcohol use/coping regulation (negative emotionality, executive function, incentive salience, and social environment) may interact to predict alcohol use or coping regulation in the moment. For example, network support for abstinence could improve decision-making and decrease likelihood of drinking. Conversely, experiences of physical pain are associated with increases in negative affect and poorer executive function, which could both increase likelihood of drinking. Both of these examples require environmental access to alcohol and a desire to drink alcohol. Treatment effectiveness will depend on the extent to which a particular treatment targets those risk factors that are most likely to increase or decrease the likelihood of drinking for each individual, as well as the personal resources that each individual brings to treatment and/or that could be enhanced in treatment. A functional analysis of contextual risk and protective factors can be critically important in guiding treatment.

Risk factors proposed in the AARDoC, including incentive salience, negative emotionality, executive function, and social environmental factors, are shown in black bold font encircling alcohol use. Contextual risk factors, including decision-making, self-efficacy, pain, craving, etc., are shown in black font in colored boxes. Risk and protective factors overlap with alcohol use and interact in predicting coping regulation and alcohol use among individual patients.

For example, there is considerable heterogeneity in treatment response to naltrexone, which may vary in efficacy in some individuals. Recent studies conducted to determine whether certain patients may benefit more from naltrexone have yielded mixed findings ( 95 ). Promising evidence suggests that individuals with the OPRM1 A118G G (Asp40) allele may have a better response to naltrexone ( 96 – 98 ); however, a prospective study of medication response among individuals stratified by presence of the Asp40 allele did not provide support for the genotype by treatment interaction ( 99 ), and recent human laboratory studies have not confirmed the hypothesized mechanisms underlying the pharmacogenomic effect ( 100 ). Initial evidence suggests that naltrexone may be more effective in reducing heavy drinking among smokers ( 101 ) and among those with a larger number of heavy drinkers in their social networks ( 102 ). With respect to reinforcement typologies, recent work has found that naltrexone may be more effective among those who tend to drink alcohol for rewarding effects ( 103 ), and acamprosate may also be more effective for individuals who drink to relieve negative affect ( 104 ).

GAPS IN SCIENTIFIC KNOWLEDGE AND NEW RESEARCH DIRECTIONS

Heterogeneity of individuals with alcohol use disorder.

This review has briefly summarized the treatments currently available for alcohol use disorder that are relatively effective, at least in some patients. Many new treatments are also being developed, and some of them seem promising. Nevertheless, numerous gaps in scientific knowledge remain. Notably, most people who drink alcohol do not develop an alcohol use disorder, most people with alcohol use disorder do not seek treatment, and most of those who do not seek treatment “recover” from alcohol use disorder without treatment ( 2 ). Very little is known about factors, particularly neurobiological, genetic, and epigenetic factors, that predict the transition from alcohol use to alcohol use disorder, although basic science models suggest that a cycle of neuroadaptations could be at play ( 15 , 16 ). We also lack a basic understanding of how individuals recover from alcohol use disorder in the absence of treatment and what neurobiological, psychological, social, and environmental factors are most important for supporting recovery from alcohol use disorder. Gaining a better understanding of recovery in the absence of treatment, particularly modifiable psychological, neurobiological, and epigenetic factors, could provide novel insights for medications and behavioral treatment development. Among many other factors, special attention is needed in future studies to shed light on the role of sex and gender in the development and maintenance of alcohol use disorder and on the response to pharmacological, behavioral, and other treatments.

The heterogeneity of alcohol use disorder presents a major challenge to scientific understanding and to the development of effective treatments for prevention and intervention ( 92 ). For example, a DSM-5 diagnosis of alcohol use disorder requires 2 or more symptoms, out of 11, over the past year. That requirement equates to exactly 2048 potential symptom combinations that would meet the criteria of alcohol use disorder. An individual who only meets criteria for tolerance and withdrawal (i.e., physiological dependence) likely requires a very different course of treatment from an individual who only meets the criteria for failure to fulfill role obligations and use of alcohol in hazardous situations. Gaining a better understanding of the etiology and course of alcohol use disorder, as well as identifying whether different subtypes of drinkers may respond better to certain treatments ( 103 , 104 ), is critical for advancing the science of alcohol use disorder prevention and treatment. Alternative conceptualizations of alcohol use disorder may also aid in improving our understanding of the disorder and reducing heterogeneity. For example, the pending International Classification of Diseases , 11th edition, will simplify the diagnosis of alcohol dependence to requiring only two of three criteria in the past 12 months: (i) impaired control over alcohol use; (ii) alcohol use that dominates over other life activities; and (iii) persistence of alcohol use despite consequences. The diagnosis will be made with or without physiological dependence, as characterized by tolerance, withdrawal, or repeated use to prevent or alleviate withdrawal ( 105 ). It remains to be seen whether simplification of the criteria set will narrow our conceptualization or potentially increase heterogeneity of this disorder among those diagnosed with alcohol dependence.

Placebo effect

An additional challenge to development of pharmacological treatments for alcohol use disorder is the high placebo response rates seen in drug trials ( 106 ). The tendency for individuals to have a good treatment response when assigned to placebo medication reflects both the high probability of recovery without treatment and the heterogeneity in the disorder itself. Many people who enter treatment are already motivated to change behavior, and receiving a placebo medication can help these individuals continue the process of change. Gaining a better understanding of which kinds of individuals respond to placebo and of the overall physiological and behavioral complexities in the placebo response is critical to identifying those individuals who will benefit the most from active medication. More generally, very little is understood about how motivation to change drinking behavior may influence the efficacy of active medications, particularly via adherence mechanisms. Additional research on targeted (i.e., as needed) dosing of medications, such as nalmefene and naltrexone ( 32 , 38 ), would be promising from the perspective of increasing adherence to medications and also raising awareness of potentially heavy drinking occasions.

Recent developments in pharmacological and behavioral approaches

In addition to gaining a better understanding of the disorder and who benefits from existing treatments, the examination of molecular targets for alcohol use disorder could open up multiple innovative directions for future translational research on the treatment of alcohol use disorder. Recent research has identified many targets that might be important for future medication trials ( 67 ). For example, most of the medication development efforts in past decades have focused on pathways and targets typically related to reward processing and positive reinforcement. While important, this approach ignores the important role of stress-related pathways (e.g., corticotropin release factor and other related pathways) in negative reinforcement and in the later stages of alcohol use disorder, which is often characterized by physical dependence, anxiety, and relief drinking [for reviews, see ( 15 , 16 )]. Furthermore, it is also becoming more and more apparent that other promising targets may be identified by looking at the brain not as an isolated system but rather as an organ with bidirectional interactions with peripheral systems. Examples of the latter approach include the growing evidence suggesting a potential role of inflammation and neuroinflammation and of the gut-liver-brain axis in the neurobiological mechanisms that regulate the development and/or maintenance of alcohol use disorder ( 107 – 109 ). Moving medications development from phase 1 to phase 2 and 3 trials has also been a difficulty in the field. Future directions that might improve translation of basic science into clinical practice include the broader use of human laboratory models and pilot clinical trials ( 110 ), as well as expanding the outcomes that might be targeted in phase 2 and phase 3 trials to include drinking reduction outcomes ( 111 , 112 ).

New directions for behavioral treatment development include a greater focus on identifying effective elements of behavioral treatments and on the components of treatment that are most critical for successful behavior change ( 89 , 113 ). Studies investigating the effects of specific treatment components are critical for refining treatment protocols to more efficiently target the symptoms of alcohol use disorder. Continued development of mobile health interventions will also help with disseminating treatment to a wider range of individuals struggling with alcohol use disorder.

Translation of addiction science to clinical practice

Last, but not the least, there is also a critical need for more research on dissemination and implementation, given the fact that many treatment programs still do not incorporate evidence-based practices, such as cognitive behavioral skills training, mindfulness-based interventions, and medications. Both pharmacological and behavioral treatments for alcohol use disorder are markedly underused; the recent Surgeon General’s report Facing Addiction in America ( 114 ) highlights the fact that only about 1 in 10 people with a substance use disorder receives any type of specialty treatment. Therefore, basic science and human research efforts will need to be accompanied by translational approaches, where effective novel medications and precision medicine strategies are effectively translated from research settings to clinical practice. Greater integration of alcohol screening and medication in primary care and other clinical settings, as well as research on best methods for implementation, has great potential for expanding access to effective treatment options ( 115 ). Because the heterogeneity of alcohol use disorder makes it highly unlikely that one single treatment will work for all individuals, it is important to provide a menu of options for pharmacological and behavioral therapies to both clinicians and patients. Reducing the stigma of alcohol use disorder and moving toward a public health approach to addressing this problem may further increase the range of acceptable treatment options.

Acknowledgment

Funding: This research was supported by a grant from NIAAA (R01 AA022328) awarded to K.W. (principal investigator). R.Z.L. is funded by NIAAA. L.L. is jointly funded by NIAAA and the National Institute on Drug Abuse (NIDA) (ZIA-AA000218). The content of this review does not necessarily represent the official views of the funders. Author contributions: K.W. wrote the first draft of the manuscript. K.W., R.Z.L., and L.L. provided additional text and edits. All authors approved the final draft. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or in the materials cited herein. Additional data related to this paper may be requested from the authors.

REFERENCES AND NOTES

Alcohol Abuse in Society: Case Studies

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The last three chapters have demonstrated how routine data may be collected from the health service and forensic medicine. These data present a view of the occurrence of alcohol and drug abuse in society which is generated from a ‘medical model’. As useful as this approach is, it does not take into account the nature and needs of specific groups. To do this a more ‘socially appropriate perspective’ can be used. The following case studies illustrate some of the problems resulting from methodological issues in this area of investigation and, in particular, from studies undertaken in short-term projects undertaken by graduate students. Important discussions relating to: ‘what level of consumption constitutes abuse ’ ‘alcohol usage by the elderly’, and ‘the effectiveness of health education’ will be introduced.

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Bonner, A., Waterhouse, J. (1996). Alcohol Abuse in Society: Case Studies. In: Bonner, A., Waterhouse, J. (eds) Addictive Behaviour: Molecules to Mankind. Palgrave Macmillan, London. https://doi.org/10.1007/978-1-349-24657-1_17

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Adolescent Motivational Interviewing

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Using Motivational Interviewing to Treat Adolescents and Young Adults with Substance Use Disorders

A case study of hazelden betty ford in plymouth.

Young people receiving treatment for substance use disorders (SUDs) present a unique clinical challenge. Though premature dropout from treatment happens with adults, as many as 50% of teens and young adults with substance use disorders do not complete treatment. In addition, many who do complete treatment do not fully engage with the treatment process (Gogel et al., 2011). Treatment engagement involves more than just being physically present; it involves actively taking part in all aspects of the treatment process and becoming emotionally invested in those processes as well as in peers attending the same services (Szapocznik et al., 2003; Wise et al., 2001). Another factor that may complicate treatment engagement is the fact that many adolescents enter treatment because of external pressures (such as parental insistence) and, as a result, may have low motivation to engage (Battjes et al., 2003). Because both retention and active engagement in treatment are associated with positive outcomes and recovery from substance use disorders (Williams and Chang, 2000; Moos & Moos, 2003; McWhirter, 2008), organizations offering treatment services to youth should focus on approaches that promote engagement and enhance the patient's intrinsic motivation and commitment to change.

The Hazelden Betty Ford Foundation has a facility in Plymouth, Minnesota , that focuses on providing substance abuse treatment to adolescents and young adults. In a recent interview with me, Dr. Joseph Lee, medical director of the Youth Continuum, stressed the importance of empathy in working with adolescent and young adult patients. A key piece of that work involves recognizing that empathy differs from identification. Empathy is the ability to imagine and accurately understand the feelings of another person and respond in a helpful way, and people with strong empathy can do this while maintaining a sense of being separate from that person (Buckman et al., 2011; Amsel, 2015). Identification, on the other hand, can be expressed as either relating to someone else so much that you lose a sense of yourself, or as identifying someone as so similar to yourself that you feel they must do and experience their situation as you do or did.

"We needed to take an honest look at how we were viewing and working with our patients," said Dr. Lee.

"This clinical introspection was especially critical as we began to treat more patients awash in the opioid epidemic . These kids are even more likely to drop out than other kids, and for them, the risk of going back out and using drugs can be fatal." The realization that empathic rapport is critical to helping the patient get better, combined with too many patients leaving treatment prematurely, particularly those with a high degree of clinical severity, prompted Lee and other clinical leaders to improve clinical practice at the therapist level.

"These kids are even more likely to drop out than other kids, and for them, the risk of going back out and using drugs can be fatal."

The Hazelden Betty Ford Foundation had therefore identified an opportunity to strengthen their empathy in working with patients, along with addressing the urgent needs to keep young patients in treatment, increase their engagement in the treatment process and increase their motivation to change. The next step in the process was to decide on a therapeutic approach to meet these objectives. As applied to patients with substance use disorders, motivational interviewing (MI) is a brief psychotherapy aimed at increasing the patient's motivation and ability to change his/her addictive behaviors (Miller, Zweben, DiClemente, & Rychtarik, 1992). It focuses heavily on therapists bringing empathy to the therapeutic process with clients. Figure 1 lists the five elements of the approach, as outlined by Miller et al. (1992). The first element is expressing empathy for the client, which can be done in a number of ways. Empathic communication signals dignity and respect for the client and helps prevent the development of a superior/inferior relationship where the therapist is telling the client what he or she should be feeling. Empathic communication involves reflective listening, communicating an acceptance of where the client is and supporting them in the process of change (Miller & Rollnick, 1991). In addition to its strong focus on empathy, MI was chosen by Plymouth staff because it is an evidence-based practice in treating substance use disorders, with several studies indicating its effectiveness for adolescent and young adult populations (Barnett et al., 2012; Brown et al., 2015).

"Once we identified that we needed to start doing MI in a more formalized, consistent way across our clinicians, we needed to map out and implement a plan for doing it," Dr. Lee observed.

As one might imagine, this plan was fairly complex. Though all staff in patient-facing roles received training, the implementation of Motivational Interviewing was heavily concentrated on two roles: alcohol/drug addiction counselors and addiction technicians. Addiction counselors are a core part of the residential program. They administer assessments, participate in treatment planning and engage in therapy with the patient around his or her unique needs and challenges. The addiction technicians help support the patient, including easing their transition between the medical services unit and the residential treatment unit, helping them get to appointments on time and filling in for other non-clinical aspects of treatment, such as conducting meditation exercises.

Systematic training of staff in these two roles was a vital first step in implementing Motivational Interviewing with patients. Several tactics were used as part of training, including the use of an Motivational Interviewing text, required attendance at several two-day workshops and in-person training by both external MINT-certified specialists and several Plymouth staff well-versed in Motivational Interviewing methods, including Dr. Lee; Travis Vanderbilt, an LADC counselor; and David Wells, a PhD-level psychologist in the mental health clinic. Once counselors and technicians were trained, Lee and other Plymouth Motivational Interviewing experts set up a process to measure how counselors conducted therapy sessions with patients. The process involves periodically taping therapy sessions and auditing them for elements of Motivational Interviewing. The conclusions of these audits are then shared with each counselor in regular supervision meetings with his/ her manager. "The results of the audits and feedback on the clinician's use of Motivational Interviewing are a vital part of the process and happens on an ongoing basis," says Dr. Lee. "But we focus on making these conversations collegial and constructive as opposed to punitive…the idea is to model Motivational Interviewing even in the practitioner/supervisor discussions."

Successful implementation of Motivational Interviewing with Plymouth staff took several months, as is typically the case with clinical programs addressing behavioral health issues. By the middle of 2016, Motivational Interviewing was fully implemented and used consistently with all residential patients. Figure 2 shows atypical discharge rates for patients as a function of when they were discharged from the Plymouth residential program. These rates represent the percentage of patients who left treatment prematurely for various reasons (against staff advice, against medical advice, or occasionally at staff request). Over the last several quarters, the percentage of atypical discharges has been trending downward in a pattern consistent with the timeframe of motivational interviewing implementation. Only 9.9% of patients discharged in Q1 of 2017 left treatment prematurely, as opposed to 13.28% of patients in Q3 of 2015 (a 25% decrease). Though several other factors may have impacted these rates for example, an increase over time in the use of Suboxone for patients with opioid use issues the results are encouraging.

Qualitative feedback from staff members at Plymouth also suggests a positive impact of Motivational Interviewing on both staff and patients. Staff members described it as a "very person centered" approach, in part because it allows the clinician to effectively build rapport through empowerment rather than directives. Young patients are very receptive to the approach because they feel they are being worked with in a collaborative way, not talked down to or ordered to do certain things. Several staff members reported being able to help emotionally distressed patients change their mind about leaving treatment. In a couple of cases, the patient had left the facility, but the counselor was able to convince them to come back. Plymouth staff members directly attributed these outcomes to their use of Motivational Interviewing. "Motivational Interviewing is helping our patients because it reduces many of the impulsive decisions and encourages them to think through their actions before doing them," said one staff member. "It also helps them process through emotions they are not used to experiencing before making important decisions." Several counselors also reported that the therapeutic alliance formed with their patients has been strengthened through the use of Motivational Interviewing, which is quite important given the role of the alliance in predicting positive outcomes after treatment (Connors et al., 1997; Cook et al., 2015).

Behavioral health provider organizations wanting to implement evidence-based clinical practices in a highly accurate, reliable way can do so through an implementation science approach. At its core, implementation science involves the use of research and measurement to ensure that practices are implemented correctly within clinical settings (Proctor et al., 2009). The first step of the approach is to identify a practice that has a strong evidence base, meaning that it has been studied in a scientific manner and found to produce positive outcomes across studies. The second step involves mapping out how to deliver the clinical practice based on the organization's current structure, staffing models, clinical workflows and other processes related to care delivery. A key part of the second step is the training of staff directly administering the program or practice. Hazelden Betty Ford in Plymouth has completed these steps with regard to implementing motivational interviewing with residential patients. Clinical leaders and other staff will focus on subsequent steps over the coming months. This work will focus on evolving and standardizing the processes for measuring how effective each counselor is at implementing Motivational Interviewing with patients. Most importantly, counselors and supervisors will make sure that these assessments are used to continuously improve Motivational Interviewing practice.

"Motivational Interviewing is helping our patients because it reduces many of the impulsive decisions and encourages them to think through their actions before doing them."

This final step, though critical, is often overlooked by organizations implementing new clinical practices. It is one thing to implement something and occasionally measure how things are going. It is another thing to use what is learned and apply it back to care delivery on a continuous, long-term basis. As more behavioral health service providers use this model to bring evidence-based practices to patients, we can expect patient engagement and outcomes to improve.

Case Study October 2017.  Download the  Adolescent Motivational Interviewing case study .

Acknowledgements

Dr. joseph lee, medical director of the youth continuum.

Joseph Lee, MD, has extensive experience in addiction treatment for youth and families from across the country and abroad, providing him an unparalleled perspective on emerging drug trends, co-occurring mental health conditions and the ever-changing culture of addiction. A triple board certified physician, Lee completed his medical degree at the University of Oklahoma, his adult psychiatry residency at Duke University Hospital and his fellowship in child and adolescent psychiatry at John Hopkins Hospital. He is a diplomat of the American Board of Addiction Medicine and is a member of the American Academy of Child and Adolescent Psychiatry's Substance Abuse Committee. He is also the author of  Recovering My Kid: Parenting Young Adults in Treatment and Beyond , which provides a candid, helpful guide for parents in times of crisis.

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• Brown, R. A., Abrantes, A. M., Minami, H., Prince, M. A., Bloom, E. L., Apodaca, T. R. et al. (2015). Motivational interviewing to reduce substance use in adolescents with psychiatric comorbidity. Journal of Substance Abuse Treatment, 59, 20-29.
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• Moos, R. H., & Moos, B. S. (2003). Long-term influence of duration and intensity of treatment on previously untreated individuals with alcohol use disorders. Addiction, 98, 325-338.
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Harnessing science, love and the wisdom of lived experience, we are a force of healing and hope ​​​​​​​for individuals, families and communities affected by substance use and mental health conditions.

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a Adjusted for age at survey, sex, race and ethnicity, marital status, educational level, annual household income, insurance status, smoking status, cancer type, age at cancer diagnosis, and currently prescribed medication and/or receiving treatment.

b Included individuals reporting races or ethnicities other than Hispanic, non-Hispanic Black, or non-Hispanic White and individuals with more than 1 race or ethnicity.

c Included breast, colon and rectum, and head and neck cancer. Esophageal cancer was not included because the association with alcohol drinking is confined largely to squamous cell carcinoma, whereas most cases of esophageal cancer were adenocarcinoma in the US. Liver cancer was not included as it was not specifically included in the All of Us Research Program survey.

d Self-reported current medication prescription and/or treatment in the Personal Medical History survey.

a Non-Hispanic White was used as the reference group.

c Included breast, colon and rectum, and head and neck cancer. Esophageal cancer was not included because the association with alcohol drinking is confined largely to squamous cell carcinoma whereas most cases of esophageal cancer were adenocarcinoma in the US. Liver cancer was not included as it was not specifically included in the All of Us Research Program survey.

e Adjusted for age at survey, sex, race and ethnicity, marital status, educational level, annual household income, insurance status, smoking status, cancer type, age at cancer diagnosis, and currently prescribed medication and/or receiving treatment.

eTable 1. Cancer Characteristics According to Sex, All of Us Research Program

eTable 2. Alcohol Use Disorders Identification Test–Consumption (AUDIT-C)

eTable 3. Characteristics of Cancer Survivors Who Underwent Cancer Treatment Within 1 Year Before the Baseline Survey, All of Us Research Program

eTable 4. Adjusted Odds Ratios of Current Drinking Among Cancer Survivors, All of Us Research Program

eTable 5. Adjusted Odds Ratios of Risky Drinking Behaviors Among Current Drinking Cancer Survivors, All of Us Research Program

eTable 6. Prevalence of Alcohol Consumption Patterns Among Survey Participants Without Prior Cancer Diagnosis According to Sex, All of Us Research Program

eFigure 1. Flow Chart of the Study Population

eFigure 2. (A) Mean AUDIT-C Score Among Cancer Survivors According to Sex; (B) Venn Diagram Showing Cancer Survivors Engaged in Exceeding Moderate Drinking, Binge Drinking and Hazardous Drinking Among 11815 Current Drinkers, All of Us Research Program

eFigure 3. Mean AUDIT-C Score Among Cancer Survivors According to Age at Cancer Diagnosis and Smoking Status, All of Us Research Program

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Shi M , Luo C , Oduyale OK , Zong X , LoConte NK , Cao Y. Alcohol Consumption Among Adults With a Cancer Diagnosis in the All of Us Research Program. JAMA Netw Open. 2023;6(8):e2328328. doi:10.1001/jamanetworkopen.2023.28328

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Alcohol Consumption Among Adults With a Cancer Diagnosis in the All of Us Research Program

• 1 Division of Public Health Sciences, Department of Surgery, Washington University in St Louis School of Medicine, St Louis, Missouri
• 2 Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison
• 3 University of Wisconsin Carbone Cancer Center, Madison
• 4 Alvin J. Siteman Cancer Center, Washington University in St Louis School of Medicine, St Louis, Missouri
• 5 Division of Gastroenterology, Department of Medicine, Washington University in St Louis School of Medicine, St Louis, Missouri

Question   What is the prevalence of current alcohol consumption and of risky alcohol consumption among cancer survivors in the US?

Findings   In this cross-sectional study of 15 199 adults with a cancer diagnosis from the All of Us Research Program, 77.7% self-reported as current drinkers, and among these, 13.0% exceeded moderate drinking, 23.8% reported binge drinking, and 38.3% engaged in hazardous drinking. Among 1839 survivors receiving cancer treatment, the prevalence of current drinking and risky drinking were similar to the overall cohort and across treatment types.

Meaning   This study suggests that current drinking and risky drinking are common among US cancer survivors even during cancer treatment.

Importance   Alcohol consumption is associated with adverse oncologic and treatment outcomes among individuals with a diagnosis of cancer. As a key modifiable behavioral factor, alcohol consumption patterns among cancer survivors, especially during treatment, remain underexplored in the United States.

Objective   To comprehensively characterize alcohol consumption patterns among US cancer survivors.

Design, Setting, and Participants   This cross-sectional study used data from May 6, 2018, to January 1, 2022, from the National Institutes of Health All of Us Research Program, a diverse US cohort with electronic health record (EHR) linkage, and included 15 199 participants who reported a cancer diagnosis and 1839 patients among a subset with EHR data who underwent treatment within the past year of the baseline survey. Data analysis was performed from October 1, 2022, to January 31, 2023.

Main Outcomes and Measures   Prevalence of current drinking and of risky drinking behaviors, including exceeding moderate drinking (>2 drinks on a typical drinking day), binge drinking (≥6 drinks on 1 occasion), and hazardous drinking (Alcohol Use Disorders Identification Test–Consumption [AUDIT-C] score ≥3 for women or ≥4 for men).

Results   This study included 15 199 adults (mean [SD] age at baseline, 63.1 [13.0] years; 9508 women [62.6%]) with a cancer diagnosis. Overall, 11 815 cancer survivors (77.7%) were current drinkers. Among current drinkers, 1541 (13.0%) exceeded moderate drinking, 2812 (23.8%) reported binge drinking, and 4527 (38.3%) engaged in hazardous drinking. After multivariable adjustment, survivors who were younger than 65 years, men, or of Hispanic ethnicity or who received a diagnosis before 18 years of age or ever smoked were more likely to exceed moderate drinking (aged <50 years: odds ratio [OR], 2.90 [95% CI, 2.41-3.48]; aged 50-64 years: OR, 1.84 [95% CI, 1.58-2.15]; men: OR, 2.38 [95% CI, 2.09-2.72]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.04-1.64]; aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.04-2.24]; former smokers: OR, 2.46 [95% CI, 2.16-2.79]; current smokers: OR, 4.14 [95% CI, 3.40-5.04]) or binge drink (aged <50 years: OR, 4.46 [95% CI, 3.85-5.15]; aged 50-64 years: OR, 2.15 [95% CI, 1.90-2.43]; men: OR, 2.10 [95% CI, 1.89-2.34]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.09-1.58]; aged <18 years at diagnosis: OR, 1.71 [95% CI, 1.24-2.35]; former smokers: OR, 1.69 [95% CI, 1.53-1.87]; current smokers: OR, 2.27 [95% CI, 1.91-2.71]). Survivors with cancer diagnosed before 18 years of age or who ever smoked were more likely to be hazardous drinkers (aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.11-2.08]; former smokers: OR, 1.83 [95% CI, 1.68-1.99]; current smokers: OR, 2.13 [95% CI, 1.79-2.53]). Of 1839 survivors receiving treatment as captured in the EHR, 1405 (76.4%) were current drinkers, and among these, 170 (12.1%) exceeded moderate drinking, 329 (23.4%) reported binge drinking, and 540 (38.4%) engaged in hazardous drinking, with similar prevalence across different types of cancer treatment.

Conclusions and Relevance   This cross-sectional study of a diverse US cohort suggests that alcohol consumption and risky drinking behaviors were common among cancer survivors, even among individuals receiving treatment. Given the adverse treatment and oncologic outcomes associated with alcohol consumption, additional research and implementation studies are critical in addressing this emerging concern among cancer survivors.

With more than 18 million cancer survivors in the United States as of 2022, 1 identifying modifiable behavioral factors that could improve survivorship and quality of life is a clinical and public health priority. Alcohol consumption, which is ubiquitous in the US and causally linked with multiple types of cancer (oral cavity, pharynx, larynx, esophagus, colorectum, liver, and female breast cancer), 2 , 3 is also associated with adverse health outcomes among individuals with a diagnosis of cancer, including higher risks of recurrence 4 , 5 or onset of new primary cancers 5 - 7 as well as death. 4 , 5 , 8 - 12 In addition, alcohol is associated with worsened treatment outcomes, such as decreased effectiveness and increased risk of complications. 13 - 17 Despite these findings, currently, no specific surveillance and counseling guidelines are in place for cancer survivors. Cancer survivors are advised to adhere to the American Cancer Society guideline on nutrition and physical activity for cancer prevention, including (1) that it is best not to drink alcohol and (2) that individuals who choose to drink alcohol should limit alcohol intake to 1 drink or fewer per day for women and 2 drinks or fewer per day for men. 18

A 2018 statement from the American Society of Clinical Oncology (ASCO) reinforces the need to prioritize alcohol consumption as a key modifiable behavioral factor in the cancer control research agenda. 19 However, our understanding of alcohol drinking patterns among cancer survivors in the US is limited. Using the National Health Interview Survey (2000-2017), Sanford et al 20 reported that 35% of cancer survivors who were current drinkers exceeded moderate drinking limits (>1 drink for women and >2 drinks for men) and 21% engaged in binge drinking (≥5 drinks during at least 1 day over the past year). However, to our knowledge, patterns of drinking, including frequency as well as the co-occurrence of multiple risky drinking behaviors, have not been described. 21 , 22 The Alcohol Use Disorders Identification Test–Consumption (AUDIT-C) score, a validated score that incorporates frequency of drinking, quantity of drinking, and binge drinking, has been used in primary care and other settings to identify individuals engaging in hazardous drinking. 23 - 26 One study in 17 European countries and Israel reported that 20% of cancer survivors aged 50 years or older engaged in hazardous drinking, 27 yet such analyses have not been conducted in the US, to our knowledge. More important, although we recently began to recognize the potential adverse effects of drinking during cancer treatment, alcohol consumption patterns during such a critical time window for cancer survivors remain underexplored. To address these knowledge gaps that are critical for short- and long-term survivorship for US cancer survivors, we aimed to comprehensively characterize alcohol consumption patterns among cancer survivors overall and during cancer treatment, using data collected from the All of Us Research Program, a diverse US cohort with electronic health record (EHR) linkage.

We identified cancer survivors enrolled in the National Institutes of Health All of Us Research Program, one of the largest, diverse biomedical cohorts within the US. 28 , 29 The All of Us Research Program collects data using survey responses, EHR data, biospecimen collection, and physical measurements. 28 , 30 The All of Us Research Program institutional review board approved all study procedures. All participants provided written informed consent to share EHRs, surveys, and other study data with qualified investigators for broad-based research. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

Among 142 100 participants who completed the Basics, Overall Health, Lifestyle, and Personal Medical History surveys, we identified 15 297 cancer survivors who self-reported a cancer diagnosis (excluding individuals with skin cancer and multiple cancers) from May 6, 2018, to January 1, 2022 (eFigure 1 in Supplement 1 ). We categorized the cancers as alcohol-related cancers (breast, colon and rectum, and head and neck) 2 and nonalcohol-related cancers (eTable 1 in Supplement 1 ). Esophageal cancer was categorized as nonalcohol related because the association with alcohol drinking is confined largely to squamous cell carcinoma, 2 whereas most cases of esophageal cancer in the US were adenocarcinoma. 31 Liver cancer was not included in alcohol-related cancers because it was not specifically included in the survey. We also retrieved information on age at cancer diagnosis (child [≤11 years], adolescent [12-17 years], adult [18-64 years], older adult [65-74 years], or elderly adult [≥75 years]) and current treatment status (“Are you currently prescribed medications and/or receiving treatment for this condition?” with an answer of yes or no).

Current alcohol consumption status (never, former, and current drinkers) was defined based on the questions in the Lifestyle survey. Participants were asked “In your entire life, have you had at least 1 drink of any kind of alcohol, not counting small tastes or sips?” which was adapted from the National Epidemiologic Survey on Alcohol and Related Conditions. We defined participants who reported not having at least 1 drink of any kind of alcohol as never drinkers, those who had at least 1 drink in their entire life but never had a drink in the past year as former drinkers, and those who had at least 1 drink in the past year as current drinkers. After excluding 98 participants without adequate information to define their current alcohol consumption status, 15 199 cancer survivors were retained in the analyses.

Among current drinkers, we further characterized risky drinking behaviors based on 3 questions: (1) frequency of drinking: “How often did you have a drink containing alcohol in the past year?” with options of never, monthly or less, 2 to 4 times a month, 2 to 3 times a week, or 4 or more times a week; (2) quantity of drinking: “On a typical day when you drink, how many drinks do you have?” with options of 1 or 2, 3 or 4, 5 or 6, 7 to 9, or 10 or more; and (3) binge drinking: “How often did you have 6 or more drinks on 1 occasion in the past year?” with options of never, less than monthly, monthly, weekly, or daily or almost daily. Exceeding moderate drinking was defined from answers about quantity of drinking as participants who drink more than 2 drinks on a typical day when they drink. Binge drinking was defined from the question about binge drinking as participants who ever had 6 or more drinks on 1 occasion. To create the AUDIT-C score (range, 0-12), we added scores of 3 questions with 5 possible answers, which were scored from 0 (less alcohol use) to 4 points (more alcohol use) (eTable 2 in Supplement 1 ). 24 Hazardous drinkers included women with AUDIT-C scores of 3 or higher and men with scores of 4 or higher. 24 , 32 , 33

We included information on age, sex, race and ethnicity, marital status, educational level, annual household income, and insurance status from the Basics survey and general health condition from the Overall Health survey. Sex was categorized based on the question “What was your biological sex assigned at birth?” as women, men, and other sex (including participants who selected “intersex,” “prefer not to answer,” “none of these,” and “skip”). Data on race and ethnicity were collected because prior research has demonstrated different drinking patterns according to racial and ethnic groups. 34 , 35 Race and ethnicity were categorized as Hispanic, non-Hispanic Black, non-Hispanic White, and other according to participant self-report. Other race included individuals reporting races other than Hispanic, non-Hispanic Black, or non-Hispanic White (Asian, Middle Eastern or North African, Native Hawaiian or Other Pacific Islander, and participants who responded that none of the provided options fully describe them) and individuals with more than 1 race and ethnicity. Smoking status was assessed in the Lifestyle survey: participants who reported not smoking at least 100 cigarettes in their entire life were categorized as never smokers, those smoking at least 100 cigarettes in their entire life but now do not smoke at all were categorized as former smokers, and those smoking at least 100 cigarettes in the entire life and now smoke every day or some days were categorized as current smokers.

After linking with the EHR, 36 we identified 10 892 cancer survivors with a first medical encounter 1 year or more before the baseline surveys and a subset of 1839 patients who underwent treatment within the past year of the baseline survey. Treatment was retrieved based on prior studies, using the Current Procedural Terminology , 4th Edition; Healthcare Common Procedure Coding System; Systematized Nomenclature of Medicine Clinical Terms; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Procedure Coding System ; and RxNorm. 37 - 39 We further classified the treatment as surgery, chemotherapy, hormone therapy, radiotherapy, and immunotherapy. We identified treatment modalities that aligned with self-reported cancer type. For surgery, we ensured to include only procedures that matched the specific cancers for which patients received a diagnosis. For instance, we did not count colectomies for any patient without a diagnosis of colorectal cancer.

Statistical analysis was performed from October 1, 2022, to January 31, 2023. We estimated the crude prevalence of current drinking among cancer survivors as well as the crude prevalence of risky drinking behaviors (including exceeding moderate drinking, binge drinking, and hazardous drinking) among current drinkers. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% CIs of current drinking and risky drinking behaviors among current drinkers, adjusting for age at survey (<50, 50-64, or ≥65 years), sex (women, men, or other), race and ethnicity (Hispanic, non-Hispanic Black, non-Hispanic White, or other), marital status (never or ever), educational level (<high school, high school or General Educational Development certification, some college, or college), annual household income (<$34 999, $35 000-$74 999, $75 000-$149 999, or ≥$150 000), insurance status (yes or no), smoking status (never, former, or current), cancer type (nonalcohol-related cancers or alcohol-related cancers), age at cancer diagnosis (<18, 18-64, or ≥65 years), and medication and/or receiving treatment (yes or no).

Among the subset of cancer survivors with EHR data who underwent treatment, we estimated the crude prevalence of current drinking and risky drinking behaviors overall and according to type of cancer treatment. To compare with the general population, we conducted secondary analyses to estimate the crude prevalence of current and risky drinking behaviors among survey participants without a prior cancer diagnosis. Data were analyzed in the All of Us Research Workbench (R, version 4.0.2 [R Group For Statistical Computing]).

In the overall cohort of 15 199 cancer survivors, the mean (SD) age at baseline was 63.1 (13.0) years, 9508 survivors (62.6%) were women, and 11 633 survivors (76.5%) were non-Hispanic White ( Table 1 ). Most cancers (11 515 [75.8%]) were diagnosed when the patient was between 18 and 64 years of age. Most cancer survivors had a college degree (9291 [61.1%]) and a high annual household income, 5333 (35.1%) were former smokers, and 997 (6.6%) were current smokers. Among 1839 cancer survivors who underwent cancer treatment within the past year of the baseline survey, their characteristics were similar to those in the overall cohort (eTable 3 in Supplement 1 ).

Of 15 199 cancer survivors, 11 815 (77.7%) were current drinkers (women, 7344 of 9508 [77.2%]; men, 3971 of 5049 [78.6%]) ( Table 2 ). After multivariable adjustment, survivors who were non-Hispanic White, with alcohol-related cancers, without self-reported current medication prescription and/or treatment, and who were ever smokers were more likely to be current drinkers ( Figure 1 ; eTable 4 in Supplement 1 ). Compared with non-Hispanic White individuals, survivors who were Hispanic (OR, 0.65; 95% CI, 0.56-0.76), non-Hispanic Black (OR, 0.71; 95% CI, 0.61-0.82), and of other race and ethnicity (OR, 0.49; 95% CI 0.41-0.58) were less likely to be current drinkers. Survivors with alcohol-related cancers were 16% more likely (OR, 1.16; 95% CI, 1.06-1.27) to be current drinkers. Compared with survivors who self-reported they were not currently receiving prescription medication or treatment, those who underwent treatment were less likely to be current drinkers (OR, 0.87; 95% CI, 0.80-0.94). Former smokers (OR, 1.27; 95% CI, 1.16-1.39) and current smokers (OR, 1.44; 95% CI, 1.22-1.70) were also more likely to be current drinkers compared with never smokers.

Of 11 815 survivors who were current drinkers, 1541 (13.0%) exceeded moderate drinking (women, 777 of 7344 [10.6%]; men, 696 of 3971 [17.5%]), and 2812 (23.8%) reported binge drinking (women, 1560 of 7344 [21.2%]; men, 1119 of 3971 [28.2%]) ( Table 2 ; eFigure 2 in Supplement 1 ). After multivariable adjustment, survivors who were younger than 65 years, who were men, who were Hispanic, with cancer diagnosed before 18 years of age, or who ever smoked were more likely to exceed moderate drinking (aged <50 years: odds ratio [OR], 2.90 [95% CI, 2.41-3.48]; aged 50-64 years: OR, 1.84 [95% CI, 1.58-2.15]; men: OR, 2.38 [95% CI, 2.09-2.72]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.04-1.64]; aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.04-2.24]; former smokers: OR, 2.46 [95% CI, 2.16-2.79]; current smokers: OR, 4.14 [95% CI, 3.40-5.04]) and engage in binge drinking (aged <50 years: OR, 4.46 [95% CI, 3.85-5.15]; aged 50-64 years: OR, 2.15 [95% CI, 1.90-2.43]; men: OR, 2.10 [95% CI, 1.89-2.34]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.09-1.58]; aged <18 years at diagnosis: OR, 1.71 [95% CI, 1.24-2.35]; former smokers: OR, 1.69 [95% CI, 1.53-1.87]; current smokers: OR, 2.27 [95% CI, 1.91-2.71]) ( Figure 2 ; eTable 5 in Supplement 1 ). The odds of engaging in more than moderate drinking or binge drinking were similar among current drinkers who reported receiving medication and/or undergoing treatment and those who did not.

A total of 4527 current drinkers (38.3%) engaged in hazardous drinking, defined by an AUDIT-C score of 3 or higher for women and 4 or higher for men, with similar prevalences among women and men. After multivariable adjustment, survivors with cancer diagnosed before 18 years of age were more likely to be hazardous drinkers (OR, 1.52; 95% CI, 1.11-2.08) compared with those diagnosed at 65 years of age or older (eTable 5 in Supplement 1 ). Compared with never smokers, former smokers were 83% more likely (OR, 1.83; 95% CI, 1.68-1.99) to be hazardous drinkers, and current smokers had more than 2-fold the odds (OR, 2.13; 95% CI, 1.79-2.53) of engaging in hazardous drinking. For survivors with the highest risk of hazardous drinking (current smokers who received a cancer diagnosis before 18 years of age), their risky drinking behaviors were associated with more frequent, heavy drinking as well as binge drinking (eFigure 3 in Supplement 1 ). No association was observed between self-reported receipt of medication or treatment and hazardous drinking. Of 119 977 survey participants without a prior cancer diagnosis, 96 058 (80.1%) were current drinkers; among these, 19 949 (20.8%) exceeded moderate drinking, 34 135 (35.5%) reported binge drinking, and 48 090 (50.1%) engaged in hazardous drinking (eTable 6 in Supplement 1 ).

Of 1839 cancer survivors who received treatment within the past year of the baseline survey, 1405 (76.4%) self-reported as current drinkers ( Table 3 ), similar to the prevalence in the overall cohort of patients who self-reported receiving medication and/or treatment and being current drinkers (4211 of 5531 [76.1%]). This prevalence was largely similar for each cancer treatment, with the highest for patients who underwent surgery (329 of 409 [80.4%]) ( Table 3 ). Of 1405 current drinkers who received treatment within the past year of the baseline survey, 170 (12.1%) exceeded moderate drinking, 329 (23.4%) reported binge drinking, and 540 (38.4%) engaged in hazardous drinking.

Our study extends the scope of prior understanding through using a diverse US cohort to characterize risky drinking behaviors comprehensively among cancer survivors. We again highlight that alcohol consumption and risky drinking behaviors are common among cancer survivors, and we found that, among current drinkers, men, Hispanic individuals, those with cancer diagnosed before 18 years of age, and smokers are more likely to engage in risky drinking behaviors. More important, by linking with EHR data to annotate treatment information, we found that drinking and risky drinking behaviors are prevalent even among individuals concurrently receiving treatment for cancer.

Similar to a prior study using a nationally representative survey, 20 we found that most cancer survivors were current drinkers, and non-Hispanic White individuals or ever smokers were more likely to be current drinkers. In addition, we found that survivors with alcohol-related cancers or without self-reported current treatment were more likely to be current drinkers. Also in line with the previous study, 20 we found that, among current drinkers, survivors who were younger, men, Hispanic, and ever smokers were more likely to exceed moderate drinking or binge drink. Comparable with previous findings, 40 our study also suggested that Hispanic individuals are less likely to drink compared with non-Hispanic White individuals, but Hispanic individuals who choose to drink are more likely to consume higher volumes of alcohol, possibly due in part to acculturation. 41 Although adolescent or young adult cancer survivors were reported to be more likely than peers without cancer to drink alcohol, 42 our study found that survivors with cancer diagnosed before 18 years of age were more likely to engage in both heavy and binge drinking. Using validated AUDIT-C scores that incorporate frequency of drinking, quantity of drinking, and binge drinking, we reported for the first time, to our knowledge, that 38.3% of cancer survivors in this diverse US cohort engaged in hazardous drinking. This higher prevalence compared with those reported in Europe by Bosque-Prous et al 27 might be explained in part by using lower cutoff points to define hazardous drinking in our study (AUDIT-C scores of ≥3 for women and ≥4 for men) vs those used by Bosque-Prous et al 27 (AUDIT-C scores of ≥4 for women and ≥5 for men). Although more studies are warranted, the high prevalence of cancer survivors engaged in hazardous drinking highlights the need for immediate interventions to reduce alcohol intake among US cancer survivors.

Alcohol consumption and risky drinking behaviors among cancer survivors are associated with various adverse long-term outcomes, including higher risk of recurrence, 4 , 5 secondary primary tumors, 5 - 7 and increased mortality. 4 , 5 , 8 - 12 In a meta-analysis involving 209 597 cancer survivors, alcohol consumption was associated with a 17% increased risk of cancer recurrence and an 8% increased risk of overall mortality. 4 More studies are warranted to elucidate the role of each risky drinking behavior and the overall pattern in long-term outcomes. Survivors with cancer diagnosed before 18 years of age or ever smokers were more likely to be hazardous drinkers. Because of the persistent excess risks for second primary cancers throughout the life course for childhood cancer survivors 43 - 45 and the elevated risks for alcohol- and tobacco-related secondary primary cancers among drinkers who ever smoke, 6 targeted efforts for alcohol reduction are needed for these 2 groups of survivors who are more susceptible.

As highlighted in the 2018 ASCO statement, 19 in addition to long-term survivorship, accumulating data support the associations between alcohol drinking and treatment outcomes among cancer survivors. For instance, alcohol use worsens postsurgical outcomes, including increased risk of surgical complications, longer hospitalizations, more surgical procedures, prolonged recovery, higher health care costs, 46 - 48 and higher mortality. 19 , 49 Alcohol use during and after radiotherapy is associated with a higher risk of osteonecrosis of the jaw among patients with head and neck cancers. 50 - 53 In addition, alcohol is well known to have neurotoxic, cardiotoxic, and hepatotoxic effects. 54 - 56 Among patients undergoing chemotherapy, alcohol has been suggested to worsen cognition and cardiotoxicity. 57 , 58 Furthermore, alcohol use is associated with hepatic dysfunction and regulates cytochrome enzymatic activity, 54 which is important for the metabolism of chemotherapeutic agents and possibly alters their effectiveness or toxic effects. Although the association of alcohol use with immunotherapy for cancer is unclear, the treatment outcomes may be somewhat affected due to alcohol-induced immune dysfunction. 59

Our understanding of alcohol consumption patterns among cancer survivors receiving treatment has just begun to emerge. In a recent pilot study of 69 patients in Wisconsin, 30% of cancer survivors reported drinking alcohol while receiving chemotherapy, and 38% of these drinkers reported at least some complications. 60 To date, the All of Us Research Program is the only national cohort that allows us to capture alcohol consumption patterns in the context of cancer treatment. Unexpectedly, a large proportion of cancer survivors undergoing cancer treatment were current drinkers (76.4%) or were engaged in risky drinking (exceeding moderate drinking, 12.1%; binge drinking, 23.4%; hazardous drinking, 38.4%); these proportions were similar across different types of cancer treatment as well as in the overall cohort. Taken together, our findings point to the immediate and unmet need to intervene on the behalf of individuals with risky drinking behaviors in oncologic care settings. Clinicians should collect alcohol consumption information while also informing survivors of the potential harms in an effort to reduce risky alcohol use. Given that drinking is deeply ingrained in societal norms and rituals, and considering the limited awareness of how alcohol consumption is associated with cancer outcomes, it is imperative to provide support to patients who are identified as alcohol users and offer them guidance. Our findings also call for large-scale epidemiologic studies to further evaluate the association of alcohol with therapeutic efficacy and treatment outcomes among cancer survivors.

This study has some strengths, including the use of a large and diverse national cohort to comprehensively characterize risky drinking behaviors, including hazardous drinking, whereas previous studies focused on exceeding moderate drinking and binge drinking only. More important, we used the EHR linkages to retrieve information on cancer treatment.

Our study also has several limitations. First, per the Dietary Guidelines for Americans 2020-2025, exceeding moderate drinking was defined as having more than 1 drink per day for women. 61 However, the All of Us Research Program survey only allowed us to define exceeding moderate drinking among women as having more than 2 drinks. Similarly, we characterized patients who consumed 6 or more drinks on 1 occasion as binge drinkers, instead of those who consumed 4 or more drinks for women or 5 or more drinks for men per the National Institute on Alcohol Abuse and Alcoholism guideline. 62 However, with these underestimates, the prevalence of women exceeding moderate drinking was high, as was the prevalence of binge drinking among both women and men, which further highlight the pressing need for reduction of alcohol consumption. Second, because the All of Us Research Program survey asked about average alcohol consumption in the past year, we retrieved cancer treatment information during the same time in the EHR. However, the exact timing of alcohol consumption in association with cancer treatment was not clear. Additional studies are required to validate and refine our findings.

This cross-sectional study found that current and risky drinking (exceeding moderate drinking, binge drinking, and hazardous drinking) were common among US cancer survivors even during cancer treatment. Given the short- and long-term adverse treatment and oncologic outcomes associated with alcohol consumption, additional research and implementation studies are critical to address this emerging concern among cancer survivors.

Accepted for Publication: June 30, 2023.

Published: August 10, 2023. doi:10.1001/jamanetworkopen.2023.28328

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Shi M et al. JAMA Network Open .

Corresponding Author: Yin Cao, ScD, MPH, Division of Public Health Sciences, Department of Surgery, Washington University in St Louis School of Medicine, 660 S Euclid Ave, Campus Box 8100, St Louis, MO 63110 ( [email protected] ).

Author Contributions: Ms Shi and Dr Cao had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ms Shi and Dr Luo contributed equally.

Concept and design: Shi, Cao.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Shi, Oduyale, Cao.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Luo, Zong, Cao.

Obtained funding: Cao.

Administrative, technical, or material support: LoConte, Cao.

Supervision: Cao.

Conflict of Interest Disclosures: Dr LoConte reported receiving personal fees from AbbVie and PDGX; and grants from Exact Sciences outside the submitted work. Dr Cao reported receiving personal fees from Geneoscopy outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grants P30 CA091842 and R21 AA027608 from the US National Institutes of Health (Dr Cao). Dr Oduyale was supported by the Foundation for Barnes-Jewish Hospital.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2 .

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• Published: 14 April 2011

A Research Strategy Case Study of Alcohol and Drug Prevention by Non-Governmental Organizations in Sweden 2003-2009

• Charli Eriksson 1 ,
• Susanna Geidne 1 ,
• Madelene Larsson 1 &
• Camilla Pettersson 1  

Substance Abuse Treatment, Prevention, and Policy volume  6 , Article number:  8 ( 2011 ) Cite this article

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Alcohol and drug prevention is high on the public health agenda in many countries. An increasing trend is the call for evidence-based practice. In Sweden in 2002 an innovative project portfolio including an integrated research and competence-building strategy for non-governmental organisations (NGOs) was designed by the National Board of Health and Welfare (NBHW). This research strategy case study is based on this initiative.

The embedded case study includes 135 projects in 69 organisations and 14 in-depth process or effect studies. The data in the case study has been compiled using multiple methods - administrative data; interviews and questionnaires to project leaders; focus group discussions and seminars; direct and participatory observations, interviews, and documentation of implementation; consultations with the NBHW and the NGOs; and a literature review. Annual reports have been submitted each year and three bi-national conferences Reflections on preventions have been held.

A broad range of organisations have been included in the NBHW project portfolio. A minority of the project were run by Alcohol or drug organisations, while a majority has children or adolescents as target groups. In order to develop a trustful partnership between practitioners, national agencies and researchers a series of measures were developed and implemented: meeting with project leaders, project dialogues and consultations, competence strengthening, support to documentation, in-depth studies and national conferences. A common element was that the projects were program-driven and not research-driven interventions. The role of researchers-as-technical advisors was suitable for the fostering of a trustful partnership for research and development. The independence of the NGOs was regarded as important for the momentum in the project implementation. The research strategy also includes elements of participatory research.

Conclusions

This research strategy case study shows that it is possible to integrate research into alcohol and drug prevention programs run by NGOs, and thereby contribute to a more evidence-based practice. A core element is developing a trustful partnership between the researchers and the organisations. Moreover, the funding agency must acknowledge the importance of knowledge development and allocating resources to research groups that is capable of cooperating with practitioners and NGOs.

Introduction

Alcohol and drug prevention is high on the public health agenda in most countries. The national initiatives differ, although action plans have been proposed by international organizations such as WHO [ 1 ]. Moreover, there is an increasing demand for evidence-based alcohol and drug prevention, causing an increased emphasis on research for prevention, an emphasis that this field shares with health promotion, prevention in general, and social work [ 2 – 8 ]. This means that prevention research needs to move "from basic to more and more applied research; from descriptive hypothesis-generating pilot studies to full-fledged, methodologically sophisticated, hypothesis-testing studies; from smaller to larger samples for testing; from greater to lesser control of experimental conditions; from more artificial 'laboratory' environments to real-world geographically defined communities; from testing the effects of single intervention strategies into more complex studies of multiple strategies integrated into intervention systems; and from research-driven outcome studies to 'demonstration' projects that evaluate the capacity of various types of communities to implement prevention programs based on prior evaluations" [[ 9 ], p 183]. It has also been more than 10 years since Nutbeam [ 10 , 11 ] noted the gap between the need for knowledge and the priorities among researchers.

Many years have passed since these recommendations, but still the gap between evidence and practice has not been bridged despite important achievements in implementation research [ 12 ], designs for effectiveness and translation research [ 13 ], and a series of initiatives regarding the evidence-practice gaps [ 14 – 22 ]. The call for more practice-based evidence is a challenge for policy-makers, practitioners, researchers, and funding agencies [ 17 , 23 ]. In several countries research on alcohol and drug issues has been incorporated into addiction research centres [ 24 – 28 ]. For many years much addiction research has been the product of specialized research centres rather than the contribution of standalone scientists. Moreover it is the specialist centres, in collaboration with the national funding agencies, which today assert leadership, set agendas, and help determine standards [ 24 ]. However, a common element in the missions of these centres is monitoring the substance use in the population, its causes, and courses, while prevention research is not high on the agendas. Furthermore, the establishment of national centres demonstrates the political administration's emphasis on scientific, evidence-based policies, but at the same time demonstrates the view that credible research is best performed within independent scientific bodies [ 26 ].

In Sweden in 2002 an innovative project portfolio for non-governmental organisations (NGOs) was designed by the National Board of Health and Welfare (NBHW). This included an integrated research and competence-building strategy to strengthen alcohol and drug prevention. This case study aims to describe and analyse this initiative.

AD prevention in Sweden - legislation, national action plans, resources, and actors

Sweden has a long tradition of a restrictive alcohol policy [ 29 ]. The temperance movement became a powerful actor in the Swedish alcoholic beverage policy [ 30 ]. Moreover, Sweden is one of the few countries in Europe with a narcotics policy that aims to create a society entirely free of illicit drugs [ 31 ].

The overall goal of the Swedish action plan on alcohol and narcotics is to promote public health by reducing the medical and social harm caused by alcohol and to create a drug-free society. The strategy for achieving this goal with regard to alcohol is to reduce the total consumption and prevent harmful drinking, taking into account differences in living conditions among boys, girls, men, and women. Six priority sub-goals have been adopted: alcohol should not be consumed in transport contexts, at workplaces, or during pregnancy; children should grow up in an alcohol-free environment; the age of alcohol debut should be postponed; drinking to point of intoxication should be reduced; there should be more alcohol-free environments; and illicit alcohol should be eliminated. The sub-goals in the action plan on narcotics are to reduce recruitment to drug abuse, induce people with substance abuse problems to give up their abuse, and to reduce the supply of drugs. Interventions targeting children, adolescents, and parents are of high priority [ 32 ].

Swedish alcohol policy is based on a combination of taxed-based price controls and the alcohol retail monopoly in order to limit the availability and accessibility of alcohol [ 32 ]. There is strong evidence for the preventive effects of an alcohol retail monopoly [ 33 , 34 ] and high prices on alcohol are regarded as one of the most effective ways of reducing total alcohol consumption and alcohol-related problems [ 35 ]. When Sweden entered the EU in 1995, the conditions changed and Sweden could no longer have an independent alcohol policy. For example, the availability of alcohol increased as a result of changed rules for private import, and alcohol taxes had to be adjusted. The numbers of alcohol shops as well as their opening hours have also increased remarkably since 1995 [ 29 ]. The increased movements across borders have also had an influence on the illicit drugs market. Almost all narcotics that are consumed in Sweden have been produced outside the country. A well-developed international collaboration is therefore of high importance for the limitation of illicit drugs in Sweden [ 32 ].

An effective alcohol and drug policy also requires national coordination. The Swedish government has established a national council for alcohol, narcotics, doping, and tobacco. The council consists of members of public authorities, civil society, and researchers, and is led by the State Secretary of the Ministry of Health and Social Affairs. The council is commissioned to advise the government on issues about alcohol, drugs, doping, and tobacco and to present information about research results [ 36 ].

There is a need for the different sectors in society to increase and deepen their cooperation for an effective prevention of the use of alcohol, tobacco, and drugs. In the Swedish action plan on alcohol and illicit drugs as well as in the government bill for public health the importance of the voluntary sector is emphasized [ 36 , 37 ]. In the latter document, A renewed public health policy , it is stated that cooperation between the state and the voluntary sector should be expanded and that the conditions for the voluntary sector's work should improve [ 37 ]. An agreement about the relations between the government, the voluntary sector in the social setting, and the Swedish Association of Local Authorities and Regions has recently been developed through a dialogue between the parties. The dialogue is another way for the government to call attention to the voluntary sector and to its ambition to strengthen the sector and improve its conditions. The goal of the agreement was to strengthen the independence of the voluntary sector as moulders of public opinion and to support the development of public medical service carried out by the voluntary sector [ 38 ]. The Swedish voluntary sector has a long tradition of alcohol prevention, especially the temperance movements [ 39 ].

NGOs in Sweden

The Swedish voluntary sector is both different and similar to those in other countries. A major difference lies in its history in that, for instance, as early as in the 16th century the responsibility for health and care was organized under the state instead of in the regime of the church. In parts of Europe the church still is an active actor in health and care [ 40 , 41 ]. Also, popular mass movements have played an important role in the development of Swedish society [ 41 , 42 ]. The Swedish voluntary sector is as large as in other industrialized countries, although quite different in character. It is dominated by organizations in the cultural and recreational field, mainly sports organizations. Since the early 1990s the Swedish voluntary sector has expanded, particularly in the two areas of culture and recreation, as well as in the area of social care [ 43 ]. It can also be called membership-based; almost everyone in Sweden is a member of some organization. Because of these differences in history and structure in different societies, the voluntary sector plays different roles. In Sweden, NGOs are more of a complement then a substitute for state programs, and have an important role as forerunners and innovators [ 44 ].

Previous research has shown that the Swedish voluntary sector was highly dependent on public financing, which is partly correct. Looking at the entire sector together, about 30 percent of its financing comes from government funding. However, within the health care and social service sector, public financing stands for more than 70 percent. That is quite high in comparison with other European countries, but not the highest [ 45 ].

Support to NGOs today

Organizational grants.

The National Board of Health and Welfare (NBHW) has a government commission to administer the grants to national organizations for the disabled, the elderly, and relatives of elderly persons; to national organizations in the social setting; and to national and local organizations. For the moment this amounts to about 300 million SEK to about 100 organizations. Also the Swedish National Institute of Public Health has funds to distribute to NGOs or to other organizations working together with NGOs. The Swedish State Inheritance Fund is also a possible source of funding for NGOs. They administer over 300 million SEK a year to provide grants to NGOs working with children, youth, and the disabled. In addition other governmental agencies such as the Swedish National Board for Youth Affairs also support NGOs.

Project grants

In the late 1990s a new system of awarding grants to NGOs in the arenas of alcohol and narcotics, vulnerable children and their families, and violence against women was prepared. The previous systems were from the late 1970s and early 1980s, and during the 1990s many investigations recommended a better, more structured follow-up and evaluation of the NGOs' work. One new idea that emerged during the 1990s was increased performance management, that is, the need to point out achieved results and effects of different activities. It was emphasized that the government should not interfere with the running of the organizations but does have the duty to monitor the use of the grants. There was also a desire that renewal efforts and collaborations should be encouraged and supported.

In the late 20th century grants were awarded through the Swedish National Institute of Public Health (with money from the Swedish State Inheritance Fund) to a number of alcohol and drug prevention projects. A final report and an internal evaluation were required from the applicants. There was also an external evaluator, who conducted an evaluation of 11 projects focusing on their working processes [ 46 ]. Among the lessons learned from this evaluation were that the way of working should be characterized by frequent contacts and dialogue between the funding agency and the project, and also by supervision. The evaluation report also suggested that the support to the project leaders should be reviewed with regard to the possibility of different types of need-based support. Moreover, the short-term thinking in the funding of these kinds of projects was not in line with the needed time-frame.

Setting the Scene: NGO strategy for alcohol and drug prevention

Non-governmental organizations have received grants from the NBHW to conduct alcohol and drug preventive work in a special venture since 2003 [ 47 ]. This initiative is part of the national plan of action to prevent alcohol-related harm and the national plan of action against narcotics and comes from the Ministry of Health and Social Affairs. The working committee, which decides who will get funding, consists of members of the NBHW, the Swedish National Institute of Public Health, and the Swedish National Board for Youth Affairs (previously members of the Swedish Alcohol Committee and the Swedish National Drug Policy Coordinator were included). The working committee, after consulting the research team at Örebro University, also decides which projects will be studied in-depth. NBHW's initiative represented a new way of thinking. One point of departure was to create a project portfolio with a broad combination of organizations to mobilize many forces in the alcohol and drug preventive work. The initiative also contains supervision for the project leaders, competence support through regular meetings for project leaders, and an integrated Research & Development (R&D) investment (Figure 1 ).

Integrated research and development for NGO alcohol and drug prevention .

Need for knowledge building and learning

There is an increasing trend towards promoting evidence-based public health initiatives. International expert committees have presented the state of science with regard to alcohol prevention: Alcohol Control Policies in Public Health Perspectives [ 48 ]; Alcohol Policy and the Public Good [ 49 ]; and Alcohol: No Ordinary Commodity -Research and Public Policy [ 33 , 50 ]. National authorities have presented reviews presenting evidence for practitioners and politicians [ 51 – 53 ]. However, there are important knowledge gaps to be filled. Among these is the lack of effectiveness studies where the external validity is high. If we want to see more evidence-based practice we need more practice-based evidence [ 54 ]. This means an improved emphasis on cooperation between researchers and practitioners [ 10 ].

A comprehensive perspective on the concept of knowledge, including scientific and practical knowledge as well as practical wisdom, is needed. Scientific knowledge about alcohol and drug issues needs to be complemented with knowledge about methods for alcohol and drug prevention. As in other public health fields, ethical issues and practical wisdom are important [ 55 ]. Moreover, the science, craft, and art of implementation are of utmost importance. There are many reasons besides practicalities that are significant for the implementation of programs [ 7 , 56 ]. In a recent review, 23 different factors were found that were of importance for the degree of the implementation [ 12 ] and that also have a great impact on the program effects.

Research on alcohol and drugs has often been organized in special research institutes, which often focus on basic research on alcohol and drugs [ 24 – 28 ]. This basic research is related both to basic biomedicine as well as social and behavioural studies. Another activity, which has been accorded great prominence, is the monitoring of alcohol and drug use in the population in general as well in different groups. Intervention research has been given less prominence in these often national research institutes. However, the national agencies, such as the Swedish Institute of Public Health, have been involved in the evaluation of different intervention projects. So far research on NGO-driven alcohol and drug prevention has been almost completely lacking. Research has been a more or less exclusive activity for the university. However, this has been based on the trust in the impartiality and objectivity of the university-based researchers. The downside of this position is that this type of research may lack the necessary cultural awareness and insights necessary for a proper understanding of basic factors for successfully planning intervention programs as well as evaluating research efforts. In other words the roles of the researcher in intervention studies need to be addressed. In a recent study, Holmila et al. [ 57 ] outlined three different positions for researchers in community intervention studies. The researcher can be an external observer, not taking part in the preventive activities - acting as an unobtrusive observer . The researcher assumes no responsibility for the design or implementation of the projects but acts as an independent conductor of process evaluation and observer of project outcomes. Another position is to be a researcher-as-technical advisor . In this role the researcher has responsibility for evaluation but also takes the responsibility for providing scientific advice on effective preventive strategies if asked for [ 58 – 60 ]. This could include training and technical assistance to the projects. Progress reports on findings as well as results from different on-going studies can be presented to the practitioners, which may use this information as they desire. A third type is researcher-as-designer , where the project is designed by the research team in partnership with the practitioner. The researcher is an active participant in project planning as well as the process of carrying it out and evaluating the effects. This approach is particularly useful when the goal is to test one or more designed prevention strategies under as close to optimal conditions as possible. Examples of such in Sweden are the STAD Project in Stockholm [ 61 ] and the Trelleborg Project [ 62 ]. The Örebro Prevention Program is an example of a program where all parts of the process were in the hands of the researchers [ 63 ].

The present paper aims to describe and analyse alcohol and drug prevention supported by the NBHW and implemented by NGOs in Sweden during 2003-2009 with a special emphasis on research and development for an evidence-based practice. The case study analyses also the integrated research strategy and its main components.

Three research questions will be addressed:

Which types of organizations and projects have received grants from the NBHW for AD prevention?

What types of research and development activities for an evidence-based practice have been included?

How can a trustful partnership develop between practitioners, national agencies, and researchers?

Methods and materials, case study approach.

A case study method was chosen as the intention was to understand a real-life phenomenon in depth and the contextual factors were highly pertinent to the study [ 64 ]. This method investigates according to Yin contemporary phenomenon in depth and within its real-life context, especially when the boundary between the phenomenon and context are not clearly evident. Moreover, the case study approach copes with the situation such as in this case in which there will be more variables of interest than data, which leads to the need for multiple sources of evidence, with data needing to converge in a triangulating fashion. Furthermore, benefits from the prior development of theoretical propositions to guide data collection and analysis [ 64 ]. The present research strategy case study is on an organisational level. It studies a social process in a situation in which we have little knowledge of the phenomenon, integration of research in alcohol and drug prevention run by NGOs. Case studies as a main research strategy are selected as this is a unique case in Sweden, the impossibility to isolate the process and the intention is to combine research and action [ 65 ].

An embedded single-case design was chosen for the study. All the projects run by the NGOs are seen as embedded units of analysis in the study with special emphasis on the fourteen in-depth studies.

Participants

The embedded case study includes 135 projects in 69 organisations and 14 in-depth process or effect studies. The participants in this research strategy case study are the NGOs applying for funding to the NBHW and especially those NGOs that have received funding during 2003-2009. The project leaders and managers in the NGOs as well as the members of the different target groups are also participants in this study. Moreover, staff at the NBHW as well as other stakeholders is included.

Case study questions

When the research program started a set of overall research questions were developed. In this paper the focus is in one of these, how can a trustful partnership for practice-based research be developed? Additional questions concerns: the role as a project leader in NGOs, the impact of competence development, methods for documentation of project development, and the added value of running projects in NGOs.

Case study protocol

A plan for the research and development activities was developed the first year and amended each year after the completion of the annual report to the NBHW. This plan consisted of several parts relating to the overall activities as well as the different in-depth studies. Notes were taken at meetings and as part of the strategy a series of presentations as progress reports were given to, project leaders, NGOs and the NBHW.

Development of a Case Study Database

In the present study a broad range of methods was used in the data collection. This includes six types of data.

Administrative data

The applications from the NGOs to the NBHW as well as the funding decisions were the initial data, which was complemented by bi-annual as well as annual progress reports from all funded projects. These reports, which were submitted following a format developed by the research team, gave information on implementation and goal achievement as well as reflections on barriers and facilitating factors. The research team introduced this approach at a meeting with the project leaders, and this reporting resulted in an annual report to the NBHW on the progress of the alcohol and drug prevention projects run by the NGOs.

Interviews and questionnaires to project leaders

Data was collected from project leaders and their organizations in the years when funding was received from the NBHW. In 2003, 2005, 2007, and 2009 all project leaders were invited to respond to a questionnaire containing questions on being a project leader in a non-governmental organization. If the same project leaders were responsible for a project for more than one year they responded to more than one questionnaire. Most of those who answered the 2003 questionnaire also answered the 2005 questionnaire, due to the fact that many of those projects receiving funding in 2003 also were being funded in 2005. In total, 84 persons participated in the questionnaire study over the years. Of these, 38 project leaders answered the questions more than one year.

Focus group discussions and seminars

Thematic discussions were held as a part of the meetings with the project leaders. These highlighted special issues related to the practice of alcohol and drug prevention. Moreover, a series of joint seminars with NGOs and the research team have been held at national and organizational conferences focusing on different projects.

Direct observations, participatory observations, interviews, and documentation of implementation of the in-depth studies

The research team collected information by a variety of methods during the planning, implementation, and evaluation of the in-depth studies. Part of this data has been used in the analysis, resulting in separate reports and scientific publications. However, in this context more process-related data will be used to give insights into the development of the partnerships between researchers and practitioners.

Consultation with the NBHW and the NGOs

In the present paper information retrieved during the management of the NBHW support to the NGOs will be an additional source of information. Regular meetings have taken place with the steering committee and the senior administrative officer, who have been the same persons during all years. The consultations with the NGOs were more intense for those organizations selected for in-depth studies, but several meetings have also taken place with other organizations. Apart of the in-depth studies was feedback on preliminary results from different studies; this never radically changed the interpretation of results but did add valuable information.

Literature review

A systematic review of the research strategies for alcohol and drug prevention has been carried out as an integral part of the research program. A number of publications related to collaboration between researchers and practitioners were found. Special thematic sections and series have been looked for. Among the key words are addiction research centre, alcohol and drug research, preventive research, practice-based research, and evidence-practice gaps.

Analytical methods

The analytical approach in this case study follows a common strategy used in research programs: to start with the ordinary preventive activities and then study what is happening [ 66 , 67 ]. Using a naturalistic approach, which is always practice-based, it has been important to let different actors and stakeholders into the knowledge-building program. This also has implications for the selection of research and evaluation methods, given a need for mixed-method approaches [ 68 – 70 ]. In studies of effects, quantitative approaches are essential, but important contributions can be achieved if qualitative studies are also included [ 71 , 72 ]. The mixed-methods approaches have been developed for some of the more extensively studied programs, which also will be included in doctoral dissertations [ 73 , 74 ].

The analysis starts with a quantitative description of the investment in NGOs by agencies awarding grants and an analysis of which organizations and projects that were supported. The types of organizations are analysed with regard to their main focus or mission. Then the investment in research is described including an overview of the participants in different empirical studies using a range of data collection methods. This includes a description of how the embedded units, the project in the NBHW portfolio, have been documented and presented in annual reports using a format for the written reports based on questions and answers in the case study database [ 64 ]. The two types of in-depth studies are briefly presented: effect studies and studies of process and implementation.

An analysis of the experiences of cross-project comparisons as well as using the multiple sources of evidence in the case study database follows. The different measures in the research program was developed in order to foster a trustful partnership is then presented. These measures were assessed by all project leaders in the annuals reporting to the research team, which reviewed the content of the research strategy each year in the annual report to the NBHW. The implementation of the research strategy with regard to evaluation initiatives together with the NGOs as well as in-depth studies was carefully documented over the years and used as indicator for developing a research partnership with the NGOs. In this case study the focus is on the implementation of the research and evaluation efforts and not on the outcome of the alcohol and drug prevention program. This has been reported in other publications [ 47 ]. The different types of data and perspectives included in the case study database are used for triangulation and finding key elements and mechanisms in the research strategy. In this case study a mixed-methods approach means parallel mixed data analysis, i.e. parallel analysis of qualitative and quantitative data from different sources. Moreover, integrated mixed data analysis also occurs in the analysis of the project portfolio and subsequent development of research initiatives. To grasp the complexity and inclusiveness of integrated methods the term inference has been proposed as the last and most important stage of research [ 70 ]. The inference process consists of a dynamic journey from ideas to results in an effort to make sense of data. In our case study the regular project leader meetings as well as the preparation of the annual evaluation and reporting to the NBHW are key activities in this process of drawing inferences. Key concepts in an integrative framework are inference quality, which is related to design quality, interpretative rigour, and inference transferability.

The results will be presented according to the three research questions. The calls for applications resulted in many proposals from many different organizations for a variety of projects engaging many project leaders.

Investing in the NGOs - Allocation of Grants 2003-2009

Since 2003 10-15 million SEK per year have been administered to this special venture (Table 1 ). The government's decisions have over the years differed somewhat according to which target groups are being specially addressed in the calls for grant applications. For the first period, which was a two-year period, the call was broad. For the second period, 2005, the main part of the grants went to projects from the earlier period. From 2006 to 2009 the target groups have been children, youth, young adults, and the workplace according to the national action plans. It has also been emphasized that the projects would be new or in the process of expanding existing activities.

About one in four applications were awarded a grant. The amount of funds provided to NGOs varies. The minimum amount of funding for one year was 40,000 SEK and the largest amount was 1,200,000 SEK. Many organizations have been funded for several years. Over the years 2003-2009 the NBHW has in total apportioned about 80,000,000 SEK to the NGOs. In addition a yearly grant has been awarded to an integrated Research & Development (R&D) program as well as funds for administration and information activities. The total allocation from the NBHW has been 95,000,000 SEK, covering 135 projects in 69 organizations funded during these years.

The projects differed in size. Table 2 presents these 219 project grants over the years 2003-2009. The reason for this lower number of project (135) is that 50 projects have been funded over more than one year, 26 projects over two years, 17 projects over three years, and two projects over four and five years each. The first period, which covered two years, had the highest number of large projects. Moreover, the number of funded project has increased between 2005 and 2008 and the number of large projects has remained relatively stable since 2005.

Organizations and projects

The strategy to involve a broad range of organizations has been successful. In Figure 2 the 69 organizations and the 135 projects are presented according to type of organization. The largest number of projects were run by the nine alcohol and drug organizations. More than half of these projects were run by the Swedish temperance organisation IOGT-NTO (24 of 38 projects) amounting to 15 million SEK. The majority of these were small one-year projects, except for two programs where effect studies were conducted by the research team and the organization jointly. Between 15 and 20 projects were run by organizations focusing on social work, assistance, and ethnic groups. About 10 projects were run by sports, adult education, and religious organizations respectively. Furthermore, 14 projects were set up by two umbrella organizations each consisting of a number of member organizations.

Organizations and projects in different types of organizations according to main objectives .

The projects have different primary target groups for their activities. A majority of the projects have children or adolescents as target groups. Some of these projects are focused on young girls with the aim of promoting self confidence and a positive self image. Sports organizations have been developing alcohol and drug policies including anti-doping initiatives. Projects run by ethnic groups have as their target group members of their organizations including children, adolescents, and parents. A few projects have the workplace as the arena for intervention.

During the first years, three community-based projects were funded. These aimed to reduce drugs in two parts of Stockholm and the island Gotland. The strategy included a range of activities and collaboration with different actors. A broad membership in the organizations seems to be important for the sustainability of the community-based prevention.

Only one project has reduction of availability as its focus. This project focused on following up the alcohol legislation concerning the sale of beer to minors in Sweden [ 75 ] and the effect of different strategies to influence shops to comply with the law [ 74 ].

Internet has a great potential in promotion and preventive work [ 76 ]. The majority of the organizations have their own website on the Internet and about one third have a project-specific site. The organizations used information technology as a source of health information in three projects, as an intervention medium in four, for professional development in two, and as a research instrument in one project. The use of e-screening as a tool for drug prevention is studied by researchers at Karolinska Institute. There are still very few scientific evaluations of the use of Internet in drug prevention [ 77 ].

Basic characteristics of the project leaders in the alcohol and drug prevention projects are given in Table 3 . All four years the proportion of women was larger than men; about two of three project leaders were women. Most of the project leaders belonged to the age group 41-50 years in the early periods (2003/2005) while in the later periods (2007/2009) an increased proportion of the project leaders were 50 years or older. Moreover, nearly one in ten project leaders was 30 years or younger. Many of the project leaders in volunteer work were members of the organization before being appointed project leaders (Table 3 ). In 2003 eight of ten project leaders were members compared with four of ten in 2007 and 2009. Nearly half of the project leaders were also doing volunteer or non-paid work in the organization. No gender differences were found in the prevalence of non-paid work.

Investing in Research and Development

A research and evaluation strategy was developed by the research team at the School of Health and Medical Sciences, Örebro University. This strategy rests on collaboration with the NGOs through regular meetings with all project leaders, development of systematic documentation of project objectives, activities, and results, annual reports to the NBHW, and biannual national conferences Reflections on prevention (2006, 2008, and 2010). The role of the researchers can most closely be characterized as researchers as technical advisors . In some projects the researcher had the position of an unobtrusive observer -for instance in following up some projects in which no longitudinal data collection was included. In addition, in no project did the researcher have the position of researcher as designer . Moreover, separate competence development and discussion of evaluation studies were conducted with a smaller number of organizations. The steering committee at the NBHW also decided, after consulting the research team, on a number of in-depth studies. Fourteen such studies were included in the funding from the NBHW (Table 4 ). The research team was also involved in three additional studies funded by other sources. These studies focused on policy development in the Swedish Football Confederation, evaluation of regional collaboration against illegal alcohol, and alcohol prevention in Novgorod, Russia.

This set of studies included systematic collection of data from children, parents, and actors in projects. A description of the empirical studies carried out between autumn 2003 and spring 2009 is given in Table 5 . Different methods, including questionnaires, personal interviews, telephone interviews, and focus group interviews, have been used depending on the purpose of the study. The main research questions have been related to the process or effect evaluations of these projects. The majority of the studies have been carried out with adolescents, as many of the projects receiving grants from the NBHW are targeting adolescents for the purpose of preventing alcohol and tobacco use. In three studies, data have been collected from both adolescents and parents, and two of these are longitudinal studies with adolescents and their parents. Dyads of adolescents and parents are identified and have been followed over the three years of secondary school. All youth surveys have been carried out in a school environment while the questionnaires to the parents have been sent by mail. Municipalities, schools, and organizations across Sweden have participated in the studies. There are many advantages with the partnerships that have been developed between the research team and the project leaders within the NGOs. For example, the large scale of the studies that have been carried out during the six years could not been managed without this cooperation. The project leaders have done much of the practical work locally, such as the dialogue with participating schools and organizations, distribution of questionnaires, and sometimes also feedback to participants.

What types of research and development have been included?

All projects in the project portfolio had to submit semi-annual and annual reports. These reports were analysis and synthesized into an annual report to the NBHW. This was based on a reporting format using questions for different important elements in the projects as well as key aspects of project management. The preparation of the annual reports included cross-project comparisons with regard to the case study questions, which resulted in some amendments and changes over the years in the research and development activities.

After the decision on potential projects for in-depth studies, planning meetings were convened with the project leaders and managers in the NGOs. Based on the project proposals and joint planning between the project leaders and the researchers, a plan for the in-depth studies was developed. Depending on the evaluation and research questions and available resources the focus, design, process, and outcome measures were set (Table 6 ). The overall results were positive; ten of the fourteen in-depth studies were completed. One project did not succeed in recruiting high-risk parents to a parental support program (IOGT-NTO Centro). Three projects were only partially completed: one started before the research team was organized, making the evaluation impossible (IOGT-NTO: Dare/Young and King); one was cancelled after a decision by the municipality (SMART Västernorrland); and in one it was impossible to follow up information from policy-makers due to a low response rate (Makalösa föräldrar). Eleven of the in-depth studies started during the first period (Table 4 ). There were some common research questions such as the effects of the projects. The NGOs wanted their approach to be studied in such a way that, in the event of positive results, the program could be regarded as evidence-based.

Effect Studies

Seven projects were considered for evaluation with effect studies, which were planned for all seven projects. However, one project was unsuccessful and two only partially completed due to overly limited implementation. One project was already implemented when the research group was appointed. It was nevertheless possible to plan and successfully complete effect studies even with short-term yearly funding.

KSAN "About small things"

The aim of this project was to develop and test an early intervention targeting pregnant women to prevent alcohol injuries in unborn children. The project was developed by the KSAN, an umbrella organization for women's organizations concerned with alcohol and drug issues, and the Swedish Association of Midwives. It was implemented in a maternal health centre in Stockholm. A randomized controlled study was completed with 454 mothers randomly assigned to either receiving an information folder with the message "Pregnancy is not a time for risk-taking" sent to their home after the telephone contact for booking the first visit to the midwife, or getting the folder during their first visit to the midwife. The effects of the intervention were measured by a questionnaire that the pregnant women answered at the maternal health centre before they met with the midwife.

IOGT-NTO: Strong and Clear

Strong and Clear is a parental support program targeting parents with children aged 13-16 years. It is a universal program aiming to prevent drinking among adolescents and to maintain parents' restrictive attitudes concerning adolescents and alcohol. The program is manual based and includes thirteen activities during the three years of secondary school. The parents can sign up for the program during the whole period the program is carried out. There are both group and self-administered activities divided into four types: parent meetings, family dialogues, friend meetings, and family meetings. The program was implemented in six schools.

The research program includes the effect study, which was designed as a longitudinal quasi-experimental study, and studies of parental attitudes and behaviour with regard to adolescents and alcohol [ 78 ] as well as reasons for non-participation [ 73 ]. In the longitudinal study, 706 children and 613 parents participated in the baseline questionnaire, which was followed by repeated data collection in the two following school years.

IOGT-NTO: Parents Together

The program Parents Together consists of three parents' meetings during three years in secondary schools. The intention is to motivate the class parents to come to an agreement on the following issues: "We enforce the 18-year limit for alcohol; We will not provide each other's children alcohol; We will get in touch with each other if we see a child we know who is not sober, is behaving badly, or is out at times and places where we would not want our own children to be."This agreement is used to strengthen the cooperation among parents. The idea is that this will make a difference with respect to the children's alcohol use. A parent-teachers meeting is held each year to update the agreement.

The design of the study is a cluster randomized controlled study in Swedish secondary schools with seven intervention and six control school. The study included almost 2000 pupils and their parents. The program Parents Together was carried out over three years in the seven intervention schools with a start in both school years 7 and 8 (Figure 3 ). The six control schools have been offered the program for parents whose children are in year 7 in the spring 2009 and the program will follow in the years 2010 and 2011. To reveal effects of the program the evaluation also includes a questionnaire about the prevention work in schools and implementation reports. The non-governmental organization IOGT-NTO is responsible for the program and the implementation in the seven intervention schools. To maintain the cooperation between the thirteen schools, the NGO, and the research team, an agreement has been signed. The agreement includes information about the responsibilities of each party such as that the researchers should the results of surveys, within six months after the data collection, are published on the website.

Design of the intervention and evaluation of the program Parents Together .

IOGT-NTO Centro: Parental Support

This project was planned to include before and after questionnaires to high risk parents. However, the project did not succeed in attracting this type of parents to the program.

Hassela solidaritet: Peer Support in School

This NGO works with training and assisting school children to be peer supporters in their own school. The aims of the project are to prevent social exclusion by reducing teenage alcohol consumption, experimentation with drugs, and bullying through peer support in schools, and to promote a school that is a positive, creative, and stimulating workplace for all. The program was first implemented in one part of the school, and was planned to be extended to the whole school. Subsequent implementation in a second school was planned. However, this extended implementation was only partly carried out due to limited resources. The evaluation included focus group interviews with peer supporters and repeated cross-sectional questionnaires to schoolchildren in school years 7-9 in the two schools.

National Federation SMART: SMART Västernorrland

The main objective of this NGO is to prevent or postpone alcohol, tobacco, and other drug use among children through positive reinforcement and signing of contracts. The parents sign the contract together with their child. The content of these contracts varies between local organizations. The membership gives the child positive benefits reinforcing positive behaviours. The program was implemented in a Swedish county, Västernorrland. The evaluation plan included an effect study among schoolchildren in Kramfors, a study of parents, and an interview of stakeholders in the county. The program was cancelled by the municipality of Kramfors with negative consequences for the effect study, which had been planned as a repeated cross-sectional study of schoolchildren in years 4-9. Data was collected with questionnaires and during the three years, 2,052 children answered the questionnaire. The research team decided to implement the evaluation as planned even if there was no intervention the third year.

The Swedish Youth Temperance Movement (UNF): Folk Beer Project

The Non-governmental organization UNF is a politically and religiously independent organization. They are a sister organization to IOGT-NTO (The Swedish Temperance organization), which is a part of the International Organization of Good Templars. All members are between 13 and 25 years of age. To be a member you have to be a teetotaller. The activities are of different kinds, for example arranging theatrical performances, discos, cafés, study circles, and a large number of courses. Besides dealing with alcohol regulations and politics regarding alcohol, they also work with international exchange and democracy issues. Their vision is a democratic and socially responsible world free from drugs. Although they are politically independent, their task is to act politically in letting the politicians know which issues are important to them. UNF has an almost 40-year history of conducting underage alcohol purchase attempts.

In 2003 UNF applied for funding for a new idea. They wanted to compare two different strategies that included underage purchase attempts. The first was an elaboration of their earlier method, which meant confronting the media with the results of the purchase attempts, reporting the check-out clerks who sold them beer to the police, and informing the municipalities of which stores that sold beer to minors. The other method was based on the idea to actively seek cooperation with the retail grocery sector, the municipality's alcohol administrator or drug coordinator (the municipalities are organized differently), the police, and the labour unions. The evaluation program was designed as a quasi-experimental study and as a follow up of the alcohol legislation concerning the sale of beer to minors in Sweden [ 75 ] and of the effect of different strategies to influence the shops to comply with the law [ 74 ].

Studies of Process and Implementation

Seven of the in-depth studies focussed on the working process in the projects. Three projects were community-based and had a clear geographical area where the programs were implemented. Motgift Gotland was an alliance for preventing the use of narcotics on the island of Gotland. Söder mot Narkotika was also an alliance against narcotics in a central district (Södermalm) of the capital Stockholm. A broad range of agencies and organizations collaborated in these efforts. A third community-based project was run by Verdandi Tensta Rinkeby. The three community-based projects were studied during 2005-2006 and included interviews with stakeholders and actors in the projects. A lesson learned is that community-based prevention needs to have broad support and cannot depend heavily on individual project leaders.

Verdandi: Get safe in Tensta - Rinkeby. Meet us!

An in-depth analysis was made of the third project in order to uncover their successful strategy. Verdandi, founded in 1896, is a Swedish workers' organization striving for social justice and a society free from alcohol-related injuries. From the very beginning, Verdandi - as an independent organization within the workers' movement - has aimed to improve people's social and financial situations. Today's aim is to analyse the development of society through the experiences and voices of those who are not heard otherwise. People of all ages, in all parts of the country, may participate in Verdandi's activities, which are quite different from place to place since they are based on local needs. According to Verdandi, without a local angle, the organization would soon lose touch with reality as well as lose credibility and members.

Verdandi runs activities for youth. The project includes support for children both in school and after. The youth in the organization can use a facility in the neighbourhood in their leisure time. Youth activities have focused on "the young leading the young" and the project has demonstrated young people's ability to organize and run a rewarding activity in the evenings and on weekends. The aim of this prevention program is to empower young people in their daily lives and help them empower their friends. This, according to the organization, contributes to young people avoiding drugs, and the neighbourhood has become calmer and safer. The activity has a bottom-up nature and the youth are involved in the planning. They have the opportunity to develop activities and thereby affect their daily lives. Among the success factors, according to the in-depth study, are: confidence in the organization, equality, youth involvement and power, memberships, support from the parents, training of leaders, common norms and roles, volunteer work, easily accessible premises, and a leadership that facilitates democratic processes.

IOGT-NTO: Dare/Young and King

This program is a redesigned version of the American program DARE [ 79 ], which was implemented before the research group was appointed. However, an adult education component, Young and King, aiming to strengthen parents was implemented and a follow-up study was completed of this component of the program.

IOGT-NTO:s Juniorförbund: Junis sisters

In this project, groups of schoolgirls in years 5 and 6 are organized with the objective to strengthen their self-esteem and promote meaningful leisure activities and thereby delay the onset of alcohol consumption by the girls. The evaluation focused on the group leaders, who were interviewed in focus groups. A lesson learned is that special effort must be put into recruiting and assisting group leaders to achieve sustainable programs.

Makalösa föräldrar: Single Parent with Teenagers

The project consisted of two main parts. One part focused on improving the knowledge about how it is to be a single parent with a teenager in the family. A survey of single parents was done in a part of Stockholm and a small newsletter was produced. The other part included self-help groups for single parents and summer camps. The evaluation of the self-help groups consisted of follow-up questionnaires to participants. An unsuccessful part of the evaluation was the follow-up of the newsletter, which was well planned and properly designed. It was not possible to get feedback from policy-makers on the publication, which may be due to lack of awareness of the publication and its contents.

The Swedish Ice Hockey Association: School Ambassadors

The project aimed to train top athletes to become school ambassadors in order to influence the attitudes of schoolchildren and give them the opportunity to try out ice hockey. Moreover, the project was also an attempt to improve the collaboration between schools and top ice hockey clubs. In the second year the specialized ice hockey secondary schools were included in the program. The evaluation consisted of following up the training of the athletes and studying the work of the secondary school ice hockey players by means of a questionnaire to schoolchildren.

In order to promote the development of a partnership a series of measures were implemented (Table 7 ). All project leaders were invited to regular meetings, which were held in Örebro as well as in Stockholm, Gothenburg, and Malmö. The agenda included presentation of project plans, information from the NBHW, and the research and development activities by the research team. Thematic lectures and discussion on issues such as the art of project management, measures to reach target groups, media advocacy, Internet as a tool for prevention, and planned communication were held at different meetings. The main objective of these meetings was to promote exchange of experiences and learning in order to strengthening the quality of the implementation of the projects as well as networking. Moreover, the systematic bi-annual and annual reports were introduced and discussed.

Depending on the needs of the different projects special project dialogues and consultations were held between individual projects, or a small group of similar projects, and the research teams. The results of these meetings ranged from refinement of project ideas to long-term collaborations. All in-depth studies started with such meetings. The competence development took different forms. In the first period an academic training program in alcohol and drug prevention was offered to the project leaders, of whom about 10 participated. Supervision in groups was implemented in three groups during the first two years, and thereafter one or two groups were run by independent supervisors annually. During 2009 the research team arranged more project leader meeting including training in project management as an alternative to supervision.

The in-depth studies were also an important measure to foster the partnership between the NGOs and the research team. Due to available resources, more extensive process and effect evaluation activities could only be implemented in a limited number of projects. Many more projects asked to be the focus of in-depth studies than the fourteen that were initiated.

The research team together with the NBHW arranged a national conference Reflections on prevention - Collaboration for better alcohol and drug prevention. Conferences were arranged in the spring of 2006, 2008, and 2010. Among the key issues discussed at the first conference were the role of parents in prevention, adolescents, community-based approaches, and supply-reducing initiatives. The second conference also discussed the role of civil society and how to promote more effective cooperation among the different stakeholders. The third conference focussed on evidence and evidence-based practice, which have received increased attention in Sweden in many sectors of society. A main emphasis has been setting the context for reflection and sharing of experiences among the participants at the conferences; therefore a series of seminars with project presentations and panel discussions have been part of the conferences. Moreover, plenary sessions as well as theatrical performances further set the stage for professional dialogues on alcohol and drug prevention. The conferences have been well received and have attracted actors from different sectors of society as well as national agencies and NGOs.

In the annual reports the project leaders also assess the implemented measures by the researchers. These have guided the future efforts of the research team. As an example, the assessments made in January 2005 are presented in Figure 4 . The financial support was very important, followed by the support from the NBHW, the project leader meetings, and the supervision. One third of the project leaders regarded the support for the documentation as very important. The academic training in alcohol and drug prevention was regarded as very important by one fifth of the project leaders, which is a high proportion given that only a small group participated in the distance education course. Only eight projects were at that time included in the in-depth studies, nevertheless one third of the project leaders reported this measure as very important. The case study data bank includes information for questionnaires, interview and other data sources for the assessment of the implementation of the research strategy.

Assessment by project leaders of measures to improve collaboration between NGO and research in 2006 .

The research strategy has been successfully implemented despite the fact that only some projects were running more than one year while new projects and project leaders are included every year. The first two years a focus in the meetings with the project leaders was on the in-depth studies which were presented by the organisations and the researchers. Then the focus changed to addressing common concerns among the project leaders such as how to reach target groups, use of Internet, different type of prevention projects and mass communication skills. The presentations from the research teams were more concentrated to the national conferences that were organized bi-annually. The networking between the projects also resulted in new applications jointly by two organisations.

An important element was the relationship between the NBHW and the research team at Örebro University. During this period the NGO portfolio was managed at the NBHW by the same senior official. However, the department director changed three times during this period. The members of the working committee also changes over the years. The chairman was the same during all years. The support to the research and development activities was nevertheless maintained and also renewed for another year. The continuity with regard to persons seems to be very important for such an endeavour as included in this case study.

Discussion - towards practice-based research for alcohol and drug prevention

The integration of the research and development component into the support from the NBHW resulted in a unique possibility to do comparative studies involving, among other things, project management and implementation as well as project results. The measures to promote a partnership for practice-based research also improved the quality and success of the different projects. A few of the in-depth studies were unsuccessful due to factors hindering the implementation, and in several cases these factors were related to a lack of resources on the part of collaborating partners in the municipalities or other organizations.

The research strategy has been based on the overall aim to contribute to the evidence base for alcohol and drug prevention, an emphasis that this field shares with health promotion, prevention in general, and social work [ 2 – 8 ]. The current development of practice-based research will give more relevant knowledge and our research program attempts to be a part of this trend. Moreover, the utilization of research results may also be improved if studies on efficacy, effectiveness, and dissemination are promoted [ 18 ]. The strategy that the NBHW developed in this program of governmental support to NGOs was an attempt to bridge this gap as described by Nutbeam [ 10 , 11 ]. This challenge for agencies to respond to the push from the funders and pull from the communities has been noted by Green and Mercier [ 23 ] and the public health researcher also needs to leave the university campus to get involved in more practice-based research. Our research program has developed along such lines.

The research strategy includes the use of qualitative, quantitative, and mixed methods. This means that data collection and data analysis are done using guidelines for these three traditions. The challenge is most apparent with regard to inference and integration. In the stages of inference in a study, quality issues such as internal and external validity in the quantitative approach and aspects of credibility, confirmability, and transferability in the qualitative approach are pertinent. Integration is the mixed-methods approach of working across strands and using meta-inferential issues related to the integration of findings and inferences from the two strands. Here design quality, interpretative rigour, and inference transferability have been proposed as indicators of quality [ 70 ]. In this research strategy case study, the set of research entities changed each year due to the funding of applications from NGOs by the NBHW. The present study covered a six-year period, and the stages of inference and integration were completed yearly in the preparation of the annual reports to the NBHW.

The research strategy also includes elements of participatory research. The organizations were involved in developing the main research questions in the in-depth studies. Sometimes the organizations also assisted in collecting questionnaires from school children; in making participatory observations, as in the studies of beer purchasing by minors; or in providing feedback to school staff and target groups, as in the parental support programs. Moreover, the organizations also played a role in discussing preliminary results as part of a validating process for the empirical studies. These discussions never changed the interpretations of the findings but often gave more insight into the noble art of implementation of preventive programs. Nevertheless, as in other research programs, a number of methodological challenges had to be dealt with. The resources were limited, which gave room for only a small number of in-depth studies. Therefore the research strategy included additional elements such as support to documentation as well as support to the project leaders in meetings and management training. The selection of these studies was mainly done by the steering committee at the NBHW. The research team developed a proper design for these studies based on the assessed potential for a successful implementation and possible options given the resources available for effect or process studies. Then the choice of methods for data collections was reviewed and target groups for the evaluation research selected. In this process the best choice from an academic point of view was often not possible due to limited staff and other resources. Nevertheless, the research program resulted in data collected from 9,568 children, 4,832 parents and 327 actors or stakeholders. Moreover, it was possible to carry out two large longitudinal studies of children and their parents in this research program. Even if the funding was granted annually, it was possible to think and plan on more long-term basis.

A broad range of organizations received project funding from the NBHW. Although the largest number of projects was run by the nine alcohol and drug organizations, the alcohol and drug prevention was successfully integrated into a range of organizations with other main objectives. Moreover, the project leaders also came from different societal sectors. This was an intended effect of the governmental initiative to strengthen the alcohol and drug prevention in Sweden. This led to another methodological challenge caused by the fact that the programs were so different. The research team developed questionnaires with common modules that could be used in different evaluations thus giving them access to data from schoolchildren and parents in different contexts and programs. This made it possible, for instance, to study the reasons for non-participation in parental support programs [ 73 ]. Another added value related to this was the possibility to organize a study of project management through a special study of the project leaders, which was integrated into the overall design of the support from the NBHW.

A challenge for the research team was that the funding for the research as well as for the alcohol and drug projects was decided annually by the NBHW. However, the research was planned with a longer time period in mind, which has actually led to a research program that has been running more than six years. A more long-term grant would have been beneficial for the development of a partnership between the NGOs and the research team. In order to overcome this barrier a multi-year agreement has been signed for the newer in-depth studies, but it was still signed on the condition of renewed funding the following year. Nevertheless, a trustful partnership was developed between all three partners: the practitioners in the NGOs, the national agencies, and the researchers. In many cases the planning and implementation were done jointly, dividing the responsibilities according to skills and keeping the roles clear and feasible to complete successfully. The validity of the results was also a major concern as well as an emphasis on a participatory approach to the research process.

Ethical concerns were very important, as stipulated by Swedish law. The effect studies were assessed by the regional research ethics boards. However, it is also important to analyse if the NGOs have vested interests in the research process. Government agencies as well as NGOs can also have a vested interest in scientific research, such as when science is misused to benefit a particular political agenda, ideology, or favoured interest group [ 80 ]. However, the problem of vested interests is more dangerous when key parts of the government sector are in conflict over their public health responsibilities; for instance health sector engagement in partnership arrangements with addictive consumption industries (particularly alcohol, tobacco, and gambling) entails too many risks [ 81 ]. In our case there have been shared visions and objectives between the government agency and the NGOs, which guided the developmental activities as well as the research work. Moreover, the division of responsibilities between the NGOs and the researcher was important. The NGOs had the responsibility for developing the proposals, conducting the interventions, and implementing the preventive programs or initiatives. The researchers had the responsibility for planning the effect evaluations after consulting with representatives of the NGOs, as well as for implementing the research components, analysis, and reporting of results, including dialogues about the outcomes, and presenting the findings for the NGOs.

The organization of the research program under the auspices of public health science at Örebro University was natural as the principal investigator holds a professorial chair in public health there. During the first two years, other members of the research group were formally employed by an NGO but worked at the university campus in Örebro. All members of the research team were subsequently offered employment at the university, giving the research team a formal independence from all NGOs.

The addiction research centres have mandates that are broader than the present research program. The centre in Michigan has the mission to develop new knowledge about the cause, course, and consequences of substance use disorder and to train the next generation of researchers [ 28 ]; and the Canadian centre in British Columbia to create an internationally recognized centre distributed across BC that is dedicated to research and knowledge exchange on substance use, harm reduction, and addiction [ 27 ]. The Swiss institute is primarily involved in collecting alcohol-related information and making it available to professionals and the general public. The Swiss Institute will continue to monitor substance use, while stepping up its prevention research activities and ensuring that it is able to react promptly to emerging phenomena [ 25 ]. Our small research team is attempting to fill a gap in knowledge about the NGO alcohol and drug prevention efforts as these offer unique opportunities [ 82 ].

The research strategy was successful in establishing prevention research for alcohol and drug prevention by NGOs, which previously had been lacking in Sweden. Moreover, added value came from having meetings for project leaders, and the capacity building led to new innovative collaboration between different NGOs, which resulted in new applications for funding and successful implementation of new initiatives. The administrative support for improving the documentation of the implementation and progress of the projects was also recognized as beneficial for the practitioners and the national agency as well as the researchers. The best approach is always transparency and discussion, disclosure and debate [ 83 , 84 ].

A weakness in the research strategy was that the funding was not sufficient for more than a limited number of in-depth studies. The role of researchers-as-technical advisors was suitable for the fostering of a trustful partnership for research and development. The independence of the NGOs was regarded as important for the momentum in the project implementation. It was beneficial because it gave the research team opportunities to address other issues. From a strictly research point of view it would have been of interest to see what could be achieved by researchers-as-designer , but this would have been very costly and all funds allocated to the integrated research activities would have been consumed by just one project. In other words, the present research strategy can be regarded as cost-effective.

The overall strategy for research and development includes capacity building for both the practitioners in the NGOs and the research team, and two doctoral dissertations will be finalized during the coming year. The NBHW has also noted that, given the limited duration of funding, this organization of knowledge development - as an integral part of the support to NGOs - is beneficial, which is indicated by the annual renewal of the contract with Örebro University. Moreover, the much more extensively funded projects in municipalities, regions, and counties still lack this strategic element. At present there is a trend that some larger governmental grants are given to such parties, but a mandatory linkage to universities for research is included in the call for proposals. This could lead to similar forms of trustful partnerships as found in the present research strategy case study.

The in-depth studies in this research strategy varied in content, design, and size. A common element was that they were program-driven and not research-driven interventions [ 9 ]. This may give the studies improved external validity [ 54 ]. The research strategy aimed at improving the evidence-base for alcohol and drug prevention. In our case this has meant using qualitative, quantitative, and mixed methods, as well a variety of designs to answer questions in practice-based settings. Including feedback and dialogue with the NGOs has further contributed to sustainable AD prevention in different settings. The missions of the NGOs differ, but the AD prevention has been included as an essential part of their activities, which in many cases meant that AD prevention has received increased priority. Moreover, the integrated research program has also been seen as beneficial and important for the organizations, which often wanted their programs to be recognized as evidence-based. Therefore, the demand for research by the NGOs is larger than what we can supply at present. This is a challenge to the funding agencies as well as research bodies. The addiction research centres seem to nurture creativity but often lack the networks and priorities for preventive research. It is important to go beyond the notion that a lack of evidence for a program is necessarily a sign of a lack of effectiveness. Therefore, practice-based research and collaboration between decision-makers, national agencies, NGOs, local authorities and researchers is needed. Using a combination of different and interactive measures it was possible to over the years built a trustful partnership between these parts. This research strategy case study shows that it is possible even in such a dynamic field as alcohol and drug prevention in NGOs where the organisations are competing for grants from the NBHW. There are added values in supporting a research group assigned to a project portfolio instead of having a series of smaller independent evaluations.

This research strategy case study shows that it is possible to integrate research into alcohol and drug prevention programs run by NGOs, and thereby contribute to a more evidence-based practice. A core element is developing a trustful partnership between the researchers and the organizations. Competence development is necessary for developing evidence for policy and practice. Given research groups assignments to address the knowledge development issues is better than having minor evaluation in individual projects. Moreover, the funding agency must acknowledge the importance of knowledge development and allocating resources to research groups that is capable of cooperating with practitioners and NGOs.

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Acknowledgements

The authors are very grateful to all the NGOs that have shared their efforts and experiences with the research team. We would also like to acknowledge Åke Setréus for his support and encouragement during the whole period. The Swedish National Board of Health and Welfare supported the study.

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The four authors of the manuscript are presented in alphabetical order and their shares of the responsibility for the paper are equal. CE is the principal investigator for the research program integrated in the NBHW support to NGOs for alcohol and drug prevention. CE, ML, and CP were involved in all aspects of the program as well as this study. SG was involved in the planning, project implementation, and writing of the section on NGOs. All authors read and approved the final manuscript.

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Eriksson, C., Geidne, S., Larsson, M. et al. A Research Strategy Case Study of Alcohol and Drug Prevention by Non-Governmental Organizations in Sweden 2003-2009. Subst Abuse Treat Prev Policy 6 , 8 (2011). https://doi.org/10.1186/1747-597X-6-8

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Robert’s story

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Drug-Impaired Driving: The Contribution of Emerging and Undertested Drugs

Impaired driving is often with alcohol use and frequently leads to accidents, injuries, and fatalities. According to the National Highway Traffic Safety Administration, one person was killed every 39 minutes in an alcohol-related crash in 2021. [1] But alcohol is not the only concern; the use of illicit drugs, legalized drugs such as cannabis, and the abuse of prescription medications may also impair a driver’s abilities. In 2022, an estimated 13.6 million people drove under the influence of illicit drugs during the prior year. [2]

In 2007, the National Safety Council (NSC) introduced testing scope and cutoff standardization for impaired driving cases and traffic fatalities to improve testing consistency. Since 2013, it has recommended that forensic toxicology labs regularly test blood for 35 of the most often encountered drugs and metabolites. Referred to as Tier I drugs ( Figure 1 ), they are now included as a testing standard in many forensic toxicology labs. [3] Furthermore, these compounds can be detected and confirmed with commonly used analytical instrumentation.

Figure 1. List of Tier I and Tier II drugs. Tier II drugs can be both individually named drugs and classes of drugs (e.g., atypical antipsychotics).

NSC also created a second drug category with significant impairment potential, termed Tier II drugs. These drugs include emerging novel psychoactive substances, prescription drugs, and traditional drugs of abuse with limited or regional prevalence, many of which require advanced instrumentation for detection. Most laboratories test for Tier I drugs, but only test for select Tier II drugs when they are regionally relevant. Therefore, the frequency and the types of Tier II substances contributing to drug-impaired driving cases and fatal crashes is not well understood.

NIJ-funded researchers from the Center for Forensic Science Research and Education examined blood samples from over 2,500 driving under the influence of drugs (DUID) cases. The goal was to create a detailed picture of both Tier I and Tier II drugs that contribute to impaired driving cases and compare results to the NSC’s recommended testing scopes. Researchers also analyzed drug presence at various blood alcohol concentrations to assess the operational impact of different testing thresholds and stop limit testing.

What is Stop Limit Testing?

If a sample meets or exceeds a pre-determined blood alcohol concentration threshold, some labs will not perform any additional drug tests. This cutoff is most commonly either 0.08% or 0.10%. [4] The legal blood alcohol limit in the U.S. across every state is 0.08%. Labs that adhere to this practice will not detect other drugs that may cause or contribute to driving impairment.

This stop limit testing can interfere with a comprehensive understanding of drug involvement in impaired driving. Why do so many labs use it?

• Toxicology labs have limited budgets and resources.
• Driving impairment can be explained by the blood alcohol concentration alone.
• A lack of enhanced penalties for drug use means there is no need to measure beyond the blood alcohol level.
• Agencies that use the laboratories’ services have requested this limit.

National Safety Council Recommendations Are Supported

Researchers estimated the frequency with which drugs contribute to the national DUID problem by testing 2,514 cases using a scope of 850 therapeutic, abused, and emerging drugs. They examined deidentified blood samples randomly selected from a pool of suspected impaired driving cases. The samples were collected from NMS Labs in Horsham, Pennsylvania, between 2017 –2020.

Of the 2,514 suspected DUID cases examined:

• The overall drug positivity (Tier I or Tier II drugs) was 79%, nearly double the 40% positive for alcohol ( Figure 2 ).
• A smaller portion of cases (23%) tested positive for both drugs and alcohol.
• Only 17% of the cases were positive for alcohol alone.
• Naturally occurring cannabinoids experienced a statistically significant increase in positivity over the four years.

Figure 2. The frequency of cases with (a) no drugs or ethanol detected (4%), (b) ethanol detected (40%), (c) drugs and ethanol detected (23%), and (d) drugs detected (79%).

Alcohol use in combination with drugs spanning multiple categories was common, as was multiple drugs used in combination. THC (the primary psychoactive component of marijuana) was most often found with ethanol (n=359), and it was frequently found with amphetamine/methamphetamine (n=146).

Samples with a blood alcohol content of 0.08% or higher that were also positive for either Tier I or Tier II drugs occurred 19% of the time (n=478). Cases with blood alcohol content of 0.10% (the cutoff used most frequently by toxicology labs) were also positive for Tier I or Tier II drugs 17.3% of the time (n=434). This suggests that laboratories employing stop limit testing may miss many drug-positive cases.

“Limiting testing based on alcohol results precludes information of drug involvement in several cases and leads to underreporting of drug contributions to impaired driving,” said Mandi Moore, one of the researchers involved in the study.

The research supported NSC’s recommendations for Tier I and Tier II testing. Tier I drugs were found in 73% of suspected impaired driving cases while only 3% contained just Tier II drugs. This suggests that Tier I testing captures the vast majority of drug-involved DUID cases. However, some Tier II drugs (diphenhydramine, gabapentin, hydroxyzine, and two novel psychoactive substances) were found as often or more often than some Tier I drugs, potentially indicating their increased prevalence and a need to re-examine guidelines.

Study Limitations

The cases used in this analysis were exclusively from Pennsylvania. Therefore, they provide a geographically limited snapshot rather than a comprehensive characterization for the entire U.S. population. However, the sample size of over 2,500 cases was “suitable to meet the research goals outlined” by the researchers.

Because Tier II and novel psychoactive substances were found in relatively low frequencies, the researchers did not develop or validate additional confirmatory methods as they had previously planned.

Filling in the Big Picture Details

This work increases awareness of drugs that labs are less likely to test for and labs’ role in addressing the DUID problem. It also demonstrates how frequently DUID cases involve drugs other than alcohol. Although stop limit testing can be justified, data on both alcohol and drug use creates the clearest picture of DUID contributing factors. Current estimates of drug frequency in DUID cases are likely to be inaccurate and actual usage is likely to be higher than previously believed due to stop limit testing. Equipping labs with sufficient resources could encourage labs to eliminate stop limit testing.

About This Article

The work described in this article was supported by NIJ award number 2020-DQ-BX-0009 , awarded to the Frederic Rieders Family Renaissance Foundation.

This article is based on the grantee report “ Assessment of the Contribution to Drug Impaired Driving from Emerging and Undertested Drugs ” (pdf, 26 pages), by Amanda L.A. Mohr and Barry Logan, The Center for Forensic Science Research and Education (CFSRE) at the Frederic Rieders Family Renaissance Foundation.

[1] NHTSA.gov, accessed January 29,2024, https://www.nhtsa.gov/risky-driving .

[2] Select Illicit Drugs include the use of marijuana, cocaine (including crack), heroin, hallucinogens, inhalants, or methamphetamine. For more information, see "Table 8.35A" in  2022 NSDUH Detailed Tables, Substance Abuse and Mental Health Services Administration,  https://www.samhsa.gov/data/sites/default/files/reports/rpt42728/NSDUHDetailedTabs2022/NSDUHDetailedTabs2022/NSDUHDetTabsSect8pe2022.htm#tab8.35a .

[3] ANSO/ASB Standard 120.

[4] Amanda D’Orazio, Amada Mohr, and Barry Logan, “Updates for Recommendations for Drug Testing in DUID & Traffic Fatality Investigations, Toxicology Laboratory Survey,” Willow Grove, PA: The Center for Forensic Science Research & Education at the Frederic Rieders Family Foundation, June 28, 2020, https://www.cfsre.org/images/content/research/toxicology/Survey_Report_Final.pdf .

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