FDA endorses drinking reductions as valid clinical endpoint in Alcohol Use Disorder Trials Researchers Review

In a significant advance for the treatment of Alcohol Use Disorder (AUD), the U.S. Food and Drug Administration (FDA) has formally recognized reductions in World Health Organization (WHO) Risk Drinking Levels (RDLs; a 5-category alcohol consumption measure that is associated with alcohol-related physical and social harm) as a valid primary endpoint in alcohol clinical trials. This shift acknowledges that meaningful reductions in drinking can lead to substantial improvements in health, social functioning and quality of life.

For over 50 years, drinking reductions have been studied in the alcohol field, beginning with behavioral treatments targeting reduced drinking. These reductions are often measured using the Timeline Follow-Back method, a calendar-based interview that tracks daily alcohol use. Accepted by the FDA, it remains a widely used standard, also adaptable to diaries or mobile health tools, and can assess diverse drinking endpoints, including WHO risk drinking levels, making it central to alcohol clinical trials.

Recently, a team of noted international AUD researchers, including University of New Mexico Distinguished Professor and Director of UNM's Center on Alcohol, Substance use, And Addictions, Katie Witkiewitz, reviewed more than 30 articles focused on the WHO RDLs associated with how individuals feel and function and or as an outcome in alcohol clinical trials to quantify WHO RDLs. The narrative review, Reductions in World Health Organization Risk Drinking Levels as a Primary Efficacy End Point for Alcohol Clinical Trials, was published today in the Journal of the American Medical Association (JAMA): Psychiatry.

The researchers reviewed clinical studies using data from multiple published studies to examine reductions in WHO RDLs and improvements in how individuals feel and function. The researchers found that reductions in WHO RDLs were associated with significant improvements in alcohol related lab tests, quality of life, health, and social functioning.

AUD is one of the most prevalent behavioral/psychiatric disorders, with lifetime rates affecting nearly 29% of Americans and at least 8% of people worldwide. The economic burden of alcohol use is immense, estimated at 2.6% of the global gross domestic product. Yet despite the scope of the problem, most individuals with AUD never receive treatment. One barrier has been the historical emphasis on abstinence, a goal that fewer than one-third of patients achieve in clinical programs.

"Most individuals with alcohol problems do not seek treatment, partially because they are not interested in abstinence goals and would potentially be more interested in treatments that target drinking reductions," said Witkiewitz. "Abstinence is absolutely associated with improvements, however, most people who receive treatment or who recover without treatment are successful in reducing their drinking without necessarily achieving total abstinence. There is also a current cultural shift toward drinking less and viewing excessive drinking as unhealthy and undesirable."

The FDA qualification package (necessary data to justify clinical use) that led to approval of the WHO RDLs as a primary endpoint for alcohol clinical trials included several validation studies that used data from the National Institute on Alcohol Abuse and Alcoholism-sponsored clinical medication trials examining the efficacy of naltrexone, varenicline, and extended-release gabapentin for alcohol treatment. The qualification package provided further evidence that reductions in WHO RDLs were associated with improvements in mental health, quality of life, and alcohol-related consequences; reductions in alcohol craving and AUD criteria; and a lower risk of AUD diagnosis.

"Most individuals with alcohol problems do not seek treatment, partially because they are not interested in abstinence goals and would potentially be more interested in treatments that target drinking reductions. Abstinence is absolutely associated with improvements, however, most people who receive treatment or who recover without treatment are successful in reducing their drinking without necessarily achieving total abstinence. There is also a current cultural shift toward drinking less and viewing excessive drinking as unhealthy and undesirable."

- Distinguished Professor Katie Witkiewitz

Shifting the standard for success
For decades, the FDA defined treatment success by abstinence or the absence of any heavy drinking days. However, growing research has questioned the validity of these binary measures, noting they fail to capture the meaningful health improvements achieved through reductions in alcohol consumption. In 2025, the FDA endorsed the WHO RDL framework, which categorizes drinking into risk levels based on average daily consumption. A reduction of at least "two risk levels" is now recognized as a primary endpoint for clinical trials. This aligns U.S. policy with the European Medicines Agency, which has already incorporated drinking reductions into new medication approval guidance.

Over 50 years of research, including more recent work by the Alcohol Clinical Trials Initiative (ACTIVE)-a public-private partnership with the FDA, the National Institute on Alcohol Abuse and Alcoholism, academia, and industry led by co-author, Dr. Raymond Anton, Distinguished University Professor Emeritus at Medical University of South Carolina-has demonstrated that reductions in WHO RDLs are strongly linked to improved outcomes.

Results from epidemiological studies, community samples, and clinical trials indicate that drinking reductions are associated with improvements in how patients feel and function, including reduced risk of substance use disorder and medical and psychiatric diseases and reductions in alcohol-related consequences, craving, and health care costs. Drinking reductions are also achieved by most clinical trial participants, and effect sizes for the WHO RDL reductions for active medications vs. placebo are similar to or better than alternative endpoints.

Findings related to a reduction in WHO Risk Drinking Level over time include:

• Reduced disease risk: Lower rates of alcohol dependence, liver disease, cardiovascular disease, depression, and anxiety.
• Improved physical health: More normal liver enzyme function, lower blood pressure, and brain health markers.
• Improved mental health and functioning: Higher quality of life, better sleep, and fewer alcohol-related social consequences.
• Economic benefits: Studies show up to 52% lower health care costs within a year of treatment when significant WHO RDL reductions are achieved.
• Mortality risk reduction: Lower rates of death over time among those achieving 1-2 level reductions.

"Results from the reviewed studies indicate that drinking reductions are associated with improvements in how people feel and function, including reduced risk of substance use disorder, medical and psychiatric diseases, and reductions in alcohol-related consequences, craving, and health care costs," said Witkiewitz.

Implications for Treatment and Research
The FDA's acceptance of WHO RDLs as a clinical trial endpoint opens the door for new treatment development and may encourage more individuals to seek treatment. By moving away from an "all-or-nothing" abstinence model, clinicians can work with patients to set realistic, individualized goals that still produce measurable health and social benefits.

"The approval of the drinking level reduction endpoint by the FDA paves the way for the development of new therapeutical approaches, including medications and digital interventions, that are geared toward supporting reductions in drinking and may be more desirable to more people," added Witkiewitz.

For clinicians, WHO RDLs provide a clear framework for assessing progress, offering patients tangible feedback on their drinking risk levels and potential benefits of reduction. For researchers, the new standard provides a validated, evidence-based measure to evaluate medication efficacy in clinical trials.

"It is noteworthy that data for our secondary analyses of drinking reductions came from publicly funded projects. Only one study (topiramate) was sponsored by industry," said co-author Professor Karl Mann, Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany. "The process is a beautiful example of the value of international collaboration: starting with World Health Organization data from Australia, through the first applications of drinking reductions approved by the European Medicines Agency in Europe to scientific proof in the United States."

In a related View Point article published in the same issue of JAMA: Psychiatry, Dr. Raymond Anton highlighted the utility of an FDA-guided public-private partnership model to harness expert knowledge across government agencies, academic experts, and industry representatives to advance the goal of improved individual and public health.

Looking Ahead
Co-authors of the JAMA Psychiatry review paper, Witkiewitz (UNM), Raymond Anton (Medical University of South Carolina), Stephanie O'Malley (Yale School of Medicine), Deborah Hasin (Columbia University), Bernard Silverman (Nirsum Laboratories), Arnie Aldridge (RTI International), Karl Mann (University of Heidelberg), and the ACTIVE Workgroup note that while the FDA's qualification of WHO RDLs is a milestone, ongoing research is needed to refine how best to apply this measure across diverse populations and treatment settings. Future studies will continue to examine its use alongside other widely used drinking outcomes and its implementation in everyday clinical practice.