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Review
. 2025 Dec 1;82(12):1246-1254.
doi: 10.1001/jamapsychiatry.2025.2508.

Reductions in World Health Organization Risk Drinking Levels as a Primary Efficacy End Point for Alcohol Clinical Trials: A Review

Katie Witkiewitz  1   2 , Raymond F Anton  3 , Stephanie S O'Malley  4 , Deborah S Hasin  5   6 , Bernard L Silverman  7 , Arnie Aldridge  8 , Karl Mann  9 ; Alcohol Clinical Trials Initiative (ACTIVE) Workgroup
Collaborators, Affiliations
Review

Reductions in World Health Organization Risk Drinking Levels as a Primary Efficacy End Point for Alcohol Clinical Trials: A Review

Katie Witkiewitz et al. JAMA Psychiatry. .

Abstract

Importance: Alcohol use disorder (AUD) is a highly prevalent and costly psychiatric disorder. Abstinence has been considered the optimal outcome of treatment for AUD. Yet, most individuals with AUD do not seek treatment because they do not have a goal of abstinence. The Food and Drug Administration (FDA) has recently qualified reductions in drinking, defined by at least a 2-level reduction in the World Health Organization risk drinking levels (WHO RDLs), as a primary end point for alcohol pharmacotherapy trials. The approval of drinking reductions as an end point for alcohol clinical trials aligns with an accumulating literature on drinking reductions in the alcohol field. This article provides a narrative review of 34 articles that have examined WHO RDLs as a surrogate marker of how people with AUD feel and function.

Observations: 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 associated with improvements in functioning and quality of life. 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 end points.

Conclusions and relevance: The FDA acceptance of reduction in WHO RDLs as a primary end point for alcohol clinical trials may increase opportunities for AUD medications development, encourage patients to seek treatments that target drinking reductions, and engage clinicians in prescribing medications shown to be effective in supporting drinking reductions. The WHO RDLs may be particularly useful for targeted drinking reductions in clinical practice. Qualification of the WHO RDL end point facilitates a paradigm shift toward a harm reduction approach in AUD treatment.

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Conflict of interest statement

KW, RFA, KM, BLS, AA, and SSO are members of Alcohol Clinical Trials Initiative (ACTIVE) Workgroup, which had been supported over a decade by up to 19 pharmaceutical companies at various times. Most recently (within the last 3 years) ACTIVE has been supported by Alkermes, Dicerna Pharmaceuticals, Eli Lilly and Company, Indivior Inc., Imbrium Therapeutics, Pear Therapeutics, and Kinnov Therapeutics. Dr Witkiewitz reported receiving personal fees from Eli Lilly and company outside the submitted work. Dr Anton reported receiving personal fees from Alkermes, Imbrium Therapeutics, Dicerna Pharmaceuticals, Denovo Biopharma, Sophosyne, Beam Therapeutics, Kinnov Therapeutics, Revel, Nanexa, Nirsum, Eli Lilly and Company, and Altimmune outside the submitted work. Dr O’Malley reported receiving nonfinancial support (study medications) from Stalicla, Novartis, and Amygdala Neurosciences; personal fees from Newleos, Dicerna, the University of New Mexico, Indiana University, and the Emmes Company, LLC; grants from Altimmune (site for a clinical trial), Tempero Bio (site for a clinical trial), and the National Institutes of Health and US Food and Drug Administration outside the submitted work. In addition, Dr O’Malley reported having a patent pending for Mavoglurant for gambling disorder with Yale and Novartis. Dr Silverman reported receiving personal fees from Nirsum Laboratories, Sophrosyne Pharmaceuticals, Tempero Bio, and Newleos outside the submitted work. In addition, Dr Silverman reported having a patent issued for morphinan derivatives for the treatment of drug overdose. No other disclosures were reported.

Figures

Figure 1.
Figure 1.
PRISMA flowchart for review
See this image and copyright information in PMC

References

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