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Individuals with alcohol use disorder (AUD) may experience distinct metabolic disruptions that intensify alcohol cravings, particularly in the setting of obesity, according to new research.

Investigators found that stress- and alcohol-related cues were associated with altered glucose and insulin responses in abstinent patients with AUD. Moreover, insulin resistance correlated with stronger craving among study participants who had both AUD and obesity.

Lead author Zachary Harvanek, MD, PhD, assistant professor of medicine at Yale School of Medicine, New Haven, Connecticut, cautioned that the findings are preliminary and require confirmation in larger studies before they can influence clinical practice. However, he said the results suggest that metabolic health may play a meaningful role in alcohol cravings and could help identify a distinct subgroup of patients with AUD at an especially high risk for relapse.

The findings also support growing interest in therapies that target metabolic pathways, including GLP-1s, as potential treatments for AUD in certain patients.

The study was published online in Alcohol, Clinical & Experimental Research.

Complex Interplay at Work

“AUD and obesity often occur together, but we don’t fully understand the biological links between them,” Harvanek told Medscape Medical News. “Both are fundamentally diseases that involve a complex interplay of biological, psychological, social, and behavioral factors.”

He and his colleagues were interested in whether metabolic signals such as glucose and insulin might actively influence behavior and craving responses, especially under stress, and thereby offer potential biological targets to prevent relapse.

To explore this possibility, researchers analyzed fasting glucose, insulin, and insulin resistance in individuals with AUD, with and without obesity, to determine how metabolic dysfunction might interact with stress- and cue-induced alcohol craving and relapse vulnerability.

The study was a secondary analysis of participants from a prior trial and included 31 inpatients with AUD who had been abstinent for 1 month while engaged in treatment. Of these, seven had both AUD and obesity. The study also included 41 healthy control participants without psychiatric illness, eight of whom had obesity.

Participants were aged 21-50 years, with a mean age in the 30s. The healthy control group included a higher proportion of women, both with and without obesity, and was approximately 6 years younger than the AUD group.

Cravings were assessed on a scale of 1-10 ranging from “not at all” to “extremely high.” Assessments were conducted before and after relaxation following imagery exposure, and then every 15 minutes for 1 hour, for a total of eight timepoints. Plasma samples were collected at the same intervals over the 3-day study period.

Imagery exposure consisted of personalized scripts designed to induce stress, alcohol triggers, or neutral emotional responses based on each participants’ experiences. Researchers used linear mixed models to evaluate interactions among study groups, laboratory conditions, timepoints, and obesity status.

Unexpected Findings

Compared with healthy control participants, participants with AUD had significantly higher glucose levels (P = .0054).

Participants with both AUD and obesity had lower homeostasis model assessment of insulin resistance (HOMA-IR) scores and lower insulin levels than healthy control participants with obesity (P = .0052 and P = .0013, respectively). By contrast, no significant differences were observed between participants with AUD and healthy controls who did not have obesity.

Higher glucose and HOMA-IR values were both associated with greater stress- and alcohol cue-related craving but only in the AUD plus obesity group (all P < .004).

Harvanek said one of the most surprising findings was that participants with both AUD and obesity had lower insulin levels and lower insulin resistance than participants with obesity alone. This pattern suggested to the investigators that AUD may be associated with a distinct metabolic profile.

In the group with both AUD and obesity, higher blood glucose predicted stronger alcohol cravings during exposure to stress or alcohol-related cues.

“This is particularly interesting in light of emerging evidence that medications targeting metabolic pathways, such as GLP-1s, might reduce alcohol use,” Harvanek said.

The authors cautioned that the findings should be considered preliminary because the study was a secondary analysis of a parent study not designed specifically to examine obesity-related questions. Additionally, the small number of participants with obesity limited statistical power and generalizability, and the cross-sectional design precluded definitive conclusions about causality.

High-Risk Phenotype

Commenting on the study for Medscape Medical News, Silvia Sookoian, MD, PhD, senior research scientist at CONICET (National Scientific and Technical Research Council) and head of clinical and molecular hepatology at CENITRES (Translational Health Research Centre), Maimonides University, Buenos Aires, Argentina, said the findings “fundamentally reframe our understanding of the physiological architecture underpinning AUD.”

The potential identification of a “metabolic-addictive” axis shifts AUD treatment away from purely neurobehavioral framework and toward a more integrated physiologic model, said Sookoian.

She added that fasting glucose and HOMA-IR could potentially serve as indicators of relapse vulnerability in patients with both AUD and obesity, given that higher glucose and insulin resistance correlated directly with stronger provoked cravings in this subgroup.

Katherine Saunders, MD, spokesperson for The Obesity Society, agreed, telling Medscape Medical News that the study underscores “that obesity, metabolic disease, and substance use disorders should not be treated in silos.”

Saunders, clinical professor of medicine at Weill Cornell Medicine, New York City, said comprehensive care should address metabolic health, mental health, and long-term chronic disease management together.

A ‘Dual-Track’ Therapeutic Approach

Sookoian said the findings “provide a strong rationale for the future clinical integration of GLP-RAs specifically for the AUD-obesity phenotype. By addressing peripheral metabolic dysfunction and central reward signaling, these agents offer a dual-track therapeutic approach.”

Also commenting for Medscape Medical News, Lorenzo Leggio, MD, PhD, clinical director and deputy scientific director at the National Institute on Drug Abuse Intramural Research Program and senior investigator and section chief at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Division of Clinical and Biological Research, National Institutes of Health (NIH), called the study “very timely,” particularly amid growing interest in GLP-1 therapies for alcohol and other substance use disorders.

“Both AUD and obesity should be understood as chronic medical conditions, rather than ‘bad behavior,’” Leggio said.

“Clinicians should be mindful of the significant overlap between these conditions when evaluating patients with either obesity or AUD. And it’s important to remember that alcohol use is a risk factor for a wide range of medical conditions, including diabetes and other metabolic disorders.”

This study was supported by the NIH/NIAAA, the Yale Center for Clinical Investigation, the NIH/National Institute of Diabetes and Digestive and Kidney Diseases, the Yale Physician-Scientist Development Award and CTSA, and the Yale Claude D. Pepper Older Americans Independence Center at Yale School of Medicine. Rajita Sinha, PhD, reported research collaborations with AELIS Farma, CT Research Pharma, and Tenacia Biotechnologies; serving as a scientific consultant and advisor to Imbrium Therapeutics, LLC; and being on the advisory board of Menda Health. All other researchers reported having no potential conflicts of interest. Sookoian, Saunders, and Leggio reported having no relevant financial relationships.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).