Addiction, depression, cognition: How GLP-1s may benefit the brain

Key takeaways:

• There is evidence that GLP-1s can ameliorate psychiatric and neurologic symptoms.
• More clinical trials on the direct and indirect effects of GLP-1s and their mechanisms of action are needed.

As the body of research expands on the potential of glucagon-like peptide-1 receptor agonists to address various health issues, recent data suggest they may improve brain health.

GLP-1 receptor agonists were initially approved as a treatment for patients with type 2 diabetes. After some of these agents received indications for weight loss due to their effects on appetite regulation, their popularity surged. As of May 2024, roughly 12% of U.S. adults said they had ever used a GLP-1 receptor agonist, and 6% currently used one, according to a survey by the Kaiser Family Foundation (KFF).

In addition to glycemic control and weight loss, certain GLP-1 receptor agonists have FDA-approved indications to lower the risk for major adverse cardiovascular events, address moderate to severe obstructive sleep apnea, and, most recently, reduce the risk for worsening kidney disease, kidney failure, and cardiovascular death.

Evidence is emerging on the additional benefits of these medications, including for psychiatric and neurologic conditions like addiction and dementia. The research is still in its early stages, and much is unknown about the mechanisms due to a dearth of direct scientific evidence. However, preliminary findings illustrate the possible off-label benefits of these drugs, and there is an advantage to further exploring their effects, according to experts.

“In treatment development, repurposing drugs already approved for other conditions has the advantage of providing data and experience from previous research and practical use,” Rebecca M. Edelmayer, PhD, vice president of scientific engagement for the Alzheimer’s Association, told Healio. “So, we may already know a lot about real-world effectiveness in other diseases and the potential side effects, which can help to speed up our understanding of how treatments may work for a new health condition.”

Addiction

GLP-1 receptor agonists may influence the very mechanisms within the brain that regulate response-reward pathways that are factors in certain addictive behaviors, Fatima Cody Stanford, MD, MPH, MPA, MBA, MACP, FAAP, FAHA, FAMWA, FTOS, an obesity medicine physician-scientist at Massachusetts General Hospital and Harvard Medical School, told Healio.

According to Stanford, research suggests that GLP-1 receptor agonists may reduce nicotine and opioid use. However, the data are less conclusive than those that suggest it may play a role in curbing cravings for alcohol.

“The proposed mechanisms by which GLP-1 receptor agonists affect substance use include altering dopamine release in the brain’s reward centers, impacting the hypothalamic-pituitary-adrenal (HPA) axis and modulating stress-related pathways,” Stanford said.

In a real-world analysis of individuals with history of opioid use disorder and alcohol use disorder (AUD), published in Addiction last October, researchers reported that GLP-1 receptor agonists and similar drugs for diabetes and weight-related conditions were associated with a 40% lower rate of opioid overdose and 50% lower rate of alcohol intoxication in people with opioid use disorder and AUDs, respectively.

Further, data from a randomized clinical trial published in JAMA Psychiatry in early February found that a low dose of semaglutide significantly reduced weekly alcohol cravings and led to reduced alcohol consumption compared with placebo over 9 weeks in 48 patients with alcohol use disorder.

Another study analyzing data from more than 227,000 individuals with alcohol use disorder from Sweden found that those who used GLP-1 receptor agonists to treat obesity or type 2 diabetes had a decreased hospitalization risk due to alcohol use.

Additionally, a recent Weight Watchers survey of more than 14,000 people showed that nearly half of those treated with anti-obesity medications — which included GLP-1 receptor agonists as well as drugs like phentermine, bupropion/naltrexone — reported a decrease in alcohol use, according to Ethan Lazarus, MD, former president of the Obesity Medicine Association. Interestingly, he said, weight-loss surgery did not appear to have the same effect as weight-loss medications. Instead, he cited a study that showed up to 33% of post-bariatric patients developed AUD following the procedure.

“Recent warnings from the Surgeon General highlighting health risks of alcohol consumption combined with the recognition that treating obesity with anti-obesity medication not only reduces problematic eating, but also problematic drinking may help encourage providers and patients to approach obesity comprehensively inclusive of anti-obesity medication,” Lazarus, owner of the Clinical Nutrition Center, a medial weight loss establishment in suburban Denver, told Healio.

While these recent studies have sparked enthusiasm, Adam Bisaga, MD, professor of clinical psychiatry at Columbia University Vagelos College of Physicians and Surgeons, told Healio that “the therapeutic use of these agents for SUDs is not yet robust enough to justify widespread promotion.” In fact, “there is an inherent danger in overstating potential benefits with low risks, setting unrealistic expectations, and allowing commercial interests to overshadow solid addiction science,” he said.

“Considering that the neurobiology of substance use disorders is highly heterogeneous, it is unlikely that a single pharmacological target could effectively address the range of SUDs, as claimed,” Bisaga said.

He also noted that the safety profile of GLP-1 receptor agonists in patients with SUDs is unclear — especially in populations with high rates of comorbid medical and psychiatric disorders.

Depression

GLP-1 receptor agonists may also address depression. This was recently demonstrated in a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies that found people who received a GLP-1 receptor agonist had a reduction in depression scale scores compared with those given placebo.

There are a variety of potential mechanisms in which GLP-1 receptor agonists may impact depression, Stanford said. For example, the agents possibly reduce neuroinflammation, promote neurogenesis, modulate neurotransmitter systems or normalize the HPA axis function, all of which could reduce depressive symptoms, she said. Also, the positive effects of GLP-1 receptor agonists on metabolic health could indirectly improve symptoms of depression.

Another possible explanation could be that these drugs directly affect the central nervous system.

“Emerging evidence suggests that GLP-1 receptors in the brain may directly affect neural circuits involved in mood and emotion,” Stanford said. “Activation of these receptors could lead to mood stabilization.”

Recent research out of Israel and published in JAMA Pediatrics in late 2024 supports this theory, as nearly 7,000 adolescents with obesity who initiated a GLP-1 receptor agonist had a 33% lower risk for suicidality compared with controls who underwent behavioral interventions.

Alternatively, other research has linked GLP-1 receptor agonists — particularly semaglutide — to an increased risk for suicidal ideation. An August 2024 study published in JAMA Network Open showed the odds for suicidal ideation were higher in individuals who took semaglutide compared with other weight-loss medications for type 2 diabetes.

The FDA launched an investigation into the effects of these drugs on suicide and found no association.

Cognition

Since GLP-1s may play a role in neurogenesis — particularly in the hippocampus, a region of the brain most often associated with mood regulation and cognitive function — they could possess cognitive benefits, Stanford said.

A study published in October in Alzheimer’s and Dementia found that, in patients with type 2 diabetes, semaglutide was associated with a 40% to 70% decreased risk for a first-time AD diagnosis within 3 years compared with other diabetes medications. The results support preclinical evidence on the protective effects of semaglutide against neurodegeneration and neuroinflammation, the researchers said.

Late-stage clinical trials have examined the cognitive effects of GLP-1 receptor agonists, according to Edelmayer. These include two 3-year trials, EVOKE and EVOKE Plus, which enrolled more than 1,800 patients with early AD who received semaglutide.

“We are in an era of unprecedented promise, with new treatments in various stages of development that slow or may possibly prevent cognitive decline due to Alzheimer’s disease,” she said. “The research on GLP-1s for Alzheimer’s and other dementias provides hope that more options for changing the course of the disease are on the horizon.”

However, more clinical trials are needed to examine the specific mechanisms, Edelmayer added.

“At this time, no one should be taking, or asking their doctor for, a GLP-1 receptor agonist to treat Alzheimer’s, dementia or memory problems. They are not approved to treat or reduce risk of these conditions,” she said.

Additional considerations

As researchers continue to investigate the psychiatric and neurologic effects of GLP-1 receptor agonists, Bisaga said there are ethical and practical issues to consider, like cost and equitable access.

A KFF analysis found that health insurance plans in the Affordable Care Act Marketplace rarely cover GLP-1 receptor agonists that are approved solely as obesity treatment. Although rebates can often offset the costs, the KFF reported that list prices of GLP-1 receptor agonists total about $1,000 per month, and their increasing demand may further drive premiums.

Also, in the context of SUDs, Bisaga warned against “over-relying on a ‘simple’ biological solution,” which could “underplay the critical role of social determinants of health and systemic inequities which greatly influence the course of SUDs and treatment response.”

“While GLP-1 receptor agonists show promise for the treatment of SUDs, this potential must be tempered by the current lack of clinical evidence and understanding of their mechanisms,” he said. “A cautious, evidence-based approach is essential to avoid potential pitfalls and ensure that interventions are both safe and effective.”

In the meantime, even without having approved indications for conditions like substance use disorders, depression and dementia, Stanford said the U.S. could see a decline in cases as the utilization of GLP-1 receptor agonists rises.

“Time will only tell,” she said.

References:

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