The classic Stephen King short horror story “Quitters, Inc.” begins with the protagonist, Dick Morrison, encountering a former classmate at an airport lounge. Unlike the protagonist, who is down on his luck, his old acquaintance, Jimmy McCann, is fit and successful — a seemingly changed person from their earlier years. As Morrison drinks and chain smokes at the bar, his classmate gestures at the overflowing ashtray and tells of his life-altering interaction with a secretive smoking-cessation organization: “I don’t suppose it’s the same for everyone, but with me it was just like dominoes falling over. I felt better…I had more energy, and my job performance picked up.”

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Although this fictional tale takes many dark turns laying out the progressively draconian ‘treatment steps’ as Morrison progresses through the program, the premise speaks to the hardships of substance use and addiction. Overcoming certain conditions, such as nicotine dependence, that encompass both physical features and psychological features can be exceedingly difficult, and there are no universally effective interventions. When combined with behavioral counseling, medications such as varenicline or bupropion can substantially improve abstinence rates, but a large proportion of people (50–75%) relapse after treatment. Alcohol use disorder has similarly high rates of relapse, despite having a limited number of evidence-based treatments, including cognitive behavioral therapy and medications, such as naltrexone and acamprosate, that can help reduce cravings in some people. Identifying the appropriate treatment modalities for a person and minimizing the potential for risk of relapse underscores the range of heterogenous factors that can impinge on treatment success, from genetics to barriers to continued access to care and social support. For many, despite efforts to ‘line up the dominoes’, treatment and maintaining abstinence may not proceed smoothly.

Substance use disorders are but one category in the constellation of mental health conditions that can be chronic, involve a risk of relapse and are associated with marked physical consequences, including premature mortality and morbidity, such as cardiometabolic disease. The sizeable collective public health burden of these conditions drives the quest to find more-efficacious treatments, whether behavioral or pharmacological. Multiple innovative lines of inquiry are increasingly being applied across the spectrum of research and development for new drugs, including techniques such as high-throughput screening for identifying target compounds, drug repositioning and/or repurposing using disease ‘-omics’ data, machine learning to compensate for sparse data and, sometimes, sheer serendipity.

One of the most exciting and transformative class of drugs to be discovered in the past decade, glucagon-like peptide-1 receptor agonists (GLP-1RAs), has followed such a momentous trajectory. The foundational work for identifying precursors of glucagon, the peptide hormone produced by the pancreas that regulates blood glucose, stretches back decades. But the introduction of GLP-1RAs in the early 2000s provided the main pivot point toward the proliferation and trialing of these medications for diabetes and obesity. These drugs are most commonly injected subcutaneously and increase insulin secretion, which inhibits the production of glucagon by α-cells in the pancreas in the service of regulating blood glucose concentrations.

Although neuropsychiatric disorders are not necessarily characterized by glycemic regulation, there are a number of reasons why GLP-1RAs have garnered so much attention for potentially being repurposed. While the mechanisms are not well understood, GLP-1 receptors seem to be uniquely involved in neuromodulatory functions, given that they are distributed in the brain and gut–brain axis. Other speculative roles for GLP-1RAs indicate the influence of satiety signals and reward processing, as well as potential neuroprotective pathways. There is also an emerging body of anecdotal accounts by people taking GLP-1RAs beyond feelings of satiety, such as increased energy levels and quality of life, suggestive of possible systemic knock-on effects that bear on mental health.

In this issue of Nature Mental Health, we publish a new Analysis from De Giorgi and coauthors that provides one the most comprehensive assessments thus far of the extant research investigating the effects of GLP-1RAs across a range of neuropsychiatric disorders. This Analysis summarizes the findings of 278 preclinical and mechanistic studies and 96 clinical studies on neurodegenerative disorders (for example, Alzheimer’s disease and Parkinson’s disease) and psychiatric disorders, including substance use disorders, mood and anxiety disorders, psychotic disorders and eating disorders. The authors carefully describe the key insights of individual studies, in addition to including meta-analyses in which randomized controlled trials for specific GLP-1RA interventions have been performed, providing a useful reference work for readers. Importantly, this Analysis highlights where the limitations of this work are. The preponderance of evidence indicates that GLP-1RA interventions are safe in all of the cognitive and mental health conditions that were examined. The authors, however, recommend that careful safety and adverse event reporting and continued regulatory agency oversight are crucial, in line with increasing GLP-1RA prescriptions and clinical studies.

This issue also includes a Research Highlight that delves into a timely example of a recent phase 2 randomized controlled trial repurposing the GLP-1RA semaglutide for the treatment of alcohol use disorder. By using a hybrid of outpatient treatment and controlled lab testing, researchers were able to assess measures of alcohol consumption and cravings in both settings. The findings demonstrate that the administration of escalating doses of semaglutide led to reduced self-administration of alcohol, lower alcohol cravings and a reduced number of cigarettes per day among smokers.

Examples of the promising repurposing of GLP-1RAs for mental health conditions, such as alcohol use disorder, that have a limited pharmacological armamentarium suggest that the field is set for rapid expansion. With that comes the excitement of breakthroughs and positive outcomes, but also an expanding need for prudence and caution. Initial concerns about access and equity to GLP-1RAs may subside somewhat now that compounded versions of patented GLP-1RAs have offset shortages and prices have begun to fall. Simultaneously, however, direct-to-consumer marketing of off-label GLP-1RA prescriptions, mainly for weight loss, have dramatically increased. The possibility of low-barrier prescribing for other conditions, such as substance use disorders, is probably on the horizon. Together, this confluence of factors reinforces the need for increased and coordinated pharmacovigilance to minimize risks. In addition to establishing efficacy, ensuring that access is safe, equitable and appropriately regulated is essential for lining up the series of GLP-1RA-based mental health treatments yet to come.