Episode 17 — Dr. Lorenzo Leggio Note: At times, this conversation gets technical. I’ve tried to keep things accurate while also taking the time to explain what we’re talking about. The video version of this episode includes annotations that you may find helpful, along with links to relevant concepts, people, and ideas for anyone who wants to go deeper. Feel free to reach out in the comments or on social media — I’m happy to help. Dr. Lorenzo Leggio (MD, PhD) is among the most prominent addiction medicine researchers in the United States. His current roles at the National Institutes of Health: Clinical Director and Deputy Scientific Director of NIDA’s Intramural Research Program; Chief of the joint NIDA/NIAAA Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section (which he founded in 2012); Chief of the NIDA Translational Addiction Medicine Branch (founded 2020). He holds adjunct professorships at Brown University, Johns Hopkins, and Georgetown. His research sits at the intersection of addiction neuroscience, endocrinology, and the gut-liver-brain axis. His lab’s work on GLP-1 receptor agonists — the drug class that includes semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) — as potential treatments for alcohol and substance use disorders is one of the most scientifically and culturally relevant areas in addiction medicine right now. It bridges the Ozempic story with addiction treatment in a way that has genuinely caught the public’s attention, and mine — I’ve been following this space for several years. Dr. Leggio trained in internal medicine in Rome, completed his postdoc at Brown University’s Center for Alcohol and Addiction Studies, transitioned into a faculty role at Brown, and was then recruited to the NIH, where he has primarily worked since. A special thanks to Max Dennis for helping coordinate this episode and for lending a hand setting up when I arrived. Links Integrating Psychological and Pharmacological Treatments for Addictive Disorders — book co-edited by Dr. Leggio Concepts Referenced in This Episode GLP-1 (Glucagon-like peptide-1) — A hormone produced in the gut and certain brainstem neurons that regulates appetite, blood sugar, and insulin secretion. The basis for the current generation of obesity and diabetes drugs, and the central molecule in Dr. Leggio’s addiction research. GIP (Glucose-dependent insulinotropic polypeptide) — A related gut hormone and the other major incretin. Tirzepatide (Mounjaro, Zepbound) targets both GLP-1 and GIP receptors simultaneously. Incretin — The class of gut-derived hormones, including GLP-1 and GIP, that stimulate insulin release in response to food. The incretin concept is the pharmacological foundation that all of these drugs are built on. Nucleus tractus solitarius (NTS) — A brainstem region that serves as a primary relay station for signals from the gut, cardiovascular system, and lungs. GLP-1 is produced by neurons here, and it plays a key role in how these drugs affect the brain. Blood-brain barrier — The selective barrier separating the brain’s circulation from the rest of the body. Relevant here because one of the open questions in GLP-1 research is exactly how and where these drugs act on the brain, and whether they cross this barrier directly or work through other pathways. GCG gene — The gene encoding proglucagon, the precursor protein that gets cleaved into GLP-1, GLP-2, glucagon, and related peptides depending on which tissue is doing the processing. Gila monster / exenatide — The origin story of the first GLP-1 drug. In the early 1990s, researchers discovered that the Gila monster’s saliva contained a peptide (exendin-4) structurally similar to human GLP-1 but far more stable. That peptide became exenatide (Byetta), the first FDA-approved GLP-1 receptor agonist, approved in 2005. Liraglutide — A second-generation GLP-1 receptor agonist (brand names Victoza and Saxenda) developed by Novo Nordisk. Once-daily injection; a major step forward from exenatide in terms of clinical manageability and efficacy. Ghrelin — A gut hormone often called the “hunger hormone.” Dr. Leggio’s lab has also studied ghrelin as a potential target in alcohol use disorder, making it part of the broader gut-brain axis story. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit mitchellpenningroth.substack.com
